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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, and Gary L. Gallia. "Establishment and characterization of a primary human chordoma xenograft model." Journal of Neurosurgery 116, no. 4 (April 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, and Andrew M. Lowy. "A novel xenograft model of gastrointestinal stromal tumors." Journal of Clinical Oncology 30, no. 4_suppl (February 1, 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, and Joanna J. Phillips. "Generation of a patient-derived chordoma xenograft and characterization of the phosphoproteome in a recurrent chordoma." Journal of Neurosurgery 120, no. 2 (February 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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Dong, Yiyu, Brandon Manley, A. Ari Hakimi, Jonathan A. Coleman, Paul Russo, and 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, no. 2_suppl (January 10, 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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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, and Yu N. Lazutin. "Experimental approach to obtaining subcutaneous xenograft of non-small cell lung cancer." Research and Practical Medicine Journal 9, no. 2 (May 4, 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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Breij, Esther CW, David Satijn, Sandra Verploegen, Bart de Goeij, Danita Schuurhuis, Wim Bleeker, Mischa Houtkamp, and 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, no. 15_suppl (May 20, 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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Dougherty, Mark, Eric Taylor, and Marlan Hansen. "TMET-34. RADIATION METABOLOMICS IN PRIMARY HUMAN MENINGIOMA AND SCHWANNOMA: EARLY EXPERIENCE AND INITIAL RESULTS." Neuro-Oncology 24, Supplement_7 (November 1, 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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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, and 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, no. 4 (April 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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Singh, Kanika, Negar Jamshidi, Roby Zomer, Terrence J. Piva, and Nitin Mantri. "Cannabinoids and Prostate Cancer: A Systematic Review of Animal Studies." International Journal of Molecular Sciences 21, no. 17 (August 29, 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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Dobbin, Zachary C., Ashwini A. Katre, Angela Ziebarth, Monjri Shah, Adam D. Steg, Ronald David Alvarez, Michael G. Conner, and Charles N. Landen. "Use of an optimized primary ovarian cancer xenograft model to mimic patient tumor biology and heterogeneity." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 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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Linskey, Mark E., A. Julio Martinez, Douglas Kondziolka, John C. Flickinger, Ann H. Maitz, Theresa Whiteside, and L. Dade Lunsford. "The radiobiology of human acoustic schwannoma xenografts after stereotactic radiosurgery evaluated in the subrenal capsule of athymic mice." Journal of Neurosurgery 78, no. 4 (April 1993): 645–53. http://dx.doi.org/10.3171/jns.1993.78.4.0645.
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✓ An experimental model with xenograft transplantation into the subrenal capsule of athymic (nude) mice was used to evaluate the early response of human acoustic schwannomas to stereotactic radiosurgery. After xenograft placement, 45 mice underwent radiosurgery with single doses of 10, 20, or 40 Gy using a 201-source 60Co gamma unit (4-mm collimator, single isocenter, 80% isodose line). The 45 radiosurgery-treated xenografts were compared with 15 untreated xenografts and 15 xenografts in mice that underwent “sham radiosurgery.” All five study groups were matched for the following pretreatment variables: patient of origin, animal weight, average xenograft diameter, and percentage of xenograft surface vascularity. Immediately prior to sacrifice of the mice all xenografts were evaluated in situ to determine the average tumor diameter, tumor volume, and percentage of surface vascularity. Mice were sacrificed 2 weeks, 1 month, or 3 months after radiosurgery. Blinded histological review was performed by an independent neuropathologist. Tumor volume was reduced 33.6% after 2 weeks (p = 0.023) and 45% after 3 months (p = 0.018) in the 40-Gy radiosurgery group. Tumor volume was reduced by 46.2% after 1 month (p = 0.0002) and 35.2% after 3 months (p = 0.032) in the 20-Gy radiosurgery group. An average volume reduction of 16.4% was observed after 3 months (p = 0.17) in the 10-Gy radiosurgery group. At 3 months after surgery, tumor surface vascularity was reduced by an average of 19.7% (p = 0.043) in the 40-Gy radiosurgery group and 5.8% (p = 0.12) in the 20-Gy radiosurgery group and was unchanged in the 10-Gy radiosurgery group and both control groups. Histological examination demonstrated a higher incidence of hemosiderin deposits (p = 0.026) and vascular mural hyalinization (p = 0.032) in radiosurgery xenografts versus control. The subrenal capsule xenograft in nude mice was an excellent model for studying the in vivo radiobiology of acoustic schwannomas after radiosurgery. Both cellular and vascular effects could be assessed serially in situ and the model was stable even 4 months after transplantation. Additional studies investigating radiobiology over periods better approximating the time course of clinical neuroimaging changes (6 to 12 months) are warranted.
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Nathan, Cherie Ann O., Oleksandr Ekshyyan, D'Antoni Carmichael Dennis, Cheryl Clark, Rong Youhua, Rong Xiaohua, and Fleurette Abreo. "R418 – Temsirolimus Preferentially Targets Tumor Microenvironment." Otolaryngology–Head and Neck Surgery 139, no. 2_suppl (August 2008): P183. http://dx.doi.org/10.1016/j.otohns.2008.05.572.
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Problem The mTOR pathway, a central regulator of cell metabolism, proliferation, and survival, is activated in a 100% of HNSCC. We have previously shown the mTOR inhibitor CCI-779 (temsirolimus; rapamycin analogue) inhibits growth of FaDu HNSCC in vitro and in vivo and significantly reduced microvessel density in HNSCC xenografts. Hence to study stromal effects of temsirolimus, FaDu cells were stably transfected with rapamycin resistant mTOR (rr-mTOR) to elucidate anti-tumor mechanisms of temsirolimus. Methods FaDu cells stably transfected with control vector or rr-mTOR. HNSCC tumor xenografts were established in nude mice by subcutaneous injection of control vector transfected (cv-FaDu) or rr-mTOR transfected (rr-FaDu) cells. Temsirolimus (5 mg/kg) was evaluated in mice treated for 3 weeks. PCR analysis of the 5'-end of an exogenous rr-mTOR sequence was performed on DNA isolated from explanted tumor tissues. Results Growth of cv-FaDu was suppressed by rapamycin (100 ng/ml), while the rr-FaDu clone was insensitive. PCR assay yielded the expected 246 b.p. product in rr-FaDu, but not in cv-FaDu xenografts indicating the presence of the exogenous rr-mTOR coding sequence in rr-FaDu xenograft tumor tissues. Temsirolimus inhibited growth of cv-FaDu and rr-FaDu xenograft tumors and was comparable in both groups suggesting the ‘anti-tumor’ activity of the drug in vivo is predominantly a consequence of its anti-stromal effects. Conclusion Results of this study suggest tumor growth inhibitory effects of temsirolimus on HNSCC xenografts are mediated mainly by the anti-stromal activity of the drug rather than by direct anti-tumor effect alone. Significance Understanding the mechanism of action of mTOR inhibition is important in the management of HNSCC as the Akt/mTOR pathway is activated in 100% of HNSCC. Support This work was supported by NCI grant R01CA102363 to Cherie-Ann O. Nathan.
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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, et al. "Targeting the PI3K signaling cascade in PIK3CA mutated endometrial cancer in a primary human xenograft model." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 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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Solovieva, O. I., E. L. Zavjalov, T. V. Teplyakova, L. R. Lebedev, and I. A. Razumov. "EFFECT OF THE MYCELIUM EXTRACT FROM DUDDINGTONIA FLAGRANS FUNGUS ON SUBCUTANEOUS XENOGRAFT OF HUMAN C33a CERVICAL CARCINOMA CELLS." Siberian journal of oncology 19, no. 6 (December 31, 2020): 93–98. http://dx.doi.org/10.21294/1814-4861-2020-19-6-93-98.
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The purpose of the study was to analyze the antitumor effects of the extract of mycelium from Duddingtonia flagrans (strain F-882) on xenografts of human C33a cervical cancer cells.Material and Methods. To evaluate the antitumor effect, we used the absolute values of xenograft volumes and calculated the tumor growth inhibition and the index of tumor growth.Results. At the first stage of the experiment, a 4-week subcutaneous injection of the water extract of F-882 resulted in an almost twofold slowdown in xenograft growth, with the tumor growth inhibition value of 50.6 %. In the second stage of the experiment, a 2.5-week subcutaneous injection followed by a 1.5-week intratumoral injection of F-882 also caused the tumor growth inhibition. After completing F-882 injections, the effect of tumor growth inhibition continued for 2.5 weeks and the tumor growth inhibition value was 58.7 %.Conclusion. The mycelium extract F-882 was shown to have an antitumor effect on subcutaneous xenografts of human C33a cervical carcinoma cells.
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He, Fei, Xiongming Zhou, Gan Huang, Qingkun Jiang, Li Wan, and Jiaxuan Qiu. "Establishment and Identification of Patient-Derived Xenograft Model for Oral Squamous Cell Carcinoma." Journal of Oncology 2022 (September 5, 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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Yada, Erica, Rika Kasajima, Atsushi Niida, Seiya Imoto, Satoru Miyano, Yohei Miyagi, Tetsuro Sasada, and Satoshi Wada. "Possible Role of Cytochrome P450 1B1 in the Mechanism of Gemcitabine Resistance in Pancreatic Cancer." Biomedicines 9, no. 10 (October 5, 2021): 1396. http://dx.doi.org/10.3390/biomedicines9101396.
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Patient-derived xenograft models reportedly represent original tumor morphology and gene mutation profiles. In addition, patient-derived xenografts are expected to recapitulate the parental tumor drug responses. In this study, we analyzed the pathways involved in gemcitabine resistance using patient-derived xenograft models of pancreatic cancer. The patient-derived xenograft models were established using samples from patients with pancreatic cancer. The models were treated with gemcitabine to better understand the mechanism of resistance to this anti-cancer drug. We performed comparative gene analysis through the next-generation sequencing of tumor tissues from gemcitabine-treated or non-treated patient-derived xenograft mice and gene set enrichment analysis to analyze mRNA profiling data. Pathway analysis of gemcitabine-treated patient-derived xenografts disclosed the upregulation of multiple gene sets and identified several specific gene pathways that could potentially be related to gemcitabine resistance in pancreatic cancer. Further, we conducted an in vitro analysis to validate these results. The mRNA expression of cytochrome P450 1B1 and cytochrome P450 2A6 was upregulated in a concentration-dependent manner following gemcitabine treatment. Moreover, the sensitivity to gemcitabine increased, and viable cells were decreased by the cytochrome P450 1B1 inhibitor, indicating that the cytochrome P450 1B1 pathway may be related to gemcitabine resistance in pancreatic cancer.
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Pham, Khoa, Allison R. Hanaford, Brad A. Poore, Micah J. Maxwell, Heather Sweeney, Akhila Parthasarathy, Jesse Alt, et al. "Comprehensive Metabolic Profiling of MYC-Amplified Medulloblastoma Tumors Reveals Key Dependencies on Amino Acid, Tricarboxylic Acid and Hexosamine Pathways." Cancers 14, no. 5 (March 3, 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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Charmsaz, Sara, Kirrilee J. Miller, Bryan W. Day, Fares El-Ajeh, Varghese Palath, Geoff T. Yarranton, Christopher R. Bebbington, Andrew M. Scott, Martin Lackmann, and Andrew W. Boyd. "Immunotherapeutic Targeting of EphA3." Blood 124, no. 21 (December 6, 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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Janjigian, Yelena Yuriy, Christopher M. Gromisch, Gregory Carbonetti, Laura H. Tang, David Paul Kelsen, Daniel G. Coit, Efsevia Vakiani, Elisa de Stanchina, and Vivian E. Strong. "Establishment of esophagogastric xenografts: A model for characterizing disease heterogeneity." Journal of Clinical Oncology 30, no. 30_suppl (October 20, 2012): 95. http://dx.doi.org/10.1200/jco.2012.30.30_suppl.95.
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95 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 cancer/intestinal type—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 NSG 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, 66 tumor samples have been implanted from which 16 xenografts have been established. The table below summarizes the results. Single-agent afatinib (pan-ErbB inhibitor) demonstrated antitumor activity in an HER2-positive xenograft established from MSKCC patient’s tumor harvested from a skin metastasis. Conclusions: We have established xenograft models of gastric cancer. In vivo testing of afatinib showed a reduction of tumor growth of HER2-positive gastric cancer. These models provide a platform to study potential therapeutics for esophagogastric cancer to further validate difference in their biology and guide rational design of clinical trials. [Table: see text]
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Hossain, Jubayer A., Md A. Latif, Lars A. R. Ystaas, Sandra Ninzima, Kristoffer Riecken, Arnaud Muller, Francisco Azuaje, et al. "Long-term treatment with valganciclovir improves lentiviral suicide gene therapy of glioblastoma." Neuro-Oncology 21, no. 7 (April 8, 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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Kijima, Noriyuki, Yoshikazu Nakajima, Daisuke Kanematsu, Tomoko Shofuda, Yuichiro Higuchi, Hiroshi Suemizu, Kanji Mori, et al. "TMOD-29. ESTABLISHMENT OF PATIENT-DERIVED XENOGRAFTS FROM RARE PRIMARY BRAIN TUMORS." Neuro-Oncology 22, Supplement_2 (November 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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Federico, Sara Michele, Elizabeth Stewart, Rachel Christine Brennan, Cori Bradley, Fan Wang, Burgess B. Freeman, Clinton F. Stewart, Jianrong Wu, and Michael A. Dyer. "Comprehensive preclinical testing for neuroblastoma using orthotopic xenografts of a patient tumor." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 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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Liu, C., Y. Liu, D. Chen, Z. Tang, W. Pan, J. Wery, and 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, no. 15_suppl (May 20, 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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Van Renterghem, Britt, Agnieszka Wozniak, Ludovica Tarantola, Andrea Casazza, Jasmien Wellens, Madita Nysen, Ulla Vanleeuw, et al. "Enhanced Antitumor Efficacy of PhAc-ALGP-Dox, an Enzyme-Activated Doxorubicin Prodrug, in a Panel of THOP1-Expressing Patient-Derived Xenografts of Soft Tissue Sarcoma." Biomedicines 10, no. 4 (April 6, 2022): 862. http://dx.doi.org/10.3390/biomedicines10040862.
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Despite poor response rates and dose-limiting cardiotoxicity, doxorubicin (doxo) remains the standard-of-care for patients with advanced soft tissue sarcoma. We evaluated the efficacy of two tetrapeptidic doxo prodrugs (PhAc-ALGP-Dox or CBR-049 and CBR-050) that are locally activated by enzymes expressed in the tumor environment, in ten sarcoma patient-derived xenografts. Xenograft models were selected based on expression of the main activating enzyme, i.e., thimet oligopeptidase (THOP1). Mice were either randomized to vehicle, doxo, CBR-049 and CBR-050 or control, doxo, aldoxorubicin (aldoxo) and CBR-049. Treatment efficacy was assessed by tumor volume measurement and histological assessment of ex-mouse tumors. CBR-049 showed significant tumor growth delay compared to control in all xenografts investigated and was superior compared to doxo in all but one. At the same time, CBR-049 showed comparable efficacy to aldoxo but the latter was found to have a complex safety profile in mice. CBR-050 demonstrated tumor growth delay compared to control in one xenograft but was not superior to doxo. For both experimental prodrugs, strong immunostaining for THOP1 was found to predict better antitumor efficacy. The prodrugs were well tolerated without any adverse events, even though molar doses were 17-fold higher than those administered and tolerated for doxo.
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Derenzini, Massimo, Lorenzo Montanaro, Alessandra Chillà, Elena Tosti, Claudio Ceccarelli, Fabio Dall'Olio, Dietmar Öfner, and 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, no. 12 (December 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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Collins, Scott D., Pamela S. Shaw, Shawn P. Fessler, Jason Wang, and Rebecca Mosher. "Abstract 1756: Antitumor effect of XMT1660, a B7H4 targeting antibody drug conjugate, in an unselected panel of patient derived xenograft models of breast cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1756. http://dx.doi.org/10.1158/1538-7445.am2022-1756.
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Abstract Introduction: XMT-1660 is a first-in-class Dolasynthen Antibody-Drug Conjugate (ADC) targeting B7-H4 and carrying a DolaLock payload with controlled bystander effect. B7-H4 is an immunoregulatory protein that is expressed in breast, ovarian and endometrial tumors. Expression of B7-H4 has been described in both tumor cells and in tumor associated macrophages, and B7-H4 shows infrequent co-expression with PD-L1, suggesting distinct immunoregulatory functions. XMT-1660 is built on the Dolasynthen platform which incorporates several attributes, including site-specific bioconjugation and precise control over drug-antibody ratio (DAR). The XMT-1660 ADC contains 6 DolaLock Auristatin F-hydroxypropyl amide (AF-HPA) anti-tubulin payloads per antibody (DAR-6). Previously, we demonstrated the cytotoxic effect of XMT-1660 in cell line xenograft and patient derived xenograft models of breast cancer known to have B7-H4 target expression. The purpose of this study was to evaluate the anti-tumor activity of XMT-1660 across an unselected panel of breast cancer patient derived xenograft (PDX) models, evaluate the level of B7-H4 expression across this panel of breast PDX models, and assess the correlation between B7-H4 expression and anti-tumor activity following a single dose of XMT-1660. Methods: A panel of 30 breast cancer patient-derived xenograft models, annotated by prior treatment history, and divided between TNBC and ER-positive subtypes, was implanted into athymic Nude-Foxn1n mice. When tumors reached an average volume of 150-300 mm3, animals (n=3) were treated with a single administration of either XMT-1660 0.15mg/kg (calculated by payload dose)/4.71 mg/kg (calculated by antibody dose) IV/QD X1 or saline vehicle. Tumor volumes were evaluated until the planned endpoint of mean tumor volume of control group of 1500 mm3 or day 28. At the endpoint, xenografts, or tumor beds (in the case of no palpable mass) were collected as formalin fixed paraffin embedded material. The xenograft material was evaluated for B7-H4 expression by protein and RNA methods and expression was compared to the anti-tumor activity. Results: In this panel of breast patient derived xenograft models, a range of anti-tumor activities has been observed following administration of a single dose of XMT-1660. The relationship between XMT-1660 anti-tumor activity and B7-H4 expression was demonstrated. Conclusion: XMT-1660 elicits a range of anti-tumor activity across a series of primary breast cancer xenograft models. XMT-1660 is currently in IND-enabling studies and is expected to enter a Phase I dose escalation clinical study in 2022. The efficacy/expression relationship of B7-H4 will be further evaluated in an upcoming clinical study with a goal to identify patients most likely to respond to XMT-1660. Citation Format: Scott D. Collins, Pamela S. Shaw, Shawn P. Fessler, Jason Wang, Rebecca Mosher. Antitumor effect of XMT1660, a B7H4 targeting antibody drug conjugate, in an unselected panel of patient derived xenograft models of breast cancer [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 1756.
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Chen, Bao-An, Ya-nan Wu, Jian Cheng, Feng Gao, Wen-lin Xu, Hui-lin Shen, Jia-hua Ding, et al. "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, no. 11 (November 16, 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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Liu, C., L.-H. Dai, D.-Q. Dou, L.-Q. Ma, and Y.-X. Sun. "A natural food sweetener with anti-pancreatic cancer properties." Oncogenesis 5, no. 4 (April 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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Tateishi, Kensuke, Nobuyoshi Sasaki, Masahito Kawazu, Yohei Miyake, Taishi Nakamura, Yukie Yoshii, Yuko Matsushita, et al. "TB-02 NF-KB CANONICAL PATHWAY ACTIVATION DRIVES GLYCOLYSIS AND TUMOR PROGRESSION IN PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA." Neuro-Oncology Advances 1, Supplement_2 (December 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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Janjigian, Yelena Yuriy, Robert Mazgaj, Gregory Carbonetti, Laura H. Tang, Blake Hefter, David Paul Kelsen, Elisa de Stanchina, and Vivian E. Strong. "Establishment of primary gastric and gastroesophageal (GE) junction xenografts: A model for characterizing disease heterogeneity." Journal of Clinical Oncology 30, no. 4_suppl (February 1, 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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Ramachandran, Cheppail, Gilda M. Portalatin, Adriana M. Prado, Karl-Werner Quirin, Enrique Escalon, and 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, no. 2 (July 19, 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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Ducker, Gregory S., Chloe Evelyn Atreya, Jeffrey Simko, Eric K. Nakakura, Emily K. Bergsland, David B. Donner, Kevan M. Shokat, and 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, no. 4_suppl (February 1, 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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Carra, Silvia, Germano Gaudenzi, Alessandra Dicitore, Maria Celeste Cantone, Alice Plebani, Davide Saronni, Silvia Zappavigna, et al. "Modeling Lung Carcinoids with Zebrafish Tumor Xenograft." International Journal of Molecular Sciences 23, no. 15 (July 23, 2022): 8126. http://dx.doi.org/10.3390/ijms23158126.
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Lung carcinoids are neuroendocrine tumors that comprise well-differentiated typical (TCs) and atypical carcinoids (ACs). Preclinical models are indispensable for cancer drug screening since current therapies for advanced carcinoids are not curative. We aimed to develop a novel in vivo model of lung carcinoids based on the xenograft of lung TC (NCI-H835, UMC-11, and NCI-H727) and AC (NCI-H720) cell lines and patient-derived cell cultures in Tg(fli1a:EGFP)y1 zebrafish embryos. We exploited this platform to test the anti-tumor activity of sulfatinib. The tumorigenic potential of TC and AC implanted cells was evaluated by the quantification of tumor-induced angiogenesis and tumor cell migration as early as 24 h post-injection (hpi). The characterization of tumor-induced angiogenesis was performed in vivo and in real time, coupling the tumor xenograft with selective plane illumination microscopy on implanted zebrafish embryos. TC-implanted cells displayed a higher pro-angiogenic potential compared to AC cells, which inversely showed a relevant migratory behavior within 48 hpi. Sulfatinib inhibited tumor-induced angiogenesis, without affecting tumor cell spread in both TC and AC implanted embryos. In conclusion, zebrafish embryos implanted with TC and AC cells faithfully recapitulate the tumor behavior of human lung carcinoids and appear to be a promising platform for drug screening.
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Ishikawa, Hiroshi, Kazutomo Ishi, Vanida Ann Serna, Rafael Kakazu, Serdar E. Bulun, and Takeshi Kurita. "Progesterone Is Essential for Maintenance and Growth of Uterine Leiomyoma." Endocrinology 151, no. 6 (April 7, 2010): 2433–42. http://dx.doi.org/10.1210/en.2009-1225.
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Uterine leiomyomata (ULs) represent the most common tumor in women and can cause abnormal uterine bleeding, large pelvic masses, and recurrent pregnancy loss. Although the dependency of UL growth on ovarian steroids is well established, the relative contributions of 17β-estradiol and progesterone are yet to be clarified. Conventionally, estradiol has been considered the primary stimulus for UL growth, and studies with cell culture and animal models support this concept. In contrast, no research model has clearly demonstrated a requirement of progesterone in UL growth despite accumulating clinical evidence for the essential role of progesterone in this tumor. To elucidate the functions of ovarian steroids in UL, we established a xenograft model reflecting characteristics of these tumors by grafting human UL tissue beneath the renal capsule of immunodeficient mice. Leiomyoma xenografts increased in size in response to estradiol plus progesterone through cell proliferation and volume increase in cellular and extracellular components. The xenograft growth induced by estradiol plus progesterone was blocked by the antiprogestin RU486. Furthermore, the volume of established UL xenografts decreased significantly after progesterone withdrawal. Surprisingly, treatment with estradiol alone neither increased nor maintained the tumor size. Although not mitogenic by itself, estradiol induced expression of progesterone receptor and supported progesterone action on leiomyoma xenografts. Taken together, our findings define that volume maintenance and growth of human UL are progesterone dependent.
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Yalcin, M., E. Dyskin, L. Lansing, D. J. Bharali, S. S. Mousa, A. Bridoux, A. H. Hercbergs, et al. "Tetraiodothyroacetic Acid (Tetrac) and Nanoparticulate Tetrac Arrest Growth of Medullary Carcinoma of the Thyroid." Journal of Clinical Endocrinology & Metabolism 95, no. 4 (April 1, 2010): 1972–80. http://dx.doi.org/10.1210/jc.2009-1926.
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Abstract Context: Tetraiodothyroacetic acid (tetrac) blocks angiogenic and tumor cell proliferation actions of thyroid hormone initiated at the cell surface hormone receptor on integrin αvβ3. Tetrac also inhibits angiogenesis initiated by vascular endothelial growth factor and basic fibroblast growth factor. Objective: We tested antiangiogenic and antiproliferative efficacy of tetrac and tetrac nanoparticles (tetrac NP) against human medullary thyroid carcinoma (h-MTC) implants in the chick chorioallantoic membrane (CAM) and h-MTC xenografts in the nude mouse. Design: h-MTC cells were implanted in the CAM model (n = 8 per group); effects of tetrac and tetrac NP at 1 μg/CAM were determined on tumor angiogenesis and tumor growth after 8 d. h-MTC cells were also implanted sc in nude mice (n = 6 animals per group), and actions on established tumor growth of unmodified tetrac and tetrac NP ip were determined. Results: In the CAM, tetrac and tetrac NP inhibited tumor growth and tumor-associated angiogenesis. In the nude mouse xenograft model, established 450–500 mm3 h-MTC tumors were reduced in size over 21 d by both tetrac formulations to less than the initial cell mass (100 mm3). Tumor tissue hemoglobin content of xenografts decreased by 66% over the course of administration of each drug. RNA microarray and quantitative real-time PCR of tumor cell mRNAs revealed that both tetrac formulations significantly induced antiangiogenic thrombospondin 1 and apoptosis activator gene expression. Conclusions: Acting via a cell surface receptor, tetrac and tetrac NP inhibit growth of h-MTC cells and associated angiogenesis in CAM and mouse xenograft models.
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Zhang, Libo, Douglass C. Vines, Deborah A. Scollard, Trevor McKee, Teesha Komal, Milan Ganguly, Trevor Do, et al. "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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Cabezas-Sáinz, Pablo, Alba Pensado-López, Bruno Sáinz, and Laura Sánchez. "Modeling Cancer Using Zebrafish Xenografts: Drawbacks for Mimicking the Human Microenvironment." Cells 9, no. 9 (August 27, 2020): 1978. http://dx.doi.org/10.3390/cells9091978.
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The first steps towards establishing xenografts in zebrafish embryos were performed by Lee et al., 2005 and Haldi et al., 2006, paving the way for studying human cancers using this animal species. Since then, the xenograft technique has been improved in different ways, ranging from optimizing the best temperature for xenografted embryo incubation, testing different sites for injection of human tumor cells, and even developing tools to study how the host interacts with the injected cells. Nonetheless, a standard protocol for performing xenografts has not been adopted across laboratories, and further research on the temperature, microenvironment of the tumor or the cell–host interactions inside of the embryo during xenografting is still needed. As a consequence, current non-uniform conditions could be affecting experimental results in terms of cell proliferation, invasion, or metastasis; or even overestimating the effects of some chemotherapeutic drugs on xenografted cells. In this review, we highlight and raise awareness regarding the different aspects of xenografting that need to be improved in order to mimic, in a more efficient way, the human tumor microenvironment, resulting in more robust and accurate in vivo results.
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Kim, Jihee, Ji Hyeong Seo, Yun-Hee Kim, YoHan Woo, Yeon Jee Lee, Yena Kim, Wonyoung Choi, et al. "Abstract 6042: Developing patient-derived organoids and tumor xenograft model for ovarian cancer for preclinical therapeutic evaluation." Cancer Research 82, no. 12_Supplement (June 15, 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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Vorontsova, M. S., T. A. Karmakova, E. A. Plotnikova, N. B. Morozova, M. A. Abakumov, R. I. Yakubovskaya, and B. Ya Alexeev. "Subcutaneous and orthotopic xenograft models of human bladder carcinoma in nude mice for epidermal growth factor receptor-targeted treatment." Russian Journal of Biotherapy 17, no. 2 (November 24, 2018): 31–40. http://dx.doi.org/10.17650/1726-9784-2018-17-2-31-40.
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Introduction.Approaches based on the principles of a targeted therapy are considered a promising strategy that is capable to improve the effectiveness of treatment for bladder cancer (BC) patients.The purposeof the study was to establish an orthotopic xenograft model of human BC in mice and to prove its suitability for experimental examination of drugs targeting the epidermal growth factor receptor (EGFR).Materials and methods.The objects of the study were ectopic subcutaneous and orthotopic human BC xenografts established using EJ and 5637 human BC cell lines. The growth of orthotopic xenografts in vivo was assessed by magnetic resonance imaging. Tumor tissues were investigated using histological and immunohistochemical techniques.Results.It was shown that EJ and 5637 xenografts exhibit a good reproducibility, a sufficient blood supply of the tumor tissues, a high level of EGFR expression, and different pattern of a subcellular receptor localization. Implantation and subsequent proliferation of human EJ or 5637 cells in the murine bladder mucosa presumably results in muscle-non-invasive tumor formation.Conclusions.The EJ and 5637 xenograft models can be useful for investigation of the efficacy of EGFR-targeted biotherapeutic treatments.
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Pham, Khoa, Brad Poore, Allison Hanaford, Micah J. Maxwell, Heather Sweeney, Akhila Parthasarathy, Jesse Alt, et al. "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 (July 1, 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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Labitzky, Vera, Anke Baranowsky, Hanna Maar, Sandra Hanika, Sarah Starzonek, Ann-Kristin Ahlers, Katrin Stübke, et al. "Modeling Spontaneous Bone Metastasis Formation of Solid Human Tumor Xenografts in Mice." Cancers 12, no. 2 (February 7, 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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Hsia, Te-Chun, Shu-Fen Peng, Fu-Shin Chueh, Kung-Wen Lu, Jiun-Long Yang, An-Cheng Huang, Fei-Ting Hsu, and Rick Sai-Chuen Wu. "Bisdemethoxycurcumin Induces Cell Apoptosis and Inhibits Human Brain Glioblastoma GBM 8401/Luc2 Cell Xenograft Tumor in Subcutaneous Nude Mice In Vivo." International Journal of Molecular Sciences 23, no. 1 (January 4, 2022): 538. http://dx.doi.org/10.3390/ijms23010538.
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Bisdemethoxycurcumin (BDMC) has biological activities, including anticancer effects in vitro; however, its anticancer effects in human glioblastoma (GBM) cells have not been examined yet. This study aimed to evaluate the tumor inhibitory effect and molecular mechanism of BDMC on human GBM 8401/luc2 cells in vitro and in vivo. In vitro studies have shown that BDMC significantly reduced cell viability and induced cell apoptosis in GBM 8401/luc2 cells. Furthermore, BDMC induced apoptosis via inhibited Bcl-2 (anti-apoptotic protein) and increased Bax (pro-apoptotic proteins) and cytochrome c release in GBM 8401/luc2 cells in vitro. Then, twelve BALB/c-nude mice were xenografted with human glioblastoma GBM 8401/luc2 cancer cells subcutaneously, and the xenograft nude mice were treated without and with BDMC (30 and 60 mg/kg of BDMC treatment) every 3 days. GBM 8401/luc2 cell xenografts experiment showed that the growth of the tumors was significantly suppressed by BDMC administration at both doses based on the reduction of tumor size and weights. BDMC did not change the body weight and the H&E histopathology analysis of liver samples, indicating that BDMC did not induce systemic toxicity. Meanwhile, treatment with BDMC up-regulated the expressions of BAX and cleaved caspase-3, while it down-regulated the protein expressions of Bcl-2 and XIAP in the tumor tissues compared with the control group. This study has demonstrated that BDMC presents potent anticancer activity on the human glioblastoma GBM 8401/luc2 cell xenograft model by inducing apoptosis and inhibiting tumor cell proliferation and shows the potential for further development to the anti-GBM cancer drug.
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Wu, Jeffrey, Samantha Holland, Leslie Muldoon, Edward Neuwelt, and Prakash Ambady. "EXTH-05. NON-CYTOTOXIC RADIATION ENHANCES DELIVERY OF ANTISENSE OLIGONUCLEOTIDES AND IMPROVES CHEMO-RADIATION EFFICACY IN BRAIN TUMOR XENOGRAFTS." Neuro-Oncology 22, Supplement_2 (November 2020): ii87. http://dx.doi.org/10.1093/neuonc/noaa215.359.
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Abstract Overexpression of O6-methylguanine DNA methyltransferase (MGMT) contributes to brain tumor chemo-resistance. Previously we found that non-cytotoxic radiation improved anti-MGMT Morpholino Oligonucleotides (AMONs) delivery to reduce MGMT levels in subcutaneous tumor xenografts. Here we evaluated if radiation enhanced the delivery of intravenous (IV) AMONs to rat brain and improved chemo-radiation therapy (CRT) efficacy using rat models of human brain tumors. Athymic nude rats bearing orthotopic cerebellar D283 medulloblastoma or intracerebral H460 non-small cell lung carcinoma (NSCLC) brain metastasis xenografts were used. The impact of cranial radiation on delivery of IV 3’-carboxyfluorescein labeled oligonucleotides across the neurovascular unit was evaluated using confocal microscopy. We found that high brain parencymal fluorescence in radiated compared to non-radiated rats. MGMT protein silencing was assessed by immunoblot in tumor-bearing rats 3 d after 2 Gy cranial radiation alone or followed in 1 d by IV AMONs (10.5 mg/kg). Radiation followed by AMONs reduced MGMT expression by 50% in both xenograft models. To evaluate efficacy, tumor-bearing rats received one dose of 2 Gy radiation plus oral temozolomide (20 mg/kg x 4d) with or without IV AMONs. AMONs concurrent with CRT reduced tumor volumes in the medulloblastoma model (p=0.012), and a similar trend was found in the NSCLC brain metastasis model. In conclusion, we demonstrate the use of a single clinically relevant radiation dose fraction to guide and enhance the delivery of oligonucleotides into brain tumor xenograft models to reduce MGMT levels and improve CRT efficacy.
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Galvin, K. M., J. Huck, O. Burenkova, K. Burke, D. Bowman, V. Shinde, B. Stringer, M. Zhang, M. Manfredi, and K. Meetze. "Preclinical pharmacodynamic studies of Aurora A inhibition by MLN8054." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 13059. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.13059.
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13059 Background: The mitotic kinase Aurora A is implicated in the development of multiple tumor types. MLN8054 is an oral, potent and selective small-molecule inhibitor of Aurora A with broad efficacy in preclinical models of cancer. Inhibition of Aurora A by MLN8054 induces accumulation of mitotic cells, followed by apoptosis. This study explores relationships between Aurora A inhibition, mitotic index, and tumor growth inhibition for xenograft models with different sensitivity to MLN8054. The marker response in mouse skin was also studied. Methods: Mice bearing subcutaneous xenografts were dosed orally qd or bid with MLN8054 for 21 days. Pharmacodynamic markers were studied after 1–2 doses. Formalin-fixed xenograft tissues were stained with the mitotic markers pHisH3 and MPM2, or with an antibody to the T288 autophosphorylation site on Aurora A. Tumor growth inhibition (TGI) was calculated using the formula 100 - [ΔT/ΔC * 100], where ΔT is the volume change for treated tumors, and ΔC is the volume change for control tumors. Results: HCT116 human colon xenografts were sensitive to MLN8054 on a qd or bid schedule (84% and 96% TGI respectively for 30mg/kg dose). The T288 autophosphorylation site was used to directly demonstrate inhibition of Aurora A, which resulted in dose-dependent duration of the elevation in mitotic index. Efficacy was similar for qd vs bid dosing of 30mg/kg MLN8054, and accordingly we found that a single dose was sufficient to elevate the mitotic index for about 20–24h in this model. SW480 human colon xenografts have MLN8054 sensitivity similar to that of HCT116, but more modest effects on mitotic index were observed. The mitotic index profile of SW480 is similar to that of MDA-MB-231 xenografts, the most insensitive model studied. Elevated mitotic index was also observed in mouse skin. Conclusions: We found that mitotic index measurements coupled with the T288 autophosphorylation site as a direct marker of Aurora A activity are useful for monitoring inhibition of Aurora A by MLN8054 in tumor and/or skin biopsies. In a sensitive model, greater duration of mitotic index elevation results in greater efficacy. Our continuing work aims to better understand the differences in marker and efficacy responses between xenograft lines, incorporating the pT288 antibody as a direct marker of Aurora A inhibition. [Table: see text]
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Iwanicki, Isabella J., Lydia Wu, Fernando Flores-Guzman, Connor Centner, Kenneth B. Bader, and Sonia Hernandez. "Histotripsy significantly decreases tumor viability in neuroblastoma xenograft model." Journal of the Acoustical Society of America 152, no. 4 (October 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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Pimentel, Helly, Helen Jarnagin, Hailing Zong, Courtney Todorov, Courtney M. Anderson, Bingqing Zhang, Christopher Bunker, and Xiao-Jun Ma. "Preclinical CAR-T cell target safety, biodistribution, and tumor infiltration analysis using in situ hybridization technology." Journal of Clinical Oncology 37, no. 8_suppl (March 10, 2019): 112. http://dx.doi.org/10.1200/jco.2019.37.8_suppl.112.
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112 Background: Chimeric antigen receptor (CAR) T cell therapy is highly effective in treating hematologic malignancies, and major efforts are being made to achieve similar efficacy in solid tumors. The greater potency of CAR-T cells compared to antibody therapeutics demands a more stringent CAR-T target safety assessment to avoid adverse events resulting from “on-target/off-tumor” activity. Furthermore, it is critical to track and monitor CAR+ T cells within intact tissue and tumor to understand the mechanisms underlying off-tumor toxicity and efficacy in tumor killing. Methods: We employed the RNAscope in situ hybridization (ISH) technology to assess target expression specificity and to track CAR-T cell distribution and activation in xenograft and host tissues using the RPMI-8226 xenograft mouse model. Results: For the CAR-T target candidates, Target X and Target Y, RNA ISH revealed that Target X was only expressed in the xenograft tumor and in no mouse organs, while Target Y was found to be expressed at low levels in mouse lung and liver, as well as in the xenograft tumor. Duplex RNA ISH assays with probes targeting the CAR 3’ UTR and either IFNG or GZMB allowed for highly sensitive and specific detection of CAR-T cells and their activation state in both tumor and normal tissues from vehicle, Target X CAR-T cell, or Target Y CAR-T cell treated mice. Activated Target X CAR-T cells expressing GZMB and IFNG were found only in the xenograft tumor, where Target X was expressed. In contrast, activated Target Y CAR-T cells were found almost exclusively in mouse lung and liver, with very few Target Y CAR-T cells being found in the xenograft tumor. Lastly, a multiplex ISH-IHC approach confirmed the presence of activated Target X CAR-T cells in the xenograft tumor through simultaneous detection of the Target X CAR 3’ UTR, IFNG, GZMB, and CD3. Conclusions: These data demonstrate how the RNAscope assay can be utilized for CAR-T cell efficacy and safety/toxicity assessment in preclinical models by detecting very low levels of target antigen expression in off-tumor tissues and monitoring CAR-T cell pharmacodynamics and activation in tumor models and can also be applied for assessing TCR-T cell activity in tumors.
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Cheng, Junsheng, Wei Han, Zheyuan Wang, Yuan Shao, Yingzhen Wang, Yawu Zhang, Zhongxin Li, Xiaodong Xu, and Youcheng Zhang. "Hepatocellular Carcinoma Growth Is Inhibited byEuphorbia helioscopiaL. Extract in Nude Mice Xenografts." BioMed Research International 2015 (2015): 1–9. http://dx.doi.org/10.1155/2015/601015.
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Euphorbia helioscopiaL. is a traditional Chinese medicine; recently research found that its ethyl acetate extract (EAE) plays an important role on tumor cell proliferation, apoptosis, invasion, and metastasisin vitro. But the effect of EAE for tumor cellsin vivohas not been reported. To explore the inhibitory effect of EAE and molecular mechanism on hepatocellular carcinoma (HCC) SMMC-7721 cellsin vivo, we utilized the nude mouse xenograft model of HCC. Treated with EAE (50, 100, and 200 μg/mL), the volume of xenograft was measured during the entire process of EAE treatment. In EAE treatment group, the volume of xenograft was significantly reduced compared with the control group (P<0.05) and the protein expressions of CyclinD1, bcl-2, and MMP-9 were reduced, while those of bax, caspase-3, and nm23-H1 were increased. A significant change trend with increasing EAE concentrations has presented, compared with controls. Moreover, the ultrastructural morphology of xenografts showed significant changes, including nuclear pyknosis and chromatin condensation, We found that EAE could effectively inhibit tumor growth, induce apoptosis, and inhibit tumor invasion and metastasisin vivo; it is suggested that EAE is a potential candidate for as a new anticancer agent.
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Nicoli, Stefania, and Marco Presta. "The zebrafish/tumor xenograft angiogenesis assay." Nature Protocols 2, no. 11 (November 2007): 2918–23. http://dx.doi.org/10.1038/nprot.2007.412.
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Lee, Wei-Hwa, Ming-Yang Yeh, and Yen-Chang Tu. "Tumor Localization of Human Brain Malignant Glioma Xenograft in Nude Mice with a Radiolabeled Monoclonal Antibody." Neurosurgery 26, no. 3 (March 1, 1990): 381–90. http://dx.doi.org/10.1227/00006123-199003000-00002.
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Abstract A murine monoclonal antibody designated as MAb 3H9 (IgGl subclass immunoglobulin, k light chain) expressed specific antibody binding activity to a human brain malignant glioma cell line (GBM8401/TSGH, NDMC) and many formalin-fixed and paraffin-embedded malignant gliomas that have been produced in our laboratory by hybridoma technology. The immunohistochemical indirect immunofluorescence, peroxidase-antiperoxidase assays, and specific electron microscopic immunogold staining revealed that 3H9 probably recognized a distinct glioma-associated surface antigen on the GBM8401 cultured cells. In vivo radioimmunolocalization of GBM8401 xenografts in nude mice by external scintigraphy with radiolabeled 3H9 has been performed to evaluate potential clinical application as diagnostic or therapeutic reagents. On the 3rd day after an intravenous injection of 15 MCi, the 125I- or 131I-radiolabeled 3H9 was successful in immunolocalization of a human brain GBM8401 xenograft in the nude mouse. In large xenografts, the radioactivity ratios of tumor to brain and tumor to blood were 11.0 and 2.4, respectively. In small xenografts, the tumor to brain and tumor to blood ratios were 14.0 and 2.9, respectively. The clearance of radiolabeled 3H9 in the bloodstream of the nude mouse was not affected by the presence of a GBM8401 xenograft. This preliminary experiment reveals that human brain GBM8401 xenografts in nude mice can be detected in vivo by radiolabeled 3H9.
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Sadadcharam, Gaitri, Morgan McCourt, Ciara Ryan, Kate O'Connor, Michael William Bennett, Derek Gerard Power, Seamus O'Reilly, Jinghuai Wang, Henry Paul Redmond, and Emmet J. Andrews. "Mice on trial: Are xenografts using human tissue a better model of cancer than xenografts formed from cell lines?" Journal of Clinical Oncology 31, no. 4_suppl (February 1, 2013): 386. http://dx.doi.org/10.1200/jco.2013.31.4_suppl.386.
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386 Background: Xenograft tumours are validated models using either patient samples (primary xenografts) or cell lines (secondary xenografts) grown in a murine host. Repeated culturing of cancer cell lines results in epigenetic changes and subsequent behaviour changes distinct from primary human cancers. The aim of this study is to form both models and compare their responses to chemotherapy agents. Methods: Fresh primary colorectal adenocarcinoma tissue or colorectal cell lines (SW480 non metastatic line / SW620 metastatic line) were inoculated subcutaneously into immunodeficient mice to form primary and secondary xenografts respectively. Both models were subjected to either a 5-fluorouracil (5-FU) or irinotecan trial. The clinical response and biological features were evaluated. Results: Secondary xenografts were more aggressive with a shorter time to tumour formation, higher uptake rate and more aggressive histological features. The mice were randomised to either the control group (saline) or to the treatment group [60mg/kg of 5FU (SW620 / primary xenografts) or 60 mg/kg of Irinotecan (SW480 / primary xenografts)] via intraperitoneal injection. In the 5FU group, the primary xenografts began regressing after Day 2 but the secondary xenografts continued to grow until Day 8. The decrease from the maximal tumor volume to the study end point (Day 12 in primary xenograft group and Day 10 in secondary xenograft group) was evaluated with primary xenografts showing a greater decrease compared to secondary xenografts (56.6% vs. 10.4%; p =0.002). Conclusions: We demonstrated the ability to grow tumours in mice from fresh human colonic adenocarcinomas. Tumours formed in mice from patient derived adenocarcinomas produce more clinically accurate testing than tumours formed from cell line and may allow for drug screening in order to personalise an individual’s chemotherapy regime.