Artykuły w czasopismach: „Xenograft tumors”

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Siu, I.-Mei, Vafi Salmasi, Brent A. Orr, Qi Zhao, Zev A. Binder, Christine Tran, Masaru Ishii, Gregory J. Riggins, Christine L. Hann i Gary L. Gallia. "Establishment and characterization of a primary human chordoma xenograft model". Journal of Neurosurgery 116, nr 4 (kwiecień 2012): 801–9. http://dx.doi.org/10.3171/2011.12.jns111123.

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Object Chordomas are rare tumors arising from remnants of the notochord. Because of the challenges in achieving a complete resection, the radioresistant nature of these tumors, and the lack of effective chemotherapeutics, the median survival for patients with chordomas is approximately 6 years. Reproducible preclinical model systems that closely mimic the original patient's tumor are essential for the development and evaluation of effective therapeutics. Currently, there are only a few established chordoma cell lines and no primary xenograft model. In this study, the authors aimed to develop a primary chordoma xenograft model. Methods The authors implanted independent tumor samples from 2 patients into athymic nude mice. The resulting xenograft line was characterized by histopathological analysis and immunohistochemical staining. The patient's tumor and serial passages of the xenograft were genomically analyzed using a 660,000 single-nucleotide polymorphism array. Results A serially transplantable xenograft was established from one of the 2 patient samples. Histopathological analysis and immunohistochemical staining for S100 protein, epithelial membrane antigen, and cytokeratin AE1/AE3 of the primary patient sample and the xenografts confirmed that the xenografts were identical to the original chordoma obtained from the patient. Immunohistochemical staining and western blot analysis confirmed the presence of brachyury, a recently described marker of chordomas, in the tumor from the patient and each of the xenografts. Genome-wide variation was assessed between the patient's tumor and the xenografts and was found to be more than 99.9% concordant. Conclusions To the best of their knowledge, the authors have established the first primary chordoma xenograft that will provide a useful preclinical model for this disease and a platform for therapeutic development.

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Sicklick, Jason Keith, Stephanie Yvette Leonard, Evangeline Mose, Randall P. French, Michele Criscuoli, Dawn V. Jaquish, Karly Maruyama, Richard B. Schwab, David Cheresh i Andrew M. Lowy. "A novel xenograft model of gastrointestinal stromal tumors." Journal of Clinical Oncology 30, nr 4_suppl (1.02.2012): 202. http://dx.doi.org/10.1200/jco.2012.30.4_suppl.202.

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202 Background: GIST treatment with imatinib has served as the prototype for targeted molecular therapy. However, patients frequently acquire drug resistance to imatinib and this has prompted the development of additional multi-kinase inhibitors. To date, preclinical testing of novel agents has predominantly been performed using cell line based subcutaneous xenografts that may overestimate drug activity in the clinic. This suggests that novel in vivo models are needed to improve prediction of clinical efficacy. We hypothesized that human GISTs could be intra-peritoneally xenografted into immunodeficient mice in order to better recapitulate the microenvironment and biology of GIST. Methods: Tumor acquisition was performed under an IRB-approved protocol. Following tumor resection, we anesthetized NOD-scid (NS) or NS gamma (NSG) mice and performed a midline laparotomy. 2′2 mm tumor fragments were sutured into the abdominal viscera of NS (N=10) or NSG (N=15) mice. Tumors were imaged every 3-4 wks with ultrasound (US). 2 mice were also evaluated with PET scan. Results: We have xenografted GISTs from 3 patients into 25 mice with an 80% success rate and 4% perioperative mortality. We observed tumor progression in the liver (9/10), renal capsule (8/10), lesser sac (2/3), or gastric wall (1/2) of mice. This included 14 primary xenografts and 11 passaged xenografts. At 21-196 d (median 46 d), tumor size averaged 473±736 mm3 (median 104 mm3, range 2.2-2683 mm3) by US. In addition, 30% (6/20) of mice developed metastatic disease based upon US, necropsy, histology and/or KIT immunostaining. We also determined that 2/2 tumors were FDG-avid on PET. Conclusions: To our knowledge, we report the first intra-peritoneal xenograft model of human GIST using patient-derived tumor tissue. This novel in vivo approach is a reproducible model of human GIST that replicates the tumor microenvironment, heterogeneity, and metastatic potential of a human GI sarcoma. As compared to current research tools/models, this approach may allow researchers to better predict chemotherapeutic responses, further understand the tumor biology of GIST, and serve as a means to propagate additional tumor tissue for subsequent experimental analyses.

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Davies, Jason M., Aaron E. Robinson, Cynthia Cowdrey, Praveen V. Mummaneni, Gregory S. Ducker, Kevan M. Shokat, Andrew Bollen, Byron Hann i Joanna J. Phillips. "Generation of a patient-derived chordoma xenograft and characterization of the phosphoproteome in a recurrent chordoma". Journal of Neurosurgery 120, nr 2 (luty 2014): 331–36. http://dx.doi.org/10.3171/2013.10.jns13598.

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Object The management of patients with locally recurrent or metastatic chordoma is a challenge. Preclinical disease models would greatly accelerate the development of novel therapeutic options for chordoma. The authors sought to establish and characterize a primary xenograft model for chordoma that faithfully recapitulates the molecular features of human chordoma. Methods Chordoma tissue from a recurrent clival tumor was obtained at the time of surgery and implanted subcutaneously into NOD-SCID interleukin-2 receptor gamma (IL-2Rγ) null (NSG) mouse hosts. Successful xenografts were established and passaged in the NSG mice. The recurrent chordoma and the derived human chordoma xenograft were compared by histology, immunohistochemistry, and phospho-specific immunohistochemistry. Based on these results, mice harboring subcutaneous chordoma xenografts were treated with the mTOR inhibitor MLN0128, and tumors were subjected to phosphoproteome profiling using Luminex technology and immunohistochemistry. Results SF8894 is a novel chordoma xenograft established from a recurrent clival chordoma that faithfully recapitulates the histopathological, immunohistological, and phosphoproteomic features of the human tumor. The PI3K/Akt/mTOR pathway was activated, as evidenced by diffuse immunopositivity for phospho-epitopes, in the recurrent chordoma and in the established xenograft. Treatment of mice harboring chordoma xenografts with MLN0128 resulted in decreased activity of the PI3K/Akt/mTOR signaling pathway as indicated by decreased phospho-mTOR levels (p = 0.019, n = 3 tumors per group). Conclusions The authors report the establishment of SF8894, a recurrent clival chordoma xenograft that mimics many of the features of the original tumor and that should be a useful preclinical model for recurrent chordoma.

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Pham, Khoa, Allison R. Hanaford, Brad A. Poore, Micah J. Maxwell, Heather Sweeney, Akhila Parthasarathy, Jesse Alt i in. "Comprehensive Metabolic Profiling of MYC-Amplified Medulloblastoma Tumors Reveals Key Dependencies on Amino Acid, Tricarboxylic Acid and Hexosamine Pathways". Cancers 14, nr 5 (3.03.2022): 1311. http://dx.doi.org/10.3390/cancers14051311.

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Reprograming of cellular metabolism is a hallmark of cancer. Altering metabolism allows cancer cells to overcome unfavorable microenvironment conditions and to proliferate and invade. Medulloblastoma is the most common malignant brain tumor of children. Genomic amplification of MYC defines a subset of poor-prognosis medulloblastoma. We performed comprehensive metabolic studies of human MYC-amplified medulloblastoma by comparing the metabolic profiles of tumor cells in three different conditions—in vitro, in flank xenografts and in orthotopic xenografts in the cerebellum. Principal component analysis showed that the metabolic profiles of brain and flank high-MYC medulloblastoma tumors clustered closely together and separated away from normal brain and in vitro MYC-amplified cells. Compared to normal brain, MYC-amplified medulloblastoma orthotopic xenograft tumors showed upregulation of the TCA cycle as well as the synthesis of nucleotides, hexosamines, amino acids and glutathione. There was significantly higher glucose uptake and usage in orthotopic xenograft tumors compared to flank xenograft tumors and cells in culture. In orthotopic tumors, glucose was the main carbon source for the de novo synthesis of glutamate, glutamine and glutathione through the TCA cycle. In vivo, the glutaminase II pathway was the main pathway utilizing glutamine. Glutathione was the most abundant upregulated metabolite in orthotopic tumors compared to normal brain. Glutamine-derived glutathione was synthesized through the glutamine transaminase K (GTK) enzyme in vivo. In conclusion, high MYC medulloblastoma cells have different metabolic profiles in vitro compared to in vivo, and key vulnerabilities may be missed by not performing in vivo metabolic analyses.

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Kijima, Noriyuki, Yoshikazu Nakajima, Daisuke Kanematsu, Tomoko Shofuda, Yuichiro Higuchi, Hiroshi Suemizu, Kanji Mori i in. "TMOD-29. ESTABLISHMENT OF PATIENT-DERIVED XENOGRAFTS FROM RARE PRIMARY BRAIN TUMORS". Neuro-Oncology 22, Supplement_2 (listopad 2020): ii234. http://dx.doi.org/10.1093/neuonc/noaa215.979.

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Abstract Patient derived xenografts are essential tools for translational research and preclinical development of novel therapeutic strategies of primary brain tumors. Recent advances in genomics of primary brain tumors revealed molecular classification of primary brain tumors, thus establishment of patient derived xenografts from each subtype of primary brain tumors is urgently needed. However, currently available patient derived xenografts are limited and are from specific subtype of primary brain tumors such as glioblastoma IDH wild type. In this study, we aim to establish patient derived xenografts from primary brain tumors with various molecular characteristics, especially rare primary brain tumors. We got primary brain tumor tissues from patients, dissociated those tissue into single cells, and orthotopically injected those cells into NOD/Shi-scid IL2Rγ KO mouse. We successfully established rare patient-derived xenografts from atypical teratoid rhabdoid tumor and CNS Ewing sarcoma family tumor with CIC alteration, which is recently described as new entity of primitive neuroectodermal tumors of the CNS. We also analyzed histopathological characteristics of these xenografts and found that each xenograft well recapitulated histopathological features of original patients’ resected tumors. These xenografts have advantages for translational research and preclinical development of novel therapeutic strategies for rare primary brain tumors. In addition, further efforts are needed to establish other types of rare primary brain tumors.

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Dougherty, Mark, Eric Taylor i Marlan Hansen. "TMET-34. RADIATION METABOLOMICS IN PRIMARY HUMAN MENINGIOMA AND SCHWANNOMA: EARLY EXPERIENCE AND INITIAL RESULTS". Neuro-Oncology 24, Supplement_7 (1.11.2022): vii269. http://dx.doi.org/10.1093/neuonc/noac209.1039.

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Abstract Introduction Meningiomas and schwannomas account for 45% of primary CNS tumors. Yet when surgery and radiation fail, no further treatments exist. Metabolomics has been used to discover new cancer therapies; however, to date few have used metabolomics to study meningiomas and schwannomas. Here we present initial results and lessons learned from this novel endeavor. METHODS Primary tumors were obtained from patients during surgery and immediately taken for culturing or xenograft implantation. Upon reaching >90% confluence, cultures were treated with 0gy, 3gy, 10gy, or 20gy gamma radiation, then flash frozen 6 or 72 hours post-treatment. Xenograft tumors were implanted in nude mice. MRI 4 weeks post-implantation confirmed tumor viability. Mice were then given 10gy, 20gy, or sham radiation treatment. Xenografts were harvested 72 hours post-treatment. Metabolites were measured with a ThermoISQ gas chromatography-mass spectrometer. RESULTS Eleven meningiomas and nine schwannomas were successfully cultured. Unsupervised hierarchical clustering of cultures demonstrated greater influence from tumor of origin than from radiation. Univariate analysis of schwannoma xenografts demonstrated elevated ornithine following radiation (fold change 1.62; P = 0.008). However, principal component analysis did not show significant between-group differentiation. Orthotopic meningioma xenografts did not produce sufficient tissue for metabolomics; however, subsequent subcutaneous implants have been successful (data forthcoming). CONCLUSION Standard cell cultures did not reveal significant metabolic changes following radiation; it is unclear whether this was due to culture technique or inter-tumor heterogeneity. In radiated schwannoma xenografts, elevated ornithine may implicate related pathways such as ornithine decarboxylase-mediated polyamide synthesis for DNA double-strand break repair. Compared to other ‘-omics’ studies, metabolomics requires more tissue per sample ( >10mg) and is more sensitive to environmental conditions. Thus, large sample sizes are needed to detect significant changes, and xenografts are likely superior to cell culture. Future plans include increased xenograft sample size and stable isotope tracing for pathway analysis.

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Dong, Yiyu, Brandon Manley, A. Ari Hakimi, Jonathan A. Coleman, Paul Russo i James Hsieh. "Comparing surgical tissue versus biopsy tissue in the development of a clear cell renal cell carcinoma xenograft model." Journal of Clinical Oncology 34, nr 2_suppl (10.01.2016): 519. http://dx.doi.org/10.1200/jco.2016.34.2_suppl.519.

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519 Background: The use of xenograft tumor models is considered the ideal platform to investigate the effects and toxicities of novel drugs in primary human tumors. The establishment of a personalized xenograft model using preoperative or pretherapy biopsy for patients with metastatic or high risk disease could improve selection of targeted therapy. We report on our xenograft model using various tissue sources including biopsies and correlation with patient’s clinical features. Methods: 56 specimens from primary and metastatic ccRCC from 48 patients were collected. After surgery (n=35) or biopsy (n=21) the specimen was transplanted either subcutaneously or after cell culture to immunodeficient mice. Tumor engraftment was followed for up to 4 months. Successfully engrafted patient-derived tumors were passaged to further mice. Conformation of xenograft tumors with formalin-fixed, paraffin-embedded and Hematoxylin and eosin stained tumor sections was done to assure morphological concordance with the patients tumor. We used a two-tailed two proportion z-test to compare the number of successful xenografts harvested from surgical tissue or biopsy tissue. Results: Overall 25 of the 56 specimens were successful in growing tumor in our immunodeficient mice. The frequency of success based on the type and site of tissue harvest may be seen in Table 1. We found biopsy tissue to be significantly more successful compared to surgical tissue, 61.9% compared to 34.2% (p-value=0.044). Conclusions: We believe our xenograft model, using biopsy tissue, demonstrates the feasibility of a real time personalized in vivo model to aid in the selection of targeted treatments for systemic therapy in ccRCC patients. [Table: see text]

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Breij, Esther CW, David Satijn, Sandra Verploegen, Bart de Goeij, Danita Schuurhuis, Wim Bleeker, Mischa Houtkamp i Paul Parren. "Use of an antibody-drug conjugate targeting tissue factor to induce complete tumor regression in xenograft models with heterogeneous target expression." Journal of Clinical Oncology 31, nr 15_suppl (20.05.2013): 3066. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.3066.

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3066 Background: Tissue factor (TF) is the main initiator of coagulation, that starts when circulating factor VII(a) (FVII(a)) binds membrane bound TF. In addition, the TF:FVIIa complex can initiate a pro-angiogenic signaling pathway by activation of PAR-2. TF is aberrantly expressed in many solid tumors, and expression has been associated with poor prognosis. TF-011-vcMMAE, an antibody-drug conjugate (ADC) under development for the treatment of solid tumors, is composed of a human TF specific antibody (TF-011), a proteaseEcleavable valine-citrulline (vc) linker and the microtubule disrupting agent monomethyl auristatin E (MMAE). Methods: TF-011 and TF-011-vcMMAE were functionally characterized using in vitro assays. In vivo anti-tumor activity of TF-011-vcMMAE was assessed in human biopsy derived xenograft models, which genetically and histologically resemble human tumors. TF expression in xenografts was assessed using immunohistochemistry. Results: TF-011 inhibited TF:FVIIa induced intracellular signaling and efficiently killed tumor cells by antibody dependent cell-mediated cytoxicity in vitro, but showed only minor inhibition of TF procoagulant activity. TF-011 was rapidly internalized and targeted to the lysosomes, a prerequisite for intracellular MMAE release and subsequent tumor cell killing by the ADC. Indeed, TF-011-vcMMAE efficiently and specifically killed TF-positive tumors in vitro and in vivo. Importantly, TF-011-vcMMAE showed excellent anti-tumor activity in human biopsyEderived xenograft models derived from bladder, lung, pancreas, prostate, ovarian and cervical cancer (n=7). TF expression in these models was heterogeneous, ranging from 25-100% of tumor cells. Complete tumor regression was observed in all models, including cervical and ovarian cancer xenografts that showed only 25-50% TF positive tumor cells. Conclusions: TF-011-vcMMAE is a promising new ADC with potent anti-tumor activity in xenograft models that represent the heterogeneity of human tumors, including heterogeneous TF expression. The functional characteristics of TF-011-vcMMAE allow efficient tumor targeting, with minimal impact on coagulation.

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Lukbanova, E. A., M. V. Mindar, E. A. Dzhenkova, A. Yu Maksimov, A. S. Goncharova, Yu S. Shatova, A. A. Maslov, A. V. Shaposhnikov, E. V. Zaikina i Yu N. Lazutin. "Experimental approach to obtaining subcutaneous xenograft of non-small cell lung cancer". Research and Practical Medicine Journal 9, nr 2 (4.05.2022): 65–76. http://dx.doi.org/10.17709/2410-1893-2022-9-2-5.

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Purpose of the study. Was was the creation of a Patient Derived Xenograft (PDX) model of non‑small cell lung cancer in immunodeficient mice adapted to growth in immunodeficient mice.Materials and methods. The study was performed using the tumor material from 14 donors implanted subcutaneously to 132 immunodeficient Balb/c Nude mice. Xenografts were maintained until the third passage. PDXs in the third passage from 3 patients were used to assess the model sensitivity to cisplatin. A histological analysis and genetic tests for the presence of EGFR mutations were performed for donor tumors from 3 patients and the corresponding xenografts in the third passage.Results. We observed a noticeable PDX growth already on the 8th day after the tumor material implantation. Successful xenograft engraftment was noted in 21 of 42 mice (50 %), which were rather successful results. A comparative histological analysis of tumor material from 3 patients showed that the PDX models retained the original histotype. We also demonstrated the identity of the EGFR mutations in the established xenografts from 3 patients and the donor tumors, which proved the value of these PDX models for preclinical studies of substances with potential antitumor activity. The analysis of the xenograft sensitivity to cytostatic cisplatin showed a statistically significant decrease in the growth rate in the xenografts obtained from 2 out of 3 patients, in comparison with the control.Conclusions. The created PDX models can be recommended as test systems for preclinical studies of the effectiveness of new pharmacological substances with potential antitumor activity.

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Dobbin, Zachary C., Ashwini A. Katre, Angela Ziebarth, Monjri Shah, Adam D. Steg, Ronald David Alvarez, Michael G. Conner i Charles N. Landen. "Use of an optimized primary ovarian cancer xenograft model to mimic patient tumor biology and heterogeneity." Journal of Clinical Oncology 30, nr 15_suppl (20.05.2012): 5036. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.5036.

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5036 Background: Current xenograft and transgenic models of ovarian cancer are mainly homogeneous and poorly predict response to therapy. Use of patient tumors may represent a better model for tumor biology and offer potential to test personalized medicine approaches, but poor take rates and questions of recapitulation of patient tumors have limited this approach. We have developed a protocol for improved feasibility of such a model and examined its similarity to the patient tumor. Methods: Under IRB and IACUC approval, 23 metastatic ovarian cancer samples were collected at the time of tumor reductive surgery. Samples were implanted either subcutaneously (SQ), intraperitoneally (IP), in the mammary fat pad (MFP), or in the subrenal capsule (SRC) and monitored for tumor growth. Cohorts from 8 xenolines were treated with combined carboplatin and paclitaxel or vehicle, and response to therapy compared between xenografts and patients. Expression of tumor-initiating cell (TIC) markers ALDH1, CD133, and CD44 was assessed by immunohistochemistry in tumors from patients and treated and untreated xenografts. Results: At least one SQ implanted tumor developed in 91.3% of xenografts, significantly higher than in the MFP (63.6%), IP (23.5%), or SRC (8%). Xenografts were similar in expression of putative TIC’s compared to patient tumors. The patients and the xenografts also have similar responses to chemotherapy in that xenografts from patients with a partial response responded more slowly than those from patients achieving a complete response (45 vs 21 days, p=.004). Treated xenografts were more densely composed of TICs. ALDH1 increased to 36.1% from 16.2% (p=0.002) and CD133 increased to 33.8% from 16.2% (p=0.026). Conclusions: Xenoline development can be achieved at a high rate when tumors collected from metastatic sites are implanted SQ. These xenografts are similar to patient tumors with regard to chemotherapy response and TIC expression.. This model may be a more accurate model for in vivo pre-clinical studies as compared to current models. Also, as treated xenografts become chemoresistant, this model is well positioned to evaluate targeted therapies aimed at the most aggressive populations in a heterogeneous tumor.

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Zhang, Libo, Douglass C. Vines, Deborah A. Scollard, Trevor McKee, Teesha Komal, Milan Ganguly, Trevor Do i in. "Correlation of Somatostatin Receptor-2 Expression with Gallium-68-DOTA-TATE Uptake in Neuroblastoma Xenograft Models". Contrast Media & Molecular Imaging 2017 (2017): 1–10. http://dx.doi.org/10.1155/2017/9481276.

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Peptide-receptor imaging and therapy with radiolabeled somatostatin analogs such as 68Ga-DOTA-TATE and 177Lu-DOTA-TATE have become an effective treatment option for SSTR-positive neuroendocrine tumors. The purpose of this study was to evaluate the correlation of somatostatin receptor-2 (SSTR2) expression with 68Ga-DOTA-TATE uptake and 177Lu-DOTA-TATE therapy in neuroblastoma (NB) xenograft models. We demonstrated variable SSTR2 expression profiles in eight NB cell lines. From micro-PET imaging and autoradiography, a higher uptake of 68Ga-DOTA-TATE was observed in SSTR2 high-expressing NB xenografts (CHLA-15) compared to SSTR2 low-expressing NB xenografts (SK-N-BE(2)). Combined autoradiography-immunohistochemistry revealed histological colocalization of SSTR2 and 68Ga-DOTA-TATE uptake in CHLA-15 tumors. With a low dose of 177Lu-DOTA-TATE (20 MBq/animal), tumor growth inhibition was achieved in the CHLA-15 high SSTR2 expressing xenograft model. Although, in vitro, NB cells showed variable expression levels of norepinephrine transporter (NET), a molecular target for 131I-MIBG therapy, low 123I-MIBG uptake was observed in all selected NB xenografts. In conclusion, SSTR2 expression levels are associated with 68Ga-DOTA-TATE uptake and antitumor efficacy of 177Lu-DOTA-TATE. 68Ga-DOTA-TATE PET is superior to 123I-MIBG SPECT imaging in detecting NB tumors in our model. Radiolabeled DOTA-TATE can be used as an agent for NB tumor imaging to potentially discriminate tumors eligible for 177Lu-DOTA-TATE therapy.

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Liu, C., L.-H. Dai, D.-Q. Dou, L.-Q. Ma i Y.-X. Sun. "A natural food sweetener with anti-pancreatic cancer properties". Oncogenesis 5, nr 4 (kwiecień 2016): e217-e217. http://dx.doi.org/10.1038/oncsis.2016.28.

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Abstract Mogroside V is a triterpenoid isolated from the traditional Chinese medical plant Siraitia grosvenorii. Mogroside V has a high degree of sweetness and a low calorific content. Herein, we found that mogroside V possesses tumor growth inhibitory activity in in vitro and in vivo models of pancreatic cancer by promoting apoptosis and cell cycle arrest of pancreatic cancer cells (PANC-1 cells), which may in part be mediated through regulating the STAT3 signaling pathway. These results were confirmed in vivo in a mouse xenograft model of pancreatic cancer. In xenograft tumors, Ki-67 and PCNA, the most commonly used markers of tumor cell proliferation, were downregulated after intravenous administration of mogroside V. Terminal deoxynucleotidyl transferase dUTP nick end labeling assays showed that mogroside V treatment promoted apoptosis of pancreatic cancer cells in the xenograft tumors. Furthermore, we found that mogroside V treatment significantly reduced the expression of CD31-labeled blood vessels and of the pro-angiogenic factor vascular endothelial growth factor in the xenografts, indicating that mogroside V might limit the growth of pancreatic tumors by inhibiting angiogenesis and reducing vascular density. These results therefore demonstrate that the natural, sweet-tasting compound mogroside V can inhibit proliferation and survival of pancreatic cancer cells via targeting multiple biological targets.

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Jeuken, Judith W. M., Sandra H. E. Sprenger, Pieter Wesseling, Hans J. J. A. Bernsen, Ron F. Suijkerbuijk, Femke Roelofs, Merryn V. E. Macville, H. Jacobus Gilhuis, Jacobus J. van Overbeeke i Rudolf H. Boerman. "Genetic reflection of glioblastoma biopsy material in xenografts: characterization of 11 glioblastoma xenograft lines by comparative genomic hybridization". Journal of Neurosurgery 92, nr 4 (kwiecień 2000): 652–58. http://dx.doi.org/10.3171/jns.2000.92.4.0652.

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Object. Human tumors implanted as subcutaneous xenografts in nude mice are widely used for the study of tumor biology and therapy. Validation of these models requires knowledge of the genetic makeup of the xenografts. The aim of this study was to establish whether chromosomal imbalances in 11 xenograft lines derived from human glioblastomas multiforme (x-GBMs) are similar to those found in GBM biopsy samples. The authors also studied genetic stability during serial passaging of three xenograft lines.Methods. Chromosomal imbalances in x-GBMs were detected using comparative genomic hybridization (CGH). The authors compared the CGH results in x-GBMs with those in the original GBMs (o-GBMs) that were used to establish three of the xenograft lines and with the GBM biopsy results reported in the literature (l-GBMs). In three xenograft lines two different passages were analyzed.Conclusions. The results show that the chromosomal imbalances in x-GBMs are similar to those in o-GBMs and l-GBMs, indicating that the GBM xenograft lines used were valid models from a genetic point of view. The CGH analysis of two different passages of three xenograft lines indicates that x-GBMs (like l-GBMs) show intratumoral genetic heterogeneity and do not acquire chromosomal imbalances as a result of serial passaging.

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Hossain, Jubayer A., Md A. Latif, Lars A. R. Ystaas, Sandra Ninzima, Kristoffer Riecken, Arnaud Muller, Francisco Azuaje i in. "Long-term treatment with valganciclovir improves lentiviral suicide gene therapy of glioblastoma". Neuro-Oncology 21, nr 7 (8.04.2019): 890–900. http://dx.doi.org/10.1093/neuonc/noz060.

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Abstract Background Suicide gene therapy for malignant gliomas has shown encouraging results in the latest clinical trials. However, prodrug application was most often restricted to short-term treatment (14 days), especially when replication-defective vectors were used. We previously showed that a substantial fraction of herpes simplex virus thymidine kinase (HSV-TK) transduced tumor cells survive ganciclovir (GCV) treatment in an orthotopic glioblastoma (GBM) xenograft model. Here we analyzed whether these TK+ tumor cells are still sensitive to prodrug treatment and whether prolonged prodrug treatment can enhance treatment efficacy. Methods Glioma cells positive for TK and green fluorescent protein (GFP) were sorted from xenograft tumors recurring after suicide gene therapy, and their sensitivity to GCV was tested in vitro. GBM xenografts were treated with HSV-TK/GCV, HSV-TK/valganciclovir (valGCV), or HSV-TK/valGCV + erlotinib. Tumor growth was analyzed by MRI, and survival as well as morphological and molecular changes were assessed. Results TK-GFP+ tumor cells from recurrent xenograft tumors retained sensitivity to GCV in vitro. Importantly, a prolonged period (3 mo) of prodrug administration with valganciclovir (valGCV) resulted in a significant survival advantage compared with short-term (3 wk) application of GCV. Recurrent tumors from the treatment groups were more invasive and less angiogenic compared with primary tumors and showed significant upregulation of epidermal growth factor receptor (EGFR) expression. However, double treatment with the EGFR inhibitor erlotinib did not increase therapeutic efficacy. Conclusion Long-term treatment with valGCV should be considered as a replacement for short-term treatment with GCV in clinical trials of HSV-TK mediated suicide gene therapy.

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Chen, Bao-An, Ya-nan Wu, Jian Cheng, Feng Gao, Wen-lin Xu, Hui-lin Shen, Jia-hua Ding i in. "Mechanism Research of Reversal of Multidrug Resistance by the Application of 5-Bromotetrandrine and Magnetic Nanoparticle of Fe3O4 Combined with Daunorubicin in a Human-Nude Mice Xenograft Model". Blood 112, nr 11 (16.11.2008): 5058. http://dx.doi.org/10.1182/blood.v112.11.5058.5058.

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Abstract Objective: To establish the xenograft leukemia model with stable multiple drug resistance in nude mice; to investigate the reversal effect of 5-Bromotetrandrine and Magnetic nanoparticle of Fe3O4 combined with DNR in vivo and to search for the possible reversal mechanisms. Methods: K562 and K562/A02 cells were respectively inoculated subcutaneously into back of athymic nude mice (1×107 cells/each) to establish the xenograft models. The tumor formation was evaluated by animal ultrasonic inspection. Tumors-bearing nude mice were assigned randomly to five groups which were treated with NS (A group); DNR 1mg/kg (B group); nanoparticle of Fe3O4 combined with DNR 0.63mg/kg(C group): 5-BrTet 2.5mg/kg combined with DNR(D group); 5-Bromotetrandrine 2.5mg/kg and Magnetic nanoparticle of Fe3O4 combined with DNR 0.63mg/kg(E group) respectively. The incidence of tumor formation, growth characteristics, weight and volume of tumor were observed. The histopathologic examination of tumors and organs were detected. For resistant tumors, the protein levels of P-glycoprotein (P-gp) were detected by Western blot. Results: The tumor incidence was 100% in the nude mice inoculated with either K562 or K562/A02 cells. In 6 to 9 days,the tumors reached a volume of more than 1 00 mm3. In vivo, MTT assay showed K562/A02 tumor maintained the drug resistance. For K562 cells xenograft tumors, there were no apparent differences in tumor suppression effect between the B AC AD AE group. For K562/A02 cells xenograft tumors, 5-BrTet and Magnetic nanoparticle of Fe3O4 combined with DNR significantly suppressed growth of tumor: the inhibition rate was 62.76% while DNR alone be used, the inhibition rate was 3.68%. Pathologic examination of resistant tumors showed the tumors necrosis obviously in E group. Application of 5-BrTet and Magnetic nanoparticle of Fe3O4 inhibited the overexpression of P-gp. Conclusion: The xenograft leukemia nude mice model was maintain the multiple drug resistance. 5-Bromotetrandrine and Magnetic nanoparticle of Fe3O4 combined with DNR had a significant tumor-suppressing effect on MDR leukemia cells xenograft model.

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Bradford, Leslie Siriya, Jose Alejandro Rauh-Hain, Rachel Marie Clark, Jolijn W. Groeneweg, Ling Zhang, Celeste M. DiGloria, Darrell R. Borger i in. "Targeting the PI3K signaling cascade in PIK3CA mutated endometrial cancer in a primary human xenograft model." Journal of Clinical Oncology 31, nr 15_suppl (20.05.2013): e13564-e13564. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e13564.

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e13564 Background: Alterations in the PI3K pathway are highly prevalent in endometrial cancer due to PIK3CA mutation and loss of PTEN. Given these data, we investigated the anti-tumor activity of the PI3K inhibitor NVP-BKM120 (BKM) as a single agent and in combination with standard cytotoxic chemotherapy in a human primary endometrial xenograft model. Methods: NOD/SCID mice bearing xenografts of primary human tumors with and without PIK3CA gene mutations were randomly divided into two- and four-arm cohorts with equivalent tumor volumes. Three single agent experiments tested the effectiveness of NVP-BKM120 against two endometrioid (PIK3CA wild type and H1047L mutant) and one carcinosarcoma (PIK3CA R88Q mutant) endometrial cancer. Three four arm experiments tested NVP-BKM120 alone and in combination with paclitaxel and carboplatin (P/C) in two endometrioid tumors (both R88Q) and one carcinosarcoma (no PIK3CA mutation detected). Following in vivo study, tumors from the NVP-BKM120 , P/C, P/C+ NVP-BKM120 and vehicle treated mice were processed for determination of PI3K/AKT/mTOR pathway activation. Wilcoxan rank sum analysis was utilized to compare tumor growth across all treatment experiments. Results: In endometrioid single agent experiments, NVP-BKM120 resulted in tumor growth suppression starting at days 5-10 compared to the linear growth observed in vehicle treated tumors (p<0.04 in all experiments). In all experiments, tumor resurgence manifested between days 14-25 (p<0.03). When combined with P/C, the NVP-BKM120 resistance pattern failed to develop in all three xenograft lines (p<0.05) while synergistic tumor growth suppression (p< 0.05) of only one xenograft tumor harboring the R88Q mutation was observed. Acute treatment with NVP-BKM120 led to a decrease in pAKT, whereas, there was no difference in pAKT levels following chronic therapy compared to vehicle. Conclusions: These data suggest that NVP-BKM120 mediated inhibition of the PI3K pathway in endometrial tumors with and without a PIK3CA mutation precludes tumor growth in a primary xenograft model. While a pattern of resistance emerges, this effect appears to be mitigated by the addition of conventional cytotoxic chemotherapy.

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Al-Gizawiy, Mona M., Robert T. Wujek, Casey J. Zoss, Ryuma Tanaka, Shama P. Mirza, Christopher R. Chitambar i Kathleen M. Schmainda. "HGG-06. CHARACTERIZATION OF THE EFFECT OF THE ORAL IRON-MIMETIC GALLIUM MALTOLATE ON PEDIATRIC GLIOBLASTOMA GROWTH IN VIVO". Neuro-Oncology 25, Supplement_1 (1.06.2023): i39. http://dx.doi.org/10.1093/neuonc/noad073.155.

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Abstract BACKGROUND Glioblastoma (GBM) is a highly aggressive CNS tumor that is associated with poor outcome. This dire prognosis is due in part to its poor response to the limited treatment options available. Iron and iron proteins play a key role in the growth of brain tumors, with our published studies showing that the ferrobiology of adult GBM can be exploited for therapeutic purposes. Here, we further elucidate the inhibitory effects of oral gallium maltolate (GaM) in pediatric GBM in vivo. METHODS Pediatric SJ-GBM2 cells were stereotactically implanted into the right striatum of male athymic rats. Advanced MR imaging at 9.4T was carried out weekly starting two weeks after implantation. Daily oral GaM (50mg/kg) or vehicle were provided on tumor confirmation. Longitudinal advanced MRI parameters were processed for enhancing tumor ROIs in OsiriX 8.5.1 (lite) with Imaging Biometrics Software (Imaging Biometrics LLC). Statistical analyses included Kaplan-Meier survival plots, linear mixed model comparisons, and t-statistic for slopes comparison. RESULTS The sensitivity of the in vivo pediatric GBM xenografts to GaM was consistent with our previous in vitro work. Median overall survival was 21 days in the controls and 49 days in the treatment group (p=0.014). GaM-treated xenograft tumors grew significantly slower than control tumors (p=0.031). Histologically, xenograft tumors recapitulated the aggressive growth features of clinical specimens, such as invasive margins. Unlike adult GBM xenografts in our previous studies, pediatric GBM xenografts did not exhibit vessel normalization or a reduction in pro-angiogenic markers in response to GaM. Additionally, MIB-1% (p=0.6583) and mitotic index (p=0.7097) were not affected by treatment. Yet, transferrin receptor and H-ferritin expression patterns in GaM-treated tumors suggested cellular iron deprivation. CONCLUSION Monotherapy with GaM provides a significant survival benefit in pediatric GBM, and further studies are planned to optimize the benefit of GaM in pediatric GBM.

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Ferragu, Matthieu, Luisa Vergori, Vincent Le Corre, Sarah Bellal, Maria del Carmen Martinez i Pierre Bigot. "Effects of Large Extracellular Vesicles from Kidney Cancer Patients on the Growth and Environment of Renal Cell Carcinoma Xenografts in a Mouse Model". Current Issues in Molecular Biology 45, nr 3 (17.03.2023): 2491–504. http://dx.doi.org/10.3390/cimb45030163.

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Plasma membrane-derived vesicles, also referred to as large extracellular vesicles (lEVs), are implicated in several pathophysiological situations, including cancer. However, to date, no studies have evaluated the effects of lEVs isolated from patients with renal cancer on the development of their tumors. In this study, we investigated the effects of three types of lEVs on the growth and peritumoral environment of xenograft clear cell renal cell carcinoma in a mouse model. Xenograft cancer cells were derived from patients’ nephrectomy specimens. Three types of lEVs were obtained from pre-nephrectomy patient blood (cEV), the supernatant of primary cancer cell culture (sEV) and from blood from individuals with no medical history of cancer (iEV). Xenograft volume was measured after nine weeks of growth. Xenografts were then removed, and the expression of CD31 and Ki67 were evaluated. We also measured the expression of MMP2 and Ca9 in the native mouse kidney. lEVs from kidney cancer patients (cEV and sEV) tend to increase the size of xenografts, a factor that is related to an increase in vascularization and tumor cell proliferation. cEV also altered organs that were distant from the xenograft. These results suggest that lEVs in cancer patients are involved in both tumor growth and cancer progression.

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Al-Gizawiy, Mona, Robert T. Wujek, Casey J. Zoss, Ryuma Tanaka, Shama P. Mirza, Christopher R. Chitambar i Kathleen M. Schmainda. "ATRT-03. THE ORAL IRON-MIMETIC GALLIUM MALTOLATE INHIBITS ATRT IN VIVO – IMAGING AND HISTOLOGICAL CHARACTERIZATION". Neuro-Oncology 25, Supplement_1 (1.06.2023): i1. http://dx.doi.org/10.1093/neuonc/noad073.003.

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Abstract BACKGROUND Atypical teratoid rhabdoid tumor (ATRT) is a highly aggressive CNS tumor that is associated with poor outcome. This dire prognosis is due in part to its poor response to the limited treatment options available. Iron and iron proteins play a key role in the growth of many solid cancers, including brain tumors. Our published studies show that the ferrobiology of brain tumors can be exploited for therapeutic purposes. Here, we further demonstrate the inhibitory effects of oral gallium maltolate (GaM) in pediatric ATRT in vivo. METHODS Pediatric CHLA-266 ATRT cells were stereotactically implanted into the right striatum of male athymic rats. Advanced MR imaging at 9.4T was carried out weekly starting two weeks after implantation. Daily oral GaM (50mg/kg) or vehicle were provided on tumor confirmation. Longitudinal advanced MRI parameters were processed for enhancing tumor ROIs in OsiriX 8.5.1 (lite) with Imaging Biometrics Software (Imaging Biometrics LLC). Statistical analyses included Kaplan-Meier survival plots, linear mixed model comparisons, and t-statistic for slopes comparison (as indicator of tumor growth rate). RESULTS In concordance with our previous in vitro work, in vivo ATRT xenografts were found to be highly sensitive to oral GaM. Median overall survival was 89 days in the control group and 170 days in the treatment group (p=0.011). GaM-treated xenograft tumors grew at a significantly slower rate than control tumors (p<0.0001). On MRI, untreated ATRT xenograft tumors, as their clinical counterparts, tended to localize near the ventricle and occasionally invade it. Histologically, xenograft tumors in our rat model recapitulated the histological features of human ATRT. A significant reduction in MIB-1% and mitotic index (p<0.001 and p<0.05, respectively) was seen in the treatment group. Transferrin receptor and H-ferritin expression in GaM-treated tumors illustrated cellular iron deprivation. CONCLUSION Monotherapy with GaM profoundly inhibited ATRT growth and prolonged survival in vivo.

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Park, Jun Won, Hyejin Um, Hanna Yang, Joo Young Cha, Kyoung-June Lee i Hark K. Kim. "CWP232291, a Wnt/β-catenin inhibitor, to suppress the growth and development of gastrointestinal cancers." Journal of Clinical Oncology 35, nr 15_suppl (20.05.2017): e15534-e15534. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e15534.

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e15534 Background: CWP232291 (JW Pharmaceutical Corp, Seoul, Korea) is a potent β-catenin inhibitor currently tested in phase I trials for AML and MM. We evaluated the preclinical efficacy of CWP232291 for gastrointestinal cancers using xenograft and genetically-engineered mouse (GEM) models. Methods: For xenograft experiments, we intraperitoneally administered 150 mg/kg of CWP232291 twice a week to 14 heterotopic and 2 orthotopic xenografts of human gastric cancer cell lines formed in NOD/SCID mice. For GEM experiments, we intraperitoneally administered 100 mg/kg of CWP232291 (n = 19) or vehicle (n = 27) twice a week for 17 weeks to 3-week-old Villin-Cre;Smad4 F/F;Trp53F/F GEM mice that spontaneously form intestinal tumors with the β-catenin signaling activation. Results: CWP232291 exhibited in vivo activity in human gastric cancer xenografts. Activity of CWP232291 was more prominent in human gastric cancer cell lines harboring mutations in the β-catenin signaling pathway, such as APC, and in the 5-FU-resistant derivative of SNU-620, than in the other xenografts (P = 0.028, t-test). In the MKN-45 orthotopic xenograft, we noted a decrease in luciferase signal intensity after 4 weeks of CWP232291 treatment. CWP232291 demonstrated synergistic activity with paclitaxel and irinotecan in the SNU-484 heterotopic xenograft. In GEM experiments, CWP232291 treatment significantly suppressed the spontaneous development of intestinal tumors (56.3% vs. 91.3% with vehicle) in Villin-Cre;Smad4 F/F;Trp53F/F mice. Furthermore, CWP232291 treatment significantly reduced the number of mice that develop intestinal adenocarcinomas (37.5% vs. 78.3% with vehicle). Immunohistochemistry revealed CD8 T cell activation within the mouse intestinal tumors. Conclusions: CWP232291 demonstrated significant preclinical efficacy in gastrointestinal tumors, especially in cancers with the β-catenin signaling activation.

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Ducker, Gregory S., Chloe Evelyn Atreya, Jeffrey Simko, Eric K. Nakakura, Emily K. Bergsland, David B. Donner, Kevan M. Shokat i Robert S. Warren. "Effect of PIK3CA and KRAS mutations on sensitivity to ATP-competitive mTOR inhibitors in a primary xenograft model of colorectal carcinoma." Journal of Clinical Oncology 30, nr 4_suppl (1.02.2012): 483. http://dx.doi.org/10.1200/jco.2012.30.4_suppl.483.

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483 Background: The mammalian target of rapamycin (mTOR) regulates cell growth by integrating nutrient and growth factor signaling and has been strongly implicated in cancer. Mutations in KRAS and the PI3K pathway are upstream of mTOR and are common in colorectal carcinoma (CRC). Currently approved mTOR inhibitors are derivatives of the natural product rapamycin and have shown little clinical efficacy in CRC. A new and potentially more efficacious class of ATP-competitive mTOR inhibitors has now entered clinical trials. Methods: Seeking a more representative preclinical model of CRC, we generated primary xenografts in nude mice of surgically resected specimens of human hepatic colorectal cancer metastases. We then treated xenograft tumors with the selective ATP-competitive mTOR inhibitor PP242 and monitored response by inhibition of tumor growth, changes in histopatholgy, and alterations in signaling pathways. Cell line experiments were performed to support observations made in the patient derived xenografts. Results: We demonstrate that in contrast to rapamycin, the mTOR inhibitor PP242 is highly effective at inhibiting tumor growth in both the primary xenograft model and in colorectal cancer cell lines. The inhibition of tumor growth in the xenografts and cell lines depended upon the strong inhibition of phosphorylation of mTOR substrate eIF4E binding protein 1 (4EBP1) but was not correlated with inhibition of phosphorylation of S6 kinase (S6K). Cells with mutant KRAS were relatively resistant to PP242 induced growth inhibition and this correlated with reduced inhibition of 4EBP1 phosphorylation. However, these effects were partially rescued in cells in which a co-mutation in PIK3CA resulted in AKT activation. Conclusions: Our studies reveal the first mTOR inhibitor resistant cell line, the genetic basis for its resistance and most importantly, these findings were revealed through the use of a primary xenograft mouse model which recapitulates morphologically the features of the tumors isolated from patients. We believe ATP-competitive inhibitors may be of limited clinical utility in mutant KRAS tumors, except for those that have concomitant activation of AKT.

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Comeaux, Evan, Wenwei Lin, Taosheng Chen, Burgess Freeman i Charles G. Mullighan. "PI3K and MEK Inhibition in Hypodiploid Acute Lymphoblastic Leukemia". Blood 128, nr 22 (2.12.2016): 1635. http://dx.doi.org/10.1182/blood.v128.22.1635.1635.

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Abstract Introduction: Hypodiploid acute lymphoblastic leukemia (ALL) is a rare, high-risk subtype of B-ALL associated with poor outcome. Genomic analysis of over 130 Hypodiploid ALL patients defined the distinct genomic landscape of this disease, defining two principal subtypes including Ras-activating alterations and IKZF3 loss in near haploid tumors (24-31 chromosomes) and mutation of TP53 coupled with homozygous IKZF2 loss in low hypodiploid tumors (32-39 chromosomes). New therapies are needed to improve outcome of this disease, necessitating preclinical studies in hypodiploid tumors in vitro, ex vivo and in vivo. Hypothesis: The observation of frequent Ras pathway activating mutations in hypodiploid ALL tumors, as well as increased phosphorylation of downstream Ras signaling targets, suggests that these tumors may be susceptible to PI3K/MEK inhibition. Ras signaling target activation was observed in hypodiploid tumors irrespective of mutational status. Here we used cell lines and representative xenograft models to explore the therapeutic efficacy of inhibiting PI3K/MAPK signaling in hypodiploid ALL. Methods: The near haploid cell lines NALM-16 and MHH-CALL-2 and eight patient-derived xenograft (PDX) models (four near haploid and four low hypodiploid) were selected for preclinical studies. Xenografts were representative of the most common genomic lesions observed in hypodiploid ALL patients, including deletion of NF1, PAG1 and IKZF3 in near haploid and mutation of TP53 and IKZF2 deletion in low hypodiploid (Holmfeldt et al. Nat Genet 2013; Mullighan et al. Blood 2015). Next-gen sequencing of xenograft and diagnosis tumor DNA confirmed the presence of key genetic alterations in the xenografts. A lentiviral vector was used for stable expression of luciferase in xenograft tumors for in vivo disease burden monitoring. Cell lines were treated in vitro with PI3K, mTOR, MEK, CDK4/6 and BET inhibitors either as single agents, inhibitor combinations or combined with chemotherapeutic agents. Xenografts were treated ex vivo with single agents and in vivo with PI3K and MEK inhibitors with or without chemotherapy. Results: NALM-16 and MHH-CALL-2 cell lines were most sensitive to PI3K, mTOR and BET inhibitors with IC50 values in the sub-micromolar range (Fig. 1).Treatment of xenografts ex vivo showed near haploid and low hypodiploid tumors to be four-fold more sensitive to pan-PI3K inhibitors and PI3K/mTOR dual inhibitors compared to PI3K α and d isoform-specific inhibitors. Near haploid and low hypodiploid xenografts were sensitive to MEK and BET inhibition ex vivo, but MEK inhibitors showed weak activity in the near haploid cell lines. Treatment with CDK4/6 inhibitors either as single agents or in combination with MEK inhibitors revealed minimal efficacy. Changes in cell signaling upon treatment was assayed by phosphoflow (Fig. 2). Akt and Erk1/2 phosphorylation was variable between tumors, whereas 4E-BP1 and S6 phosphorylation was consistently elevated, suggesting strong signaling through mTOR pathways. Pan-PI3K and PI3K/mTOR dual inhibitors showed potent activity against hypodiploid ALL tumors in vitro and ex vivo, however PI3K inhibition alone was insufficient to eliminate tumors in vivo. Substantial weight loss in mice treated with PI3K/mTOR dual inhibitors limited prolonged study in vivo. MAPK inhibition showed activity in both near haploid and low hypodiploid tumors ex vivo and displayed a modest reduction in tumor growth as a single agent in vivo. Combining the MEK inhibitor GDC-0973 with dexamethasone treatment increased efficacy, but induced significantly more weight loss than either monotherapy. Conclusion: Treatment of hypodiploid cell lines and xenografts in vitro and ex vivo, respectively, with PI3K and MEK inhibitors showed promising results, however the anti-tumor effect in vivo appeared mostly cytostatic and inhibitors were not sufficient as single agents to kill the tumor cells. MEK inhibitors showed stronger activity than PI3K inhibitors on xenografts in vivo and ex vivo, but this was not significantly increased when combined with dexamethasone treatment. The notable resistance of hypodiploid cells to dexamethasone may underlie this limited efficacy in addition to the increase in GDC-0973 clearance observed upon combination. Our findings also highlight the need to consider the PK properties of agents in the preclinical setting, particularly in combinations. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

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He, Fei, Xiongming Zhou, Gan Huang, Qingkun Jiang, Li Wan i Jiaxuan Qiu. "Establishment and Identification of Patient-Derived Xenograft Model for Oral Squamous Cell Carcinoma". Journal of Oncology 2022 (5.09.2022): 1–7. http://dx.doi.org/10.1155/2022/3135470.

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Oral squamous cell carcinoma is the most common head and neck malignancy with high morbidity and mortality. Currently, platinum-based chemotherapy is the conventional chemotherapy regimen for patients with oral squamous cell carcinoma. However, due to the heterogeneity of tumors and individual differences of patients, chemotherapy regimens lacking individualized evaluation of tumor patients are often less effective. Therefore, personalized tumor chemotherapy is one of the effective methods for the future treatment of malignant tumors. The patient-derived xenograft model is a relatively new tumor xenograft model that relies on immunodeficient mice. This model can better maintain various histological characteristics of primary tumor grafts, such as pathological structural features, molecular diversity, and gene expression profiles. Therefore, the patient-derived xenograft model combined with drug screening technology to explore new tumor chemotherapy is the critical research direction for future tumor treatment. This study successfully established the patient-derived xenograft model of oral squamous cell carcinoma. It was verified by hematoxylin-eosin staining and immunohistochemistry that the constructed patient-derived xenograft model retained the pathological and molecular biological characteristics of primary tumors. Our patient-derived xenograft model can be used further to study the oncological characteristics of oral squamous carcinoma and can also be applied to personalize the treatment of oral squamous carcinoma patients, providing a practical resource for screening chemotherapy drugs.

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Zhang, Huiyuan, Lin Qi, Yuchen Du, L. Frank Huang, Frank K. Braun, Mari Kogiso, Yanling Zhao i in. "Patient-Derived Orthotopic Xenograft (PDOX) Mouse Models of Primary and Recurrent Meningioma". Cancers 12, nr 6 (5.06.2020): 1478. http://dx.doi.org/10.3390/cancers12061478.

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Background. Meningiomas constitute one-third of all primary brain tumors. Although typically benign, about 20% of these tumors recur despite surgery and radiation, and may ultimately prove fatal. There are currently no effective chemotherapies for meningioma. We, therefore, set out to develop patient-derived orthotopic xenograft (PDOX) mouse models of human meningioma using tumor. Method. Of nine patients, four had World Health Organization (WHO) grade I tumors, five had WHO grade II tumors, and in this second group two patients also had recurrent (WHO grade III) meningioma. We also classified the tumors according to our recently developed molecular classification system (Types A, B, and C, with C being the most aggressive). We transplanted all 11 surgical samples into the skull base of immunodeficient (SCID) mice. Only the primary and recurrent tumor cells from one patient—both molecular Type C, despite being WHO grades II and III, respectively—led to the formation of meningioma in the resulting mouse models. We characterized the xenografts by histopathology and RNA-seq and compared them with the original tumors. We performed an in vitro drug screen using 60 anti-cancer drugs followed by in vivo validation. Results. The PDOX models established from the primary and recurrent tumors from patient K29 (K29P-PDOX and K29R-PDOX, respectively) replicated the histopathology and key gene expression profiles of the original samples. Although these xenografts could not be subtransplanted, the cryopreserved primary tumor cells were able to reliably generate PDOX tumors. Drug screening in K29P and K29R tumor cell lines revealed eight compounds that were active on both tumors, including three histone deacetylase (HDAC) inhibitors. We tested the HDAC inhibitor Panobinostat in K29R-PDOX mice, and it significantly prolonged mouse survival (p < 0.05) by inducing histone H3 acetylation and apoptosis. Conclusion. Meningiomas are not very amenable to PDOX modeling, for reasons that remain unclear. Yet at least some of the most malignant tumors can be modeled, and cryopreserved primary tumor cells can create large panels of tumors that can be used for preclinical drug testing.

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John, T., M. Li, D. Panchal, F. Hui, F. Meng, B. Bandarchi-Chamkhaleh, D. Kohler, C. Zhu, F. A. Shepherd i M. Tsao. "Correlation of primary tumor engraftment in immune deficient mice and relapse rate in patients with early-stage non-small cell lung carcinoma (NSCLC)". Journal of Clinical Oncology 27, nr 15_suppl (20.05.2009): 11082. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.11082.

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11082 Background: Compared to cell lines, primary tumor xenografts potentially are more clinically relevant cancer models as they more closely reflect the phenotype and genotype of the original cancer. However, only a minority of tumors engraft successfully in severe combined immune deficient (scid) mice and can be passaged serially. Although xenograft models are used extensively, few studies have investigated whether tumors that engraft represent a distinct clinical subset. We hypothesized that NSCLC tumors with more aggressive clinical and histological features have greater engraftment capacity than those with a less aggressive phenotype. Methods: Fresh primary tumors were harvested from NSCLC patients who underwent curative resection. Tumor fragments were implanted into the subcutaneous tissue of non-obese diabetic-scid mice within 24 hrs of excision. Patient characteristics for tumors that engrafted (XG) and did not engraft (No-XG) were compared. Only tumors from patients with >1-yr follow-up were evaluated for time to progression (TTP) and to correlate clinicopathological features with engraftment. Results: Between March 2005 and October 2008, 110 tumors were implanted. Of these, 45 (41%) engrafted and were passaged serially in vivo. The histological features of the primary were retained in 93% of XG tumors. Squamous cell carcinomas engrafted significantly more than adenocarcinomas (57% versus 26%, p=0.03). There were no significant differences in differentiation grade or clinical stage between the XG and No-XG groups. XG patients had significantly shorter TTP than the No-XG group (10.19 versus 18.64 months, p=0.003). In multivariate analysis the ability to form a xenograft was an independent predictor of relapse (HR 4.15 95% CI 1.152–14.94, p=0.03). Conclusions: Xenograft models can be established from the histological spectra of NSCLC encountered in the clinical setting and mimic closely the features of their primary tumors. The capacity of these tumors to engraft may be predictive of a more aggressive phenotype and poorer clinical outcome. No significant financial relationships to disclose.

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Chen, Selby, Timothy Peterson, S. Keith Anderson, Jeanette Eckel-Passow, Paul A. Decker, Jann Nagina Sarkaria i Ian F. Parney. "Genotypes of human glioma xenografts compared with glioma stem cell-derived tumors." Journal of Clinical Oncology 31, nr 15_suppl (20.05.2013): 2072. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.2072.

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2072 Background: Human glioma stem cells and xenograft lines are common translational models in neuro-oncology but it has not been established if they are genetically and phenotypically comparable. This study aimed to determine if human glioma xenografts and stem cell-derived tumors had similar genotypes. Methods: Matched glioma stem cell cultures and subcutaneous xenograft lines were generated from four human glioblastoma specimens (BT114, BT116, BT120, BT132). Comparison was made between subcutaneous stem cell-derived tumors (flank) and xenografts established in nude mice. Copy number variation (CNV) and gene expression microarray studies were performed. Results: Various differences in copy number and gene expression were seen. Observed CNVs included regions within EGFR, myc, and p16 (INK). For example, EGFR copy number was two fold higher in xenografts vs. stem cell-derived tumor in one line (BT114). This difference was corroborated by western blot. Other differences included a heat shock protein homolog (DNAJA4), tetraspanin 13, and a p53 family target gene (ISG20L1). Two lines (BT114, BT116) had a greater than two fold increase in DNAJA4 expression in xenografts vs. stem cell-derived tumors (p = 0.04, 0.01). Two cell lines (BT116, BT120) had a two to eight fold increase in tetraspanin 13 expression in xenografts (p = 0.02, 0.05). However, neither copy number nor gene expression variations were consistent across all cell lines. Conclusions: Xenografts and glioma stem cell-derived tumors established from the same patient specimens have distinct genotypes. Further work is needed to establish if these differences are random or represent characteristic changes selected by different in vitro or in vivo pressures. However, these variations raise questions regarding which model is ideal for studying glioma biology, and which ones best replicate glioma characteristics in human patients.

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Singh, Kanika, Negar Jamshidi, Roby Zomer, Terrence J. Piva i Nitin Mantri. "Cannabinoids and Prostate Cancer: A Systematic Review of Animal Studies". International Journal of Molecular Sciences 21, nr 17 (29.08.2020): 6265. http://dx.doi.org/10.3390/ijms21176265.

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Prostate cancer is a major cause of death among men worldwide. Recent preclinical evidence implicates cannabinoids as powerful regulators of cell growth and differentiation, as well as potential anti-cancer agents. The aim of this review was to evaluate the effect of cannabinoids on in vivo prostate cancer models. The databases searched included PubMed, Embase, Scopus, and Web of Science from inception to August 2020. Articles reporting on the effect of cannabinoids on prostate cancer were deemed eligible. We identified six studies that were all found to be based on in vivo/xenograft animal models. Results: In PC3 and DU145 xenografts, WIN55,212-2 reduced cell proliferation in a dose-dependent manner. Furthermore, in LNCaP xenografts, WIN55,212-2 reduced cell proliferation by 66–69%. PM49, which is a synthetic cannabinoid quinone, was also found to result in a significant inhibition of tumor growth of up to 90% in xenograft models of LNCaP and 40% in xenograft models of PC3 cells, respectively. All studies have reported that the treatment of prostate cancers in in vivo/xenograft models with various cannabinoids decreased the size of the tumor, the outcomes of which depended on the dose and length of treatment. Within the limitation of these identified studies, cannabinoids were shown to reduce the size of prostate cancer tumors in animal models. However, further well-designed and controlled animal studies are warranted to confirm these findings.

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Carter, W. B., i M. Sekharam. "Human chorionic gonadotropin (HCG) induction of apoptosis in breast cancer". Journal of Clinical Oncology 24, nr 18_suppl (20.06.2006): 10658. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.10658.

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10658 Background: Apoptotic induction in cancer cells may improve the efficacy of local or systemic therapy. Human Chorionic Gonadotropin (HCG) injection directly into Kaposi’s sarcoma or melanoma has been shown to increase the apoptotic index in these tumor types. The rapid induction of apoptosis in breast cancer immediately preceding local or systemic therapy may improve the response to therapy or local control. We hypothesized that HCG would rapidly increase the apoptotic index in breast cancer after intratumoral injection. The primary objective of this preclinical trial was to determine if intratumoral injection of HCG would significantly increase the apoptotic index in breast cancer xenografts. Methods: Using a human breast cancer xenograft model in Nude mice, 5 × 106 SK-BR3 human breast cancer cells were injected subcutaneously into each flank of nu/nu mice. When the tumors reached 6 mm, 50 uL (100 U/mL) of non-recombinant, naturally occuring HCG (A.P.L., Wyeth) or saline vehicle control was injected directly into the xenograft tumors. After 24 hrs, the tumors were harvested, and the xenografts tested for proliferation (Ki-67) and apoptosis (by TUNEL assay). The apoptotic index was calculated (apoptosis/proliferation) and statistical analysis performed using paired T-test. Results: Seven pairs of SK-Br3 xenografts were tested. There were no differences in proliferation by Ki-67 determination between control or treated xenografts. Apoptosis increased in HCG treated xenografts compared to vehicle controls. Apoptosis increased from a mean of 5% (range 1– 20%) in control xenografts to a mean of 28% (range 1–70%) in HCG treated tumors (p = 0.038). Conclusions: Naturally-derived HCG induces apoptosis in human breast cancer xenografts after intratumoral injection. Substantial induction of apoptosis may improve the efficacy of local and systemic therapy in breast cancer. Injection of HCG into breast tumors immediately prior to surgical, radiation, or systemic therapy has the potential to improve local control or response to treatment. Futher elucidation of potential synergy with therapeutic modalities is justified. No significant financial relationships to disclose.

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Logié, Armelle, Philippe Boudou, Liliane Boccon-Gibod, Eric Baudin, Gilles Vassal, Martin Schlumberger, Yves Le Bouc i Christine Gicquel. "Establishment and Characterization of a Human Adrenocortical Carcinoma Xenograft Model*". Endocrinology 141, nr 9 (1.09.2000): 3165–71. http://dx.doi.org/10.1210/endo.141.9.7668.

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Abstract Adrenocortical carcinomas are rare malignant tumors. They have a poor prognosis, as they are often diagnosed late and are usually resistant to chemotherapy. The lack of a suitable animal model for these tumors has been a major obstacle to the evaluation of new therapeutic agents. The aim of this study was to establish and characterize xenografts of the human adrenocortical carcinoma NCI H295R cell line as a model of adrenocortical carcinoma for future therapeutic trials. This cell line was sc injected (6 × 106 cells) into nude mice (n = 20). Solid tumors were locally measurable after 45 days at 90% of the inoculation sites. The xenografts were similar histologically to the original adrenocortical carcinoma from which the cell line was derived. The xenografts precisely reproduced the dysregulation of the insulin-like growth factor (IGF) system[ overexpression of the IGF-II and IGF-binding protein-2 (IGFBP-2) genes] typical of adrenocortical carcinoma. Similarly to adrenocortical carcinomas, human IGFBP-2 (but not IGF-II) was secreted in mouse plasma. We analyzed steroid production (cortisol, 17-hydroxypregnenolone, 17-hydroxyprogesterone, dehydroepiandrosterone,Δ 4-androstenedione, 11-deoxycortisol, corticosterone, and testosterone). Xenografts produced all three class of steroids, with the preferential production of androgens of the Δ4 pathway. The H295R xenograft model is a good model of human adrenocortical carcinoma, as it mimics dysregulation of the IGF system usually found in these tumors. It also produces IGFBP-2 and steroids that can be used as tumor markers. This model may therefore be useful for evaluating therapeutic agents.

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Janjigian, Yelena Yuriy, Robert Mazgaj, Gregory Carbonetti, Laura H. Tang, Blake Hefter, David Paul Kelsen, Elisa de Stanchina i Vivian E. Strong. "Establishment of primary gastric and gastroesophageal (GE) junction xenografts: A model for characterizing disease heterogeneity." Journal of Clinical Oncology 30, nr 4_suppl (1.02.2012): 51. http://dx.doi.org/10.1200/jco.2012.30.4_suppl.51.

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51 Background: Gastric cancer is a heterogeneous disease that may be subdivided into distinct subtypes—proximal/gastroesophageal (GE) junction, diffuse/signet ring type, and distal gastric cancers—based on histopathologic and anatomic criteria. Each subtype is associated with unique epidemiology and gene expression. Human epidermal growth factor receptor (HER2) is a validated treatment target in gastric cancer. For patients with metastatic disease, the available cytotoxic agents are applied indiscriminately to all disease subtypes, and with only modest success. The purpose of this study is to establish xenograft models from gastric cancer subtypes to improve our understanding of disease heterogeneity and develop therapies geared for each subtype of gastric cancer. Methods: Fresh specimens obtained from resected primary or metastatic tumors under aseptic conditions. 1 g tumor samples injected SQ into flanks of NOD/SCID mice. Xenografts established after 5 passages and maintained by serial transplantation into new mice. Cell cultures established after 5 in vitro passages; cell lines after 15 passages. Results: To date 26 tumor samples have been implanted from which 8 xenografts have been established. Table below summarizes the results. Cell line established from HER2-positive, trastuzumab refractory tumor resected from brain metastasis. Conclusions: HER2-positive tumors have a favorable xenograft yield. Prior chemo or radiation therapy does not impact engraftment. Standard and experimental therapies are being tested on these xenografts to further validate difference in their biology and guide rational design of clinical trials. [Table: see text]

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Rotermund, Arne, Martin S. Staege, Sarah Brandt, Jana Luetzkendorf, Henrike Lucas, Lutz P. Mueller i Thomas Mueller. "Luciferase Expressing Preclinical Model Systems Representing the Different Molecular Subtypes of Colorectal Cancer". Cancers 15, nr 16 (16.08.2023): 4122. http://dx.doi.org/10.3390/cancers15164122.

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Colorectal cancer (CRC) is a heterogeneous disease. More insight into the biological diversity of CRC is needed to improve therapeutic outcomes. Established CRC cell lines are frequently used and were shown to be representative models of the main subtypes of CRC at the genomic and transcriptomic level. In the present work, we established stable, luciferase expressing derivatives from 10 well-established CRC cell lines, generated spheroids and subcutaneous xenograft tumors in nude mice, and performed comparative characterization of these model systems. Transcriptomic analyses revealed the close relation of cell lines with their derived spheroids and xenograft tumors. The preclinical model systems clustered with patient tumor samples when compared to normal tissue thereby confirming that cell-line-based tumor models retain specific characteristics of primary tumors. Xenografts showed different differentiation patterns and bioluminescence imaging revealed metastatic spread to the lungs. In addition, the models were classified according to the CMS classification system, with further sub-classification according to the recently identified two intrinsic epithelial tumor cell states of CRC, iCMS2 and iCMS3. The combined data showed that regarding primary tumor characteristics, 3D-spheroid cultures resemble xenografts more closely than 2D-cultured cells do. Furthermore, we set up a bioluminescence-based spheroid cytotoxicity assay in order to be able to perform dose–response relationship studies in analogy to typical monolayer assays. Applying the established assay, we studied the efficacy of oxaliplatin. Seven of the ten used cell lines showed a significant reduction in the response to oxaliplatin in the 3D-spheroid model compared to the 2D-monolayer model. Therapy studies in selected xenograft models confirmed the response or lack of response to oxaliplatin treatment. Analyses of differentially expressed genes in these models identified CAV1 as a possible marker of oxaliplatin resistance. In conclusion, we established a combined 2D/3D, in vitro/in vivo model system representing the heterogeneity of CRC, which can be used in preclinical research applications.

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Liu, C., Y. Liu, D. Chen, Z. Tang, W. Pan, J. Wery i Y. Chen. "Establishment of human primary non-small cell lung cancer xenograft models for test of cytotoxic and targeted anticancer drugs". Journal of Clinical Oncology 27, nr 15_suppl (20.05.2009): 11008. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.11008.

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11008 Background: New oncology drug development has moved from general cytotoxic agents to molecular target-directed therapeutics. Consequently, there is a need to identify tumor types and individual patient tumors that express the target and could benefit from more selective therapies in clinical trials. Therefore, the in vivo models used in preclinical development should be“disease-oriented” and target-directed. Recently, we developed non-small cell lung cancer (NSCLC) xenograft models by transplanting human fresh tumor fragments into nude mice, which have been used for test of cytotoxic and targeted anticancer drugs. Methods: The fresh NSCLC tumors were collected from local hospitals. The tumor fragments were subcutaneously implanted into nude mice. The EGFR and K-ras mutation status of the tumors were investigated and compared with the efficacy results. The test drugs included paclitaxel, gemcitabine, and the epidermal growth factor receptor (EGFR) inhibitor erlotinib. Results: A total of 72 NSCLC samples were implanted, and 13 tumor models were established (tumor taking rate 18%) for the first passage. The tumor taking rates were higher in the second and third passages (80–100%). Paclitaxel and gemcitatbine produced tumor growth inhibition rates of 50–53% regardless of the EGFR and K-ras mutation status. While erlotinib demonstrated a significant antitumor activity only in the tumors bearing EGFR mutation with wild-type K-ras, which were consistent with their clinical findings. The tumor xenografts’ architecture, the cell and histopathological morphology from the three generations mirrored the original patient cancers. Conclusions: These results suggest that human primary tumor xenograft models provide a unique renewable source of tumor material for test of novel anticancer agents. They may predict more relevant clinical response rates and higher correlation with clinical findings than use of xenograft models established from long-term cultured cancer cell lines, especially for test of target-oriented therapeutics in new drugs development programs. No significant financial relationships to disclose.

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Zhao, Yunqi, Ran Chen, Yun Wang i Yixin Yang. "α-Pinene Inhibits Human Prostate Cancer Growth in a Mouse Xenograft Model". Chemotherapy 63, nr 1 (26.10.2017): 1–7. http://dx.doi.org/10.1159/000479863.

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Background: α-Pinene is one of the most widely found terpenoids in nature. Substantial evidence shows that α-pinene has cancer prevention properties. In this study, the PC-3 cell line was used to establish subcutaneous xenograft tumors in nude mice. Methods: Cytotoxicity was measured with the MTT assay, and apoptosis and cell cycle analyses were conducted using flow cytometry in vitro. The PC-3 cell line was used to establish subcutaneous xenograft tumors in nude mice. Results: We found that treatment with α-pinene significantly inhibited human prostate cancer cell growth and induced apoptosis and cell cycle arrest in the cell line-based model. Furthermore, tumor progression was inhibited more in mice treated with α-pinene than in control mice. We detected less Ki67 and proliferation cell nuclear antigen in paraffin sections from xenograft tumor specimens taken from α-pinene-treated mice than in those from the control group. Meanwhile, α-pinene treatment induced apoptosis in xenograft tumors as determined by the TUNEL assay. Conclusions: These data strongly suggest that α-pinene inhibits prostate cancer growth in a xenograft model and may be an effective therapeutic agent for prostate cancer treatment.

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Wang, Hexuan, Michael D. Nieskoski, Kayla Marra, Jason R. Gunn, Stuart B. Trembly, Brian W. Pogue i Marvin M. Doyley. "Elastographic Assessment of Xenograft Pancreatic Tumors". Ultrasound in Medicine & Biology 43, nr 12 (grudzień 2017): 2891–903. http://dx.doi.org/10.1016/j.ultrasmedbio.2017.08.008.

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Federico, Sara Michele, Elizabeth Stewart, Rachel Christine Brennan, Cori Bradley, Fan Wang, Burgess B. Freeman, Clinton F. Stewart, Jianrong Wu i Michael A. Dyer. "Comprehensive preclinical testing for neuroblastoma using orthotopic xenografts of a patient tumor." Journal of Clinical Oncology 30, nr 15_suppl (20.05.2012): e13584-e13584. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e13584.

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e13584 Background: Neuroblastoma is an aggressive malignancy that accounts for 15% of pediatric cancer deaths. There are limited well characterized neuroblastoma models for use in preclinical trials. We characterized a human neuroblastoma orthotopic xenograft, performed comprehensive preclinical studies, and evaluated the pharmacokinetics of drugs targeting the PI3K pathway. Methods: Tumor tissue (MAST3) was obtained from a 2 year old with stage IV metastatic MYCN amplified neuroblastoma. Using ultrasound guidance, MAST3 cells were injected into the para-adrenal space of nod-scid mice. Tumors were monitored for growth with routine ultrasound and passaged. The initial patient tumor (MAST3) and tumor from each passage were extensively analyzed including: histology, electron microscopy (EM), gene expression profiling, single nucleotide polymorphism (SNP ) microarrays, whole genome sequencing (WGS), and spectral karyotyping (SKY). Using this orthotopic xenograft model, a randomized preclinical trial was conducted to evaluate the response to standard chemotherapeutic agents. Pharmacokinetic studies of oral BEZ-235, BKM-120, OSI-906 and everolimus were conducted. Results: Analysis of the histology, EM, gene expression profiling, SNP microarrays, WGS, and SKY showed minimal variability between the MAST3 tumor and the passaged tumors in the orthotopic xenografts. Notably, MAST3 metastasized to the liver, lung and spleen in vivo. Administering standard chemotherapeutic agents every 3 weeks for a total of 6 courses, we observed a significant response in 40% of treated mice. Further ongoing preclinical trials will evaluate the comparative efficacy of IGFR/PI3K/mTOR molecular targeted therapies. Conclusions: We developed the first well characterized neuroblastoma orthotopic xenograft. Our comprehensive characterization of this xenograft indicates that it retains many of the molecular, cellular and genetic properties of the primary lesion. A preclinical trial using standard chemotherapeutic agents has provided a valuable baseline for comparison with novel therapeutics and will inform our selection of the most promising agents to move into clinical trials.

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Pham, Khoa, Brad Poore, Allison Hanaford, Micah J. Maxwell, Heather Sweeney, Akhila Parthasarathy, Jesse Alt i in. "OTME-9. Comprehensive Metabolic Profiling Of high MYC Medulloblastoma Reveals Key Differences Between In Vitro And In Vivo Glucose And Glutamine Usage". Neuro-Oncology Advances 3, Supplement_2 (1.07.2021): ii15. http://dx.doi.org/10.1093/noajnl/vdab070.060.

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Abstract Reprograming of cellular metabolism is a hallmark of cancer. The metabolic alterations in cancer cells is not only defined by series of genetic mutations, but also reflecting the crosstalk between cancer cells and other factors in the microenvironment. Altering metabolism allows cancer cells to overcome unfavorable conditions, to proliferate and invade. Medulloblastoma is the most common malignant brain tumor of children. Genomic amplification of MYC is a hallmark of a subset of poor-prognosis medulloblastoma. However, the metabolism of high MYC amplified medulloblastoma subgroup remains underexplored. We performed comprehensive metabolic studies of human MYC-amplified medulloblastoma by comparing the metabolic profiles of tumor cells in different environments – in vitro, in flank xenografts and in orthotopic xenografts. Principal component analysis showed that the metabolic profiles of brain and flank high-MYC medulloblastoma tumors clustered closely together and separated away from normal brain and the high-MYC medulloblastoma cells in culture. Compared to normal brain, MYC-amplified medulloblastoma orthotopic xenograft tumors showed upregulation of nucleotide, hexosamine biosynthetic pathway (HBP), TCA cycle, and amino acid and glutathione pathways. There was significantly higher glucose up taking and usage in orthotopic xenograft tumor compared to flank xenograft and cells in culture. The data demonstrated that glucose was the main carbon source for the glutamate, glutamine and glutathione synthesis through the TCA cycle. The glutaminase ii pathway was the main pathway utilizing glutamine in MYC-amplified medulloblastoma in vivo. Glutathione was found as the most abundant upregulated metabolite. Glutamine derived glutathione was mainly synthesized through glutamine transaminase K (GTK) enzyme in vivo. In conclusion, we demonstrated that high MYC medulloblastoma adapt to different environments by altering its metabolic pathways despite carrying the same genetic mutations. Glutamine antagonists may have therapeutic applications in human patients.

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Winter, Gordon, Andrea B. F. Koch, Jessica Löffler, Mika Lindén, Christoph Solbach, Alireza Abaei, Hao Li, Gerhard Glatting, Ambros J. Beer i Volker Rasche. "Multi-Modal PET and MR Imaging in the Hen’s Egg Test-Chorioallantoic Membrane (HET-CAM) Model for Initial In Vivo Testing of Target-Specific Radioligands". Cancers 12, nr 5 (15.05.2020): 1248. http://dx.doi.org/10.3390/cancers12051248.

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The validation of novel target-specific radioligands requires animal experiments mostly using mice with xenografts. A pre-selection based on a simpler in vivo model would allow to reduce the number of animal experiments, in accordance with the 3Rs principles (reduction, replacement, refinement). In this respect, the chick embryo or hen’s egg test–chorioallantoic membrane (HET-CAM) model is of special interest, as it is not considered an animal until day 17. Thus, we evaluated the feasibility of quantitative analysis of target-specific radiotracer accumulation in xenografts using the HET-CAM model and combined positron emission tomography (PET) and magnetic resonance imaging (MRI). For proof-of-principle we used established prostate-specific membrane antigen (PSMA)-positive and PSMA-negative prostate cancer xenografts and the clinically widely used PSMA-specific PET-tracer [68Ga]Ga-PSMA-11. Tracer accumulation was quantified by PET and tumor volumes measured with MRI (n = 42). Moreover, gamma-counter analysis of radiotracer accumulation was done ex-vivo. A three- to five-fold higher ligand accumulation in the PSMA-positive tumors compared to the PSMA-negative tumors was demonstrated. This proof-of-principle study shows the general feasibility of the HET-CAM xenograft model for target-specific imaging with PET and MRI. The ultimate value for characterization of novel target-specific radioligands now has to be validated in comparison to mouse xenograft experiments.

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Labitzky, Vera, Anke Baranowsky, Hanna Maar, Sandra Hanika, Sarah Starzonek, Ann-Kristin Ahlers, Katrin Stübke i in. "Modeling Spontaneous Bone Metastasis Formation of Solid Human Tumor Xenografts in Mice". Cancers 12, nr 2 (7.02.2020): 385. http://dx.doi.org/10.3390/cancers12020385.

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The majority of cancer-related deaths are due to hematogenous metastases, and the bone marrow (BM) represents one of the most frequent metastatic sites. To study BM metastasis formation in vivo, the most efficient approach is based on intracardiac injection of human tumor cells into immunodeficient mice. However, such a procedure circumvents the early steps of the metastatic cascade. Here we describe the development of xenograft mouse models (balb/c rag2-/- and severe combined immunodeficient (SCID)), in which BM metastases are spontaneously derived from subcutaneous (s.c.) primary tumors (PTs). As verified by histology, the described methodology including ex vivo bioluminescence imaging (BLI) even enabled the detection of micrometastases in the BM. Furthermore, we established sublines from xenograft primary tumors (PTs) and corresponding BM (BM) metastases using LAN-1 neuroblastoma xenografts as a first example. In vitro “metastasis” assays (viability, proliferation, transmigration, invasion, colony formation) partially indicated pro-metastatic features of the LAN-1-BM compared to the LAN-1-PT subline. Unexpectedly, after s.c. re-injection into mice, LAN-1-BM xenografts developed spontaneous BM metastases less frequently than LAN-1-PT xenografts. This study provides a novel methodologic approach for modelling the spontaneous metastatic cascade of human BM metastasis formation in mice. Moreover, our data indicate that putative bone-metastatic features get rapidly lost upon routine cell culture.

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Iwanicki, Isabella J., Lydia Wu, Fernando Flores-Guzman, Connor Centner, Kenneth B. Bader i Sonia Hernandez. "Histotripsy significantly decreases tumor viability in neuroblastoma xenograft model". Journal of the Acoustical Society of America 152, nr 4 (październik 2022): A248. http://dx.doi.org/10.1121/10.0016165.

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Children diagnosed with high-stage neuroblastoma (NB) have a <50% 5-year survival rate, resisting intensive treatment. Histotripsy, a focused ultrasound method, can ablate subcutaneous tumors. Here, we characterize histotripsy in an abdominal NB-xenograft model.Intrarenal injection of NGP-Luciferase cells in female NCr Nude mice generated 1–2 g NB tumors after 5–6 weeks. We assessed tumor viability with bioluminescence before, after, and 24h after Histotripsy. A 1-MHz focused source under ultrasound image guidance delivered 4–6 pulses per tumor with individual targets separated by ∼1 mm. Immunostains of the apoptosis marker TUNEL, endothelial marker Isolectin-B4, and hypoxia-marker pimonidazole were imaged or scanned. Statistics were performed using Graphpad.Histotripsy decreased bioluminescence by ∼50% (p = 0.02, n = 7), suggesting a decrease in viability. Untreated tumors did not change (n = 4). TUNEL staining increased in Histotripsy-treated tumors compared to controls (56 ± 6 versus 9 ± 3 %area, n = 3 to 8, p < 0.0001). Histotripsy increased pimonidazole positivity adjacent to targeted areas, suggesting hypoxia. Finally, Histotripsy increased red blood cells compared to controls. Histotripsy dramatically reduces tumor viability by inducing apoptosis of targeted areas. Hypoxia patterns suggest histotripsy alters perfusion and/or permeability within the tumor, indicating potential for synergy with chemotherapy.

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Kim, Jihee, Ji Hyeong Seo, Yun-Hee Kim, YoHan Woo, Yeon Jee Lee, Yena Kim, Wonyoung Choi i in. "Abstract 6042: Developing patient-derived organoids and tumor xenograft model for ovarian cancer for preclinical therapeutic evaluation". Cancer Research 82, nr 12_Supplement (15.06.2022): 6042. http://dx.doi.org/10.1158/1538-7445.am2022-6042.

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Abstract Purpose: Patient-derived organoid (PDO) and patient derived xenografts (PDX) models has been shown strong potential as experimental and preclinical research model which preserve original tumor characteristics. Here we represent our protocols setup process for ovarian cancer organoid establishment and PDX after data review and cell line xenograft experiments. Methods: First, we reviewed the histologic subtype of ovarian cancer of biobank in national cancer center, Korea then tried to match common subtype ovarian cancer cell line by literature review for xenograft experiments. Patient specimens were collected from histologically confirmed cancer patients under informed consent (NCC2020-0219). We obtained fresh tumor tissue from standard primary surgery of ovarian cancer patient and tissue was dissociated. Then we plated cells in matrigel with modified growth factors media. Organoids were passaged with diameter larger than 50µm and genetic analysis were performed to compare with original tumor. For PDX condition establishment, xenograft models using OVCAR3 in athymic nude and NOG mouse strains were compared, then SKOV3, SNU840, SNU251, and ES2 cell line subcutaneous xenograft growth were observed in NOG mouse. Results: Frequency of subtype of ovarian cancers (n=733) in biobank represented as following: serous adenocarcinoma (70%, n=509), endometrioid tumors (11%), clear cell tumors (10%), mucinous tumors (4%) and others (5%). After adjustment of organoid culture condition, PDOs (10 patients and 11 samples) were successfully long term cultured over 5 passages and the subtypes were including high grade serous type (n=5, 50%), clear cell carcinoma (n=2), mucinous carcinoma (n=2) and low grade serous type (n=1). The median age was 65 (28-82) years and stage III-IV (n=6) were frequent. Among them, number of recurred patients was three. Currently, the genetic information of each organoid is ongoing with CNV analysis, and the sensitivity and comparative analysis of the drug will be performed. Xenografts of OVCAR3 represented higher tumor growth rate in NOG mice than in athymic nude mice (p=0.03) then comparison of growth between cell lines in NOG mice showed fast as following in order: ES2, SKOV3, OVCAR3, SNU840, and SNU251 Conclusions: PDO from ovarian cancer were established and it might provide tools for personalized drug screening. To improve success rate we are continuing adjustment of PDO culture condition and PDX. (This work was supported by National Research Foundation of Korea grant, founded by the Korea government (MSIT) [No.2020R1A2C2010566]) Citation Format: Jihee Kim, Ji Hyeong Seo, Yun-Hee Kim, YoHan Woo, Yeon Jee Lee, Yena Kim, Wonyoung Choi, Young Ju Kim, Chong Woo Yoo, Sang Yoon Park, Myong Cheol Lim, Sun-Young Kong. Developing patient-derived organoids and tumor xenograft model for ovarian cancer for preclinical therapeutic evaluation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6042.

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Ramachandran, Cheppail, Gilda M. Portalatin, Adriana M. Prado, Karl-Werner Quirin, Enrique Escalon i Steven J. Melnick. "In Vivo Antitumor Effect of Supercritical CO2 Extract of Mango Ginger (Curcuma amada Roxb) in U-87MG Human Glioblastoma Nude Mice Xenografts". Journal of Evidence-Based Complementary & Alternative Medicine 22, nr 2 (19.07.2016): 260–67. http://dx.doi.org/10.1177/2156587216659390.

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Glioblastoma multiforme (GBM) is one the most aggressive and lethal human neoplasms with poor prognosis and very limited positive treatment options. The antitumor effect of supercritical CO2 extract of mango ginger ( Curcuma amada Roxb) (CA) with and without irinotecan (IR) was analyzed in U-87MG human glioblastoma multiforme (GBM) cells in vitro and in nude mice xenografts. CA is highly cytotoxic to GBM cells and is synergistic with IR as indicated by the combination index values of <1 in the CompuSyn analysis. CA inhibits tumor growth rate in GBM xenografts, the inhibition rate being higher than in IR treated group. GBM xenograft mice treated with IR + CA combination showed almost complete inhibition of tumor growth rate. Gene expression analysis of xenograft tumors indicated that IR + CA treatment significantly downregulated anti-apoptotic (Bcl-2 and mutant p53), inflammation-associated (COX-2) and cell division–associated (CCNB2) genes and upregulated pro-apoptotic genes (p21 and caspase-3). These results confirmed the therapeutic efficiency of IR + CA combination against GBM and the need for further clinical investigations.

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Cobb, Dustin A., Lixia Liu, Barbara Dziegielewska, Philip Mollica, Maria Lee i Daniel W. Lee. "Abstract 577: Control of solid tumors by alphav beta3 CAR T cells is accompanied by profound tumor penetration and prevention of metastasis in pre-clinical models". Cancer Research 82, nr 12_Supplement (15.06.2022): 577. http://dx.doi.org/10.1158/1538-7445.am2022-577.

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Abstract Purpose: Using in vitro and xenograft models we aimed to determine the efficacy of αvβ3 CAR T cells deployed against melanoma and breast cancer tumors, two malignancies previously recognized for harnessing the αvβ3 pathway for angiogenic and invasion purposes. Procedures: CAR T cells expressing an anti-αvβ3 scFv containing either a CD28 or 4-1BB co-stimulatory domain and CD3zeta were generated by retroviral transduction. In vitro cytotoxicity of αvβ3 CAR T cells was assessed by co-culture with melanoma or breast tumor cells assayed with bioluminescent- and impedance-based methods and effector cytokine production by ELISA. Xenograft studies, including melanoma (SK-MEL-28) and orthotopic breast tumors (MD-AMB-231), were carried out in NSG mice to evaluate in vivo efficacy of systemically administered αvβ3 CAR T cells. Immunohistochemistry was performed to evaluate T cell infiltration of melanoma tumors and changes within the tumor microenvironment. NSG mice harboring orthotopic breast tumors were monitored for disease progression, development of metastases using bioluminescent imaging and flow cytometry analysis of lung tissue, and overall survival. Results: αvβ3 CAR T cells exhibited robust cytotoxicity and cytokine production against several melanoma and triple-negative breast tumor cell lines. Systemic administration of αvβ3 CAR T cells potently inhibited growth of SK-MEL-28 melanoma xenografts as demonstrated by significant differences in tumor volume relative to CD19 CAR treatment. Immunohistochemical analysis of tumors at the experimental endpoint revealed striking infiltration of residual tumors by human T cells in mice administered αvβ3.28z CARs, but to a lesser extent in αvβ3.BBz CAR-treated xenografts. This T cell infiltration was accompanied by marked expression of PD-L1 that was mostly absent in tumors of CD19 CAR-treated controls, suggesting treatment-induced up-regulation of PD-L1. In orthotopic xenografts of MD-AMB-231 breast tumors, αvβ3 CAR T cells were able to control tumor growth, prevent the formation of lung metastases, and resulted in enhanced overall survival. Conclusions: These pre-clinical studies highlight a renewed potential for targeting integrins, specifically αvβ3, for the treatment of solid tumors. Data from this study suggests that αvβ3 CAR T cell therapy for melanoma may be further improved by combination therapy with checkpoint inhibition. Together with our prior work demonstrating robust efficacy of αvβ3 CAR T cells to treat glioblastoma and DIPG xenografts, these results highlight the broad applicability of utilizing CAR T cells targeting αvβ3 for treatment of multiple cancer types with reduced risk of on-target, off-tumor toxicity due to the restricted expression of αvβ3 in normal tissues. Results of these studies warrant further development of αvβ3 CAR T cells for clinical use. Citation Format: Dustin A. Cobb, Lixia Liu, Barbara Dziegielewska, Philip Mollica, Maria Lee, Daniel W. Lee. Control of solid tumors by alphav beta3 CAR T cells is accompanied by profound tumor penetration and prevention of metastasis in pre-clinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 577.

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Tatman, Philip, Tadeusz Wroblewski, Anthony Fringuello, Sam Scherer, William Foreman, Denise Damek, Samy Youssef, Kevin Lillehei, David Ormond i Michael Graner. "DDRE-43. SCREENING OF FDA-APPROVED COMPOUNDS FOR THE TREATMENT OF CHORDOMA, WITH IN VIVO VALIDATION USING THREE DIFFERENT XENOGRAFT MODELS, IDENTIFIES BRIGATINIB AS A POTENTIAL TREATMENT". Neuro-Oncology 23, Supplement_6 (2.11.2021): vi83—vi84. http://dx.doi.org/10.1093/neuonc/noab196.327.

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Abstract BACKGROUND Chordoma is a rare malignant tumor with poor surgical control and no existing pharmacotherapies. Therefore, these tumors require additional research into novel therapeutics for their treatment. METHODS In this study we created a high-throughput drug screen and culture system to evaluate the efficacy of existing FDA-approved compounds in 10 chordoma cell lines and primary tumors. The cell lines were graciously donated by the Chordoma Foundation. Primary tumors were collected from our operating room. In vivo validation using three separate chordoma xenograft models was also performed through the Chordoma Foundation. One model was a primary clival pediatric tumor, the second was a metastatic sacral tumor, and the third model was a recurrent skull base tumor. RESULTS Using a 127 FDA-approved compound library, we screened 6 donated chordoma cell lines and 4 tumors resected from our institution. 5 of the chordomas were primary, 3 were recurrent, and 2 were metastatic. 6 chordoma were located in the sacrum, three were located in the mobile spine, and one was located in the clivus. Five tumors came from female patients and five came from male patients. After a single 72-hour 1um dose of brigatinib, the average tumor viability in our drug screen was reduced to 81.5% +/-9.5SD (p=1.61x10-13). In the in vivo studies, brigatinib achieved a full response in the metastatic sacral chordoma xenograft model (TGI=100%, p< 0.0001), a partial response in the recurrent skull base xenograft model (TGI=54%, p=0.3048), and no response in the primary clival pediatric xenograft model (TGI = 0%, p >0.9). CONCLUSIONS Brigatinib may be a viable treatment option for recurrent and metastatic chordomas.

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Charmsaz, Sara, Kirrilee J. Miller, Bryan W. Day, Fares El-Ajeh, Varghese Palath, Geoff T. Yarranton, Christopher R. Bebbington, Andrew M. Scott, Martin Lackmann i Andrew W. Boyd. "Immunotherapeutic Targeting of EphA3". Blood 124, nr 21 (6.12.2014): 3720. http://dx.doi.org/10.1182/blood.v124.21.3720.3720.

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Abstract Eph receptors form the largest family of receptor tyrosine kinases. Eph receptors interact with cell-surface ephrin ligands to direct cell growth and migration. High expression of Eph receptors in a number of cancers has been linked to progression through facilitation of invasiveness and metastatic spread. EphA3 protein, which was originally described in leukemia, has also reported to be expressed in sarcomas, lung cancer, prostate cancer, melanoma and glioblastoma. The EphA3-specific monoclonal antibody, IIIA4, binds and activates human and mouse EphA3 with similar affinities. Binding is followed by internalization of receptor-antibody complexes. High expression of EphA3 has been reported on LK63 pre-B acute lymphoblastic leukemia (ALL) cell line and contrasts with lack of expression of EphA3 in the Reh, a similar pre-B ALL cell line. We investigated the effect of IIIA4 monoclonal antibody treatment in LK63 and Reh NOD/SCID xenograft models. In the LK63 xenograft model, administration of the IIIA4 antibody led to inhibition of tumor growth and decreased spread from bone marrow to the spleen and other organs with a corresponding increase in survival, however no reduction in engraftment was observed in Reh xenograft model, suggesting that the effect was directed against the leukemic cells rather than the stromal and vascular elements in these tumors. To confirm the tumor-specific effect of IIIA4 therapy, LK63 EphA3-knockdown and Reh EphA3-expressing cell lines were developed and tested in the xenograft model of leukemia. Similar to LK63 xenograft model, upon treatment with IIIA4 monoclonal antibody, the EphA3-expressing Reh xenografts showed reduction in the bone marrow engraftment and slowing of the disease progression. Consistent with the effect of EphA3 monoclonal antibody treatment on Reh xenograft model, the LK63 EphA3-knockdown xenografts showed minimal difference between treated and control group but had a notably significant reduction in the splenic engraftment compared to the normal LK63 model. To understand the mechanism leading to therapeutic effect of IIIA4 on EphA3-expressing leukemic xenografts, the effect of EphA3 activation on the LK63 and LK63 EphA3-knockdown cells was examined. This analysis showed elevated level of Src kinase activity upon stimulation with either IIIA4 or ephrinA5-Fc. Src kinases have been implicated in Eph-mediated signalling in other systems, and its activation appears to target adhesive mechanisms, particularly integrins, and cell motility functions consistent with the observed effects of antibody on cell movement. Given the capacity of the antibody to induce internalisation of EphA3, the possibility of linking a cytotoxic payload to IIIA4 was examined. The alpha-particle emitting radio-active isotope bismuth-213 was linked to IIIA4 and tested in the LK63 model with a considerably enhanced therapeutic effect specifically a significant increase in survival. More importantly, no toxicity to normal tissues was observed, as EphA3 is expressed at very low level or is entirely absent on normal tissues. A Humaneered® form (FA225-C10) of IIIA4 antibody has been generated for clinical development. This antibody binds to EphA3 with an improved affinity and has retained the direct apoptotic activity of mouse IIIA4 antibody. In the xenograft model of leukemia the antibody directly affects the tumor cells with no effect on stromal and vascular elements. In human tumor xenografts of prostate cell line DU-145 in nude mice, FA225-C10 antibody produced a significant inhibition of tumor growth. In this model the tumor cells do not express EphA3 but the tumor stroma and neovasculature express EphA3 and treatment with antibody reduced both tumor stroma and new vessel density. In Summary targeting EphA3 tumor cells and/or tumor stromal fibroblasts may therefore constitute a novel approach to treating solid tumors as well as hematologic malignancies. The Phase 2 component of a clinical study in acute myeloid leukemia (AML), myelodysplastic syndrom (MDS) and myelofibrosis (MF) patients is ongoing in which the activity of KB004 will be characterized. Future clinical studies might be extended to other cancers including acute lymphoblastic leukaemia (ALL) and other solid tumors. Disclosures Yarranton: Glaxo: Equity Ownership; Stemline Therapeutics: Equity Ownership; EnGen: Equity Ownership, Science Advisor, Science Advisor Other; KaloBios: Employment.

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Tateishi, Kensuke, Nobuyoshi Sasaki, Masahito Kawazu, Yohei Miyake, Taishi Nakamura, Yukie Yoshii, Yuko Matsushita i in. "TB-02 NF-KB CANONICAL PATHWAY ACTIVATION DRIVES GLYCOLYSIS AND TUMOR PROGRESSION IN PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA". Neuro-Oncology Advances 1, Supplement_2 (grudzień 2019): ii10. http://dx.doi.org/10.1093/noajnl/vdz039.045.

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Abstract Recent genomic analyses have identified highly recurrent genetic alterations in PCNSL. However, due to the lack of clinically representative PCNSL preclinical models, the pathogenic mechanisms of these alterations remains largely unknown. Here, we established the largest panel of 12 clinically relevant PCNSL patient-derived orthotopic xenografts retained the histopathologic phenotype, lymphoma expression subtype, copy number alterations and 90% of the non-synonymous mutations of primary tumors, with 100% concordance of MYD88 and CD79B mutations, which are highly recurrent in PCNSL. Patient tumor regression with high-dose methotrexate correlated with in vitro sensitivity to methotrexate in corresponding PCNSL models. By knocking down canonical NF-kB pathway genes, we found that successful orthotopic xenograft formation was dependent on NF-kB canonical pathway activation induced by MYD88 mutation or overexpression of EBV-related LMP1. Metabolically, PCNSL xenografts phenocopied the high 18F-fluorodeoxyglucose uptake observed in patients and demonstrated glycolytic dependence, revealing new potential therapeutic strategies in PCNSL. Collectively, we found NF-kB canonical pathway activation as a crucial driver of PCNSL xenograft progression and found that NF-kB canonical pathway induced an addiction to glycolysis, revealing a novel potential therapeutic strategy. Our PCNSL xenograft panel represents a valuable and reproducible preclinical tool that has the potential to help decipher how genetic and/or epigenetic alterations contributes to lymphomagenesis and tumor maintenance and enhance the development of novel therapeutic strategies in PCNSL.

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Derenzini, Massimo, Lorenzo Montanaro, Alessandra Chillà, Elena Tosti, Claudio Ceccarelli, Fabio Dall'Olio, Dietmar Öfner i Davide Treré. "Evaluation of Thymidylate Synthase Protein Expression by Western Blotting and Immunohistochemistry on Human Colon Carcinoma Xenografts in Nude Mice". Journal of Histochemistry & Cytochemistry 50, nr 12 (grudzień 2002): 1633–40. http://dx.doi.org/10.1177/002215540205001207.

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In this study we investigated the relationship between thymidylate synthase (TS) protein expression, evaluated by Western blotting analysis and by immunohistochemistry (IHC), and growth rate in human colon xenograft tumors in nude mice. Human colon cancer cell lines were used to induce xenograft tumors and the tumor mass growth rate was calculated by measuring tumor size variations over time. TS 106 monoclonal antibody was used for both Western blotting and IHC TS detection. Tumor cell growth fraction was measured by Ki67/MIB1 immunolabeling and tumor cell growth rate by evaluating the mean nucleolar size in silver-stained sections. TS Western blotting values were related to tumor mass growth rate ( p<0.001) and cell growth rate ( p=0.002) but not to cell growth fraction ( p=0.676). The degree of the IHC staining showed only a trend to be associated with TS protein expression measured on Western blotting, and was not related either to tumor mass growth or cell proliferation rate. Tumor xenografts were also characterized for TS promoter tandem repeat and p53 status. No relationship was observed between these variables and TS expression evaluated by both Western blotting and IHC analysis. Our results demonstrate that TS expression evaluated by Western blotting analysis is directly related to the tumor mass growth rate and question the use of the IHC approach to obtain precise quantitative information on TS expression in tumor samples.

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Tanaka, Tomohito, Ruri Nishie, Shoko Ueda, Shunsuke Miyamoto, Sousuke Hashida, Hiromi Konishi, Shinichi Terada i in. "Endometrial Cancer Patient-Derived Xenograft Models: A Systematic Review". Journal of Clinical Medicine 11, nr 9 (6.05.2022): 2606. http://dx.doi.org/10.3390/jcm11092606.

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Background: Because patient-derived xenograft (PDX) models resemble the original tumors, they can be used as platforms to find target agents for precision medicine and to study characteristics of tumor biology such as clonal evolution and microenvironment interactions. The aim of this review was to identify articles on endometrial cancer PDXs (EC-PDXs) and verify the methodology and outcomes. Methods: We used PubMed to research and identify articles on EC-PDX. The data were analyzed descriptively. Results: Post literature review, eight studies were selected for the systematic review. Eighty-five EC-PDXs were established from 173 patients with EC, with a total success rate of 49.1%. A 1–10 mm3 fragment was usually implanted. Fresh-fragment implantation had higher success rates than using overnight-stored or frozen fragments. Primary tumors were successfully established with subcutaneous implantation, but metastasis rarely occurred; orthotopic implantation via minced tumor cell injection was better for metastatic models. The success rate did not correspond to immunodeficiency grades, and PDXs using nude mice reduced costs. The tumor growth period ranged from 2 weeks to 13 months. Similar characteristics were observed between primary tumors and PDXs, including pathological findings, gene mutations, and gene expression. Conclusion: EC-PDXs are promising tools for translational research because they closely resemble the features of tumors in patients and retain molecular and histological features of the disease.

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Ji, Xiwei, Xiangrui Meng, Qingfeng He, Xiaoqiang Xiang, Yufei Shi i Xiao Zhu. "Foretinib Is Effective against Triple-Negative Breast Cancer Cells MDA-MB-231 In Vitro and In Vivo by Down-Regulating p-MET/HGF Signaling". International Journal of Molecular Sciences 24, nr 1 (1.01.2023): 757. http://dx.doi.org/10.3390/ijms24010757.

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This study investigated the antitumor effects of foretinib on triple-negative breast cancer cells MDA-MB-231 xenograft tumors in vivo underlying phosphorylated mesenchymal to epithelial transition (p-MET)/ hepatocyte growth factor (HGF)-related mechanism, as well as its pharmacokinetic characteristics. The MDA-MB-231 human breast cancer cell line was used for in vitro experiments, and the tumor xenograft model was established for in vivo experiments. MDA-MB-231 xenograft mice received oral foretinib (15 or 50 mg/kg/day) or vehicle for 18 days. The xenograft tumors were collected. Protein expressions of p-MET and HGF were examined with Western blotting and immunohistochemical staining. The mRNA expression of MET was examined with real-time PCR. Blood samples were collected from the mice treated with foretinib under different doses of 2, 10, and 50 mg/kg, and the pharmacokinetic profiles of foretinib were evaluated. We found that foretinib treatment caused a significant inhibition in tumor growth in a dose-dependent manner, whereas the continuous administration did not result in weight loss in treated nude mice. In both MDA-MB-231 cells and xenograft tumors, foretinib suppressed the expression of p-MET and HGF. These findings reveal that the decrease of p-MET and HGF may play an important role in the anti-breast cancer properties of foretinib.

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Huang, Jianzhong, Jason S. Frischer, Tamara New, Eugene S. Kim, Anna Serur, Alice Lee, Angela Kadenhe-Chiwishe i in. "TNP-470 promotes initial vascular sprouting in xenograft tumors". Molecular Cancer Therapeutics 3, nr 3 (1.03.2004): 335–43. http://dx.doi.org/10.1158/1535-7163.335.3.3.

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Abstract TNP-470 (AGM-1470), an analogue of fumagillin, was one of the first molecules proposed to have antiangiogenic properties. This concept was based on its ability to inhibit both endothelial proliferation in vitro and tumor growth in vivo in a number of xenograft models. Yet, subsequent investigations indicated that the biochemical activities associated with TNP-470 are not selective for endothelial cells. Moreover, recent evidence suggests that this agent inhibits tumor growth in vivo, but without a corresponding decrease in angiogenesis. Therefore, we performed a detailed comparison of TNP-470 to a validated antiangiogenic agent, a VEGF inhibitor termed VEGF-Trap, using a xenograft model of Wilms tumor. Treatment with TNP-470 for 5 weeks significantly suppressed xenograft growth (83%). Surprisingly, this inhibition was not associated with a decrease in angiogenesis, but instead with an increase in tiny neovessels. To determine whether this was a direct effect of TNP-470 on tumor vessels, we examined its effect in a short-term assay using large tumors with established vasculature. In contrast to treatment with VEGF-Trap, which led to rapid vessel regression and tumor hypoxia, tumors exposed to TNP-470 for 1 day displayed increased capillary sprouting, with significantly increased microvessel density, vessel length, and branch points. TNP-470 did not induce tumor hypoxia as demonstrated by minimal pimonidazole staining and VEGF expression. TNP-470 did, however, cause a marked increase in apoptosis of tumor cells. Our results indicate that the antitumor effects of TNP-470 cannot be attributed to prevention of neoangiogenesis, but instead to its direct action on tumor cells.

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Suvilesh, Kanve Nagaraj, Yulia I. Nussbaum, Vijay Radhakrishnan, Yariswamy Manjunath, Diego M. Avella, Kevin F. Staveley-O’Carroll, Eric T. Kimchi i in. "Abstract 267: Xenograft models of non-metastatic non-small cell lung cancer reveals micrometastasis-associated single cell composition". Cancer Research 82, nr 12_Supplement (15.06.2022): 267. http://dx.doi.org/10.1158/1538-7445.am2022-267.

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Abstract Background: Circulating tumor cells (CTCs) represent micrometastatic disease and may offer unique insights into future recurrences in lethal malignancies, including non-small cell lung cancer (NSCLC). Due to CTC rarity and limited stability, no CTC-derived xenograft (CDX) models have ever been generated from non-metastatic NSCLC patients directly. Alternative strategies are needed to molecularly characterize CTCs in this potentially curable patient group. Methods: Surgically resected NSCLC primary tumor tissues were implanted in immunodeficient mice to establish ten patient-derived xenografts (PDXs). CTCs from 2/10 PDX models led to generation of two stable metastatic models that were studied by single cell sequencing. Results: Single cell analysis revealed an additional alveolar epithelial type II (AT2) population in metastatic tumors, besides a common AT2 cluster in PDX/metastatic tumors. This was consistent with an external validation set analysis in primary and metastatic NSCLC patient tumors. Further, AT2 clusters of metastatic tumors expressed higher cancer stemness genes versus primary PDX tumor that was recapitulated in patients primary and metastatic tumors. Conclusions: Stable metastatic models from early stage NSCLC patients can be generated with CTCs from PDX models. The distinct AT2 population identified in CDX tumors with cancer stemness features might be critical mediator of metastasis that deserves further study to discover personalized strategies against NSCLC micrometastases. Citation Format: Kanve Nagaraj Suvilesh, Yulia I. Nussbaum, Vijay Radhakrishnan, Yariswamy Manjunath, Diego M. Avella, Kevin F. Staveley-O’Carroll, Eric T. Kimchi, Aadel A. Chaudhuri, Chi-Ren Shyu, Guangfu Li, Klaus Pantel, Wesley C. Warren, Jonathan B. Mitchem, Jussuf T. Kaifi. Xenograft models of non-metastatic non-small cell lung cancer reveals micrometastasis-associated single cell composition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 267.

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