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Buxbaum, C., A. Deo, B. Manobla, S. Levin, S. Ash i Y. Shaked. "P16.07.A STUDYING NEUROBLASTOMA TUMOR MICROENVIRONMENT THROUGH A NOVEL PRE-CLINICAL MODEL". Neuro-Oncology 26, Supplement_5 (październik 2024): v85. http://dx.doi.org/10.1093/neuonc/noae144.282.
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Abstract BACKGROUND Neuroblastoma is a pediatric cancer that develops from neural crest cells. It has a dramatically variable course, ranging from very aggressive disease to benign differentiation and even spontaneous regression. In neuroblastoma, a crucial prognostic marker is the distinct cutoff at 18 months of age. Thus, children older than 18 months have a significantly worse prognosis than younger children. This age cutoff was studied thoroughly, but no explanatory mechanism has been found. All current pre-clinical research encompasses models in adult subjects while the development of tumors is greatly impacted by its microenvironment, which varies between young and adult individuals, thus creating disparate biological conditions. Therefore, the development of age-relevant neuroblastoma models is of great interest, especially when age is a major prognostic factor. MATERIAL AND METHODS C57BL/6 mice aged 12-days (young) and 8-weeks (adults) were used to reflect the different age groups, where 12-day-old mice correspond to children younger than 18-month. Mice were orthotopically implanted into the adrenal gland with 0.5 million 9464D-luciferase tagged murine neuroblastoma cells. Tumor growth assessment was performed once a week using micro-ultrasound to estimate tumor volume. At the endpoint, tumors were harvested and prepared for histopathological and immune characterization using flow and mass cytometry. RESULTS Tumors exhibited divergent growth patterns when comparing young and adult mice. In the initial week following implantation, tumors in young mice showed inhibited growth in contrast to those in adult mice (0.65mm3 vs. 5.44mm3 p=0.005). Following this initial phase, tumors in young mice started to grow rapidly, eventually leading to an equal final tumor load in both groups. The tumor characteristics were notably different between the groups. For example, the tumor immune cell infiltration exhibited a significantly increased number of B cells (3.598 vs. 10.01 p=0.01), CD4 cells (31.2 vs. 41.24 p=0.32) in young mice. Conversely, adults exhibited a higher number of G-MDS’c (32.2 vs. 13.856 p=0.005). CONCLUSION Our study reveals a delayed development of neuroblastoma in young mice during the early post-implantation phase. This observation mimics the natural biological behavior of this disease and potentially emulates the spontaneous regression seen in children under 18 months-old. In our investigation of the tumor microenvironment, we analyzed immune cell populations, revealing notable differences between the age groups. Further and updated findings are forthcoming. This study proposes a new approach for neuroblastoma research and potentially for all preclinical studies of pediatric cancer.
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Becker, William J., Purevdorj B. Olkhanud i Jay A. Berzofsky. "Triple synergy between vaccine and checkpoint inhibitors in a pre-clinical tumor model". Journal of Immunology 208, nr 1_Supplement (1.05.2022): 118.14. http://dx.doi.org/10.4049/jimmunol.208.supp.118.14.
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Abstract Despite advances in checkpoint inhibitor (CPI) therapy for cancer treatment, many malignancies remain resistant. Tumors deemed ‘cold’ based on lack of T cell infiltration into the stroma of the tumor show reduced potential for CPI therapy and finding the right combination to balance safety and efficacy is arduous. To study ways to circumvent these limitations, we used the preclinical mouse model of TC1 tumor cells resistant to conventional CPI therapy. The TC1 cells are transfected with oncogenes E6 and E7 of HPV16, and we designed a tumor-vaccine specific for an E7(43–77) peptide. We show the synergy between the tumor-antigen specific vaccine and the combination of two CPIs, anti-TIGIT and anti-PD-L1. The synergistic effect of the triple combination provides more protection against tumor growth than either treatment alone or any pairwise combination and significantly improves survival in a CD8+ T cell dependent manner. Combining the tumor-specific vaccine with CPIs induces tumor-specific CD8+ T cells that infiltrate the tumor in young and aged mice, although aged mice show less protection than their younger counterparts. These data show proof-of-concept for a novel combination of a vaccine designed to elicit de novo anti-tumor T cell responses that can be amplified by synergistic CPIs that lead to greater survival. Supported by Intramural NCI funding: ZIA-C-004020
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Ernst, Kati, Konstantin Okonechnikov, Laura von Soosten, Nina Hofmann, Norman Mack, Benjamin Schwalm, Robert J. Wechsler-Reya i in. "BIOL-07. DISTINCTIVE FEATURES OF HIGH-GRADE GLIOMA MOUSE MODELS REVEALED BY SINGLE-NUCLEUS RNA-SEQUENCING GUIDE PRE-CLINICAL MODEL SELECTION". Neuro-Oncology 25, Supplement_1 (1.06.2023): i7. http://dx.doi.org/10.1093/neuonc/noad073.026.
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Abstract Glioma is the most common pediatric central nervous system tumor, with high-grade gliomas (HGG) having one of the worst prognoses of all human cancers. In order to develop better diagnostics and therapies, it is essential to use faithful disease models. Currently, highly passaged patient-derived xenograft (PDX) models are most widely used in preclinical studies, although alternative immunocompetent models are becoming increasingly available. Here, we compare several in vivo glioma models on a single-cell level and investigate their similarity to primary human tumors. Single-nucleus sequencing was used to analyze >125,000 nuclei of primary patient samples, xenografts, autochthonous mouse tumors and related allografts including early and late in vivo passages – with a focus on MET-fusion-driven as well as H3 K27M-mutant HGG. Transcriptomic profiles of single tumor cells and associated stromal/immune components reveal insights into model-specific intratumoral heterogeneity, tumor evolution, and similarities between mouse models and patient samples. In addition, matched tumors engrafted into immunocompromised and immunocompetent animals are used to examine tumor-immune crosstalk and the modifying role of the tumor microenvironment. This improved understanding of how the analyzed model systems evolve over time and how they reflect patient’s tumor compositions will allow to prioritize and refine modern preclinical trials.
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Ahmed, Eman N., Lauren C. Cutmore i John F. Marshall. "Syngeneic Mouse Models for Pre-Clinical Evaluation of CAR T Cells". Cancers 16, nr 18 (18.09.2024): 3186. http://dx.doi.org/10.3390/cancers16183186.
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Chimeric antigen receptor (CAR) T cells have revolutionized the treatment of hematological malignancies. Unfortunately, this improvement has yet to be translated into the solid tumor field. Current immunodeficient models used in pre-clinical testing often overestimate the efficacy of CAR T cell therapy as they fail to recapitulate the immunosuppressive tumor microenvironment characteristic of solid tumors. As CAR T cell monotherapy is unlikely to be curative for many solid tumors, combination therapies must be investigated, for example, stromal remodeling agents and immunomodulators. The evaluation of these combination therapies requires a fully immunocompetent mouse model in order to recapitulate the interaction between the host’s immune system and the CAR T cells. This review will discuss the need for improved immunocompetent murine models for the pre-clinical evaluation of CAR T cells, the current use of such models and future directions.
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Klose, Johannes, Stefan Trefz, Tobias Wagner, Luca Steffen, Arsalie Preißendörfer Charrier, Praveen Radhakrishnan, Claudia Volz i in. "Salinomycin: Anti-tumor activity in a pre-clinical colorectal cancer model". PLOS ONE 14, nr 2 (14.02.2019): e0211916. http://dx.doi.org/10.1371/journal.pone.0211916.
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Weeber, Fleur, Salo N. Ooft, Krijn K. Dijkstra i Emile E. Voest. "Tumor Organoids as a Pre-clinical Cancer Model for Drug Discovery". Cell Chemical Biology 24, nr 9 (wrzesień 2017): 1092–100. http://dx.doi.org/10.1016/j.chembiol.2017.06.012.
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Serritella, Anthony V., Pablo Saenz-Lopez Larrocha, Payal Dhar, Sizhe Liu, Milan M. Medd, Shengxian Jia, Qi Cao i Jennifer D. Wu. "The Human Soluble NKG2D Ligand Differentially Impacts Tumorigenicity and Progression in Temporal and Model-Dependent Modes". Biomedicines 12, nr 1 (16.01.2024): 196. http://dx.doi.org/10.3390/biomedicines12010196.
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NKG2D is an activating receptor expressed by all human NK cells and CD8 T cells. Harnessing the NKG2D/NKG2D ligand axis has emerged as a viable avenue for cancer immunotherapy. However, there is a long-standing controversy over whether soluble NKG2D ligands are immunosuppressive or immunostimulatory, originating from conflicting data generated from different scopes of pre-clinical investigations. Using multiple pre-clinical tumor models, we demonstrated that the impact of the most characterized human solid tumor-associated soluble NKG2D ligand, the soluble MHC I chain-related molecule (sMIC), on tumorigenesis depended on the tumor model being studied and whether the tumor cells possessed stemness-like properties. We demonstrated that the potential of tumor formation or establishment depended upon tumor cell stem-like properties irrespective of tumor cells secreting the soluble NKG2D ligand sMIC. Specifically, tumor formation was delayed or failed if sMIC-expressing tumor cells expressed low stem-cell markers; tumor formation was rapid if sMIC-expressing tumor cells expressed high stem-like cell markers. However, once tumors were formed, overexpression of sMIC unequivocally suppressed tumoral NK and CD8 T cell immunity and facilitated tumor growth. Our study distinguished the differential impacts of soluble NKG2D ligands in tumor formation and tumor progression, cleared the outstanding controversy over soluble NKG2D ligands in modulating tumor immunity, and re-enforced the viability of targeting soluble NKG2D ligands for cancer immunotherapy for established tumors.
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Breen, Kevin, Tuesday Haynes, Masashi Watanabe i Mark Gilbert. "Abstract 2663: Determining the role of tumor mutational burden in a pre-clinical model of glioblastoma". Cancer Research 84, nr 6_Supplement (22.03.2024): 2663. http://dx.doi.org/10.1158/1538-7445.am2024-2663.
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Abstract Despite advances in care in many cancer types, patients with glioblastoma (GBM) have a grim prognosis of 15 to 21 months and unchanged standard therapy since 2005. These tumors have a profoundly immunosuppressive tumor immune microenvironment. Immunotherapy, including the checkpoint inhibitors (ICIs) targeting PD-1 and CTLA-4, has transformed the treatment of many cancers but has failed in trials of both newly diagnosed and recurrent GBM. Tumor mutational burden (TMB) has been proposed as a predictor of response to ICI treatment, presumably through an increase in neoantigens that can be recognized by cytotoxic CD8+ T cells leading to tumor rejection. GBM typically has a low TMB, a feature speculated as a contributor to poor response to ICI treatment. However, cases with an extremely high TMB (i.e., patients with the biallelic mismatch repair deficiency syndrome) do show response to immunotherapy. To begin to investigate the impact of mutational burden on immune response in GBM, we created a murine syngeneic tumor model using CRISPR-Cas9 to knockout (KO) the mismatch repair protein Msh2, the lynchpin to mismatch recognition, in the SB28 GBM model that has a low TMB (108 mutations) at baseline. Msh2 KO increased the TMB from 2 to 12-fold depending on single cell sorted clone, resulting in between 150 and 200 predicted strong MHC-I binding neoantigens estimated by the NetMHC algorithm. Preliminary studies have demonstrated that in vitro proliferation is similar amongst low TMB and high TMB SB28 clones. Flank implantation of high TMB SB28 clones revealed slower growth compared to the low TMB SB28 tumors. Furthermore, treatment with ICIs did provide a survival advantage in this flank model. However, no survival advantage was noted when the high TMB clones were implanted intracranially either with or without ICI treatment. These results suggested that either there is poor immune cell trafficking to the intracranial tumors, or a robust immune response was causing increased intracranial pressure that is prematurely causing death. Use of dexamethasone starting at day 11 to control cerebral edema has shown some survival improvement with ICI treatment, supporting that an inflammatory response is at least partially responsible for the lack of improved survival in early studies. We are currently evaluating CD4+ and CD8+ T cell clonality, earlier timepoints to evaluate the immune infiltrate and anti-tumor immune response, and alterations in chemokines/cytokines in the tumor microenvironment. By creating high mutation burden clones from a GBM with a low mutational burden, we will be able to interrogate potential mechanisms of heightened immunogenicity that has been reported in other cancers. Citation Format: Kevin Breen, Tuesday Haynes, Masashi Watanabe, Mark Gilbert. Determining the role of tumor mutational burden in a pre-clinical model of glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2663.
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Longe, Harold O., Anupama Sinha, Douglas V. Faller i Gerald V. Denis. "Telomere-Based Pre-Clinical Therapy of Human Lymphoid Malignancy in a SCID Xenograft Model." Blood 108, nr 11 (16.11.2006): 4761. http://dx.doi.org/10.1182/blood.v108.11.4761.4761.
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Abstract We continue to develop and extend our novel adjuvant therapy approach to lymphoid malignancy. We supplement CHOP with DNA oligonucleotides that mimic the chromosomal telomere, which we call a “T oligo.” These agents are homologous to the 3′ overhang nucleotide sequence of telomeres and have previously been shown to have anti-tumor activity in animal models of malignant melanoma and breast cancer. They are currently being evaluated in melanoma and breast cancer patients. If introduced into human or murine normal, proliferating primary B cells or T cells, T oligo causes transient cell cycle arrest, while exerting no toxicity, but if introduced into human or murine malignant B cells or T cells, the arrest is followed by p53 phosphorylation, p21 message induction and ultimately p53-dependent apoptosis. Other p53-related effector molecules, such as p73, are also likely to be involved. The mechanism immediately suggests a novel method of chemotherapy for leukemia and lymphoma as an adjuvant with CHOP. Furthermore, we have previously shown with in vitro assay and in vivo mouse models of diffuse large B cell lymphoma (DLCL) that T oligo produces a more-than-additive toxicity towards lymphoma cells when combined with vincristine. T oligo alone or in combination with sub-therapeutic doses of CHOP, the standard of care for DLCL, dramatically reduced lymphoma burden in spleen, lung, bone marrow and peritoneum. In combination, which we refer to as T-CHOP, there was a greater reduction in tumor burden than with either therapy alone. We now show in SCID mouse xenograft models of human T cell malignancies, using a Jurkat T cell leukemic line or a MOLT-4 T cell leukemic line that T oligo also works alone to reduce tumor burden dramatically and increase survival. Interestingly, because T oligo-driven apoptosis occurs in p53-null, human lymphoid tumors, even chemotherapy-resistant lymphoid tumors are nevertheless sensitive to T oligo treatment, which may have profound benefit for relapsed leukemia or lymphoma patients.
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Ippagunta, Siri, Erik Emanus, Kelsey Bertrand i Stephen Mack. "TRLS-16. RAPID GENERATION OF EPENDYMOMA MOUSE MODELS FOR PRE-CLINICAL STUDIES". Neuro-Oncology 25, Supplement_1 (1.06.2023): i82. http://dx.doi.org/10.1093/neuonc/noad073.319.
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Abstract Pediatric Ependymomas are the leading cause of cancer death among children & adolescents with the 5-year progression free survival (PFS)rate being < 30%. Despite this poor prognosis there has been less success in development of targeted therapies. A major drawback in developing new therapeutics is lack of proper models of disease. Objective of out work has been to develop orthogonal models of various distinct groups of ependymoma to enable understanding of tumor microenvironment thus leading to strategies targeting potential therapeutic sites. In this regard we have developed two models of ZFTA-RELA Ependymoma: 1) In Utero Electroporation Model: DNA plasmids are transfected into developing forebrain, 2) Allograft Model: Primary tumor derived or in vitro transducer cells are allografted into various regions of brain. Further we have shown that these models molecularly resemble patient-derived tumors using RNA sequencing. Using these ZFTA-RELA mouse models we have shown that NSG mice (n=8/treatment group) treated with Selinexor (an XPO1 inhibitor) in combination with chemotherapy have lower tumor volumes by 40% as compared to vehicle or chemotherapy alone treated mice (P<0.05). Furthermore the combination therapy treated mice have improved survival by 28 days as compared to vehicle mice. In conclusion, we have shown that our novel models of ependymomas not only closely resemble disease in patients, but can also be used to develop effective targeted therapies.
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Boi, Shannon Kathryn, Rachael M. Orlandella i Lyse A. Norian. "Improving immunotherapeutic efficacy against metastatic tumors in a pre-clinical model of murine renal cell carcinoma." Journal of Immunology 198, nr 1_Supplement (1.05.2017): 79.9. http://dx.doi.org/10.4049/jimmunol.198.supp.79.9.
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Abstract Renal and pelvic cancers are the ninth most common cancer in the U.S., and although five-year survival rates for localized renal tumors are >90%, those for metastasized tumors are <12%. Metastatic renal cell carcinoma (RCC), the most common type of renal neoplasm, is resistant to radio- and chemotherapies. Immune-based therapies, including checkpoint blockade, are being pursued in an attempt to amplify protective adaptive immunity but overall response rates remain at 20–30%. We hypothesized that a therapeutic strategy employing T cell priming plus checkpoint blockade would result in improved clearance of renal tumors verses checkpoint alone. Utilizing our previously described in vivo T cell priming therapy, adenovirus-encoded tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) (AdTRAIL) with class B oligonucleotides (CpG), we evaluated therapeutic effects on primary tumor outgrowth and metastatic burden in a pre-clinical model of orthotopic murine RCC. We report here that administration of intra-renal AdTRAIL/CpG in combination with α-CTLA-4, but not α-PD-1, causes significant decreases in primary tumor burdens. Strikingly, we observed that this therapeutic strategy caused significant reductions in metastatic lung burdens – equating to a 98% reduction over no therapy controls. Flow cytometric analysis revealed increases in CD8+ T cells in AdTRAIL-treated groups over no therapy/checkpoint alone; results were further supported by immunosuppressive CD4+ to CD8+ T cell ratios that were in favor of anti-tumoral responses. Our results suggest AdTRAIL/CpG can be used as an effective upstream therapeutic approach to enhance the efficacy of α-CTLA-4 checkpoint blockade in a pre-clinical model of murine RCC.
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Thomsen, Martin K., i Morten Busk. "Pre-Clinical Models to Study Human Prostate Cancer". Cancers 15, nr 17 (22.08.2023): 4212. http://dx.doi.org/10.3390/cancers15174212.
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Prostate cancer is a common cancer among men and typically progresses slowly for several decades before becoming aggressive and spreading to other organs, leaving few treatment options. While large animals have been studied, the dog’s prostate is anatomically similar to humans and has been used to study spontaneous prostate cancer. However, most research currently focuses on the mouse as a model organism due to the ability to genetically modify their prostatic tissues for molecular analysis. One milestone in this research was the identification of the prostate-specific promoter Probasin, which allowed for the prostate-specific expression of transgenes. This has led to the generation of mice with aggressive prostatic tumors through overexpression of the SV40 oncogene. The Probasin promoter is also used to drive Cre expression and has allowed researchers to generate prostate-specific loss-of-function studies. Another landmark moment in the process of modeling prostate cancer in mice was the orthoptic delivery of viral particles. This technology allows the selective overexpression of oncogenes from lentivirus or the use of CRISPR to generate complex loss-of-function studies. These genetically modified models are complemented by classical xenografts of human prostate tumor cells in immune-deficient mice. Overall, pre-clinical models have provided a portfolio of model systems to study and address complex mechanisms in prostate cancer for improved treatment options. This review will focus on the advances in each technique.
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Fayyad Zaman, Mohammad, Marc Daou, Lynette M. Phillips, Sanjay Singh, Lihong Long, Joy Gumin, Daniel Ledbetter i Frederick F. Lang. "TMIC-46. TRANSCRIPTIONAL HETEROGENEITY AND MECHANISTIC PATHWAYS OF RECURRENT GLIOBLASTOMA: INSIGHTS FROM A PRE-CLINICAL RECURRENT TUMOR MODEL". Neuro-Oncology 26, Supplement_8 (1.11.2024): viii308. http://dx.doi.org/10.1093/neuonc/noae165.1224.
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Abstract Despite aggressive therapy combining surgical resection, radiation and chemotherapy, glioblastoma (GBM) almost always recurs. Currently, there is no standard treatment for recurrent GBM, and patient inclusion in clinical trials is based on the genetic and molecular profile of the primary tumor even though the effects of chemoradiation on the transcriptional subtype in matched primary and recurrent GBM remain largely understudied. Paralleling the GLASS consortium, we sought to perform a longitudinal assessment of GBM recurrence after therapy based on molecular subtype with the hypothesis that recurrent tumors exhibit a distinct transcriptional landscape different from treatment-naive tumors. To address this, we utilized primary tumor-derived glioma stem cells (GSCs) representing classical and proneural subtypes. We then undertook in vivo intracranial implantation studies and performed standard concomitant treatment that mimics the Stupp protocol. Upon bulk RNAseq data analyses of untreated (n=21) and recurrent tumors (n=17) we identified that while the molecular subtype of recurrent tumors does not change post therapy, their transcriptional profile is more heterogenous compared to untreated tumors for both subtypes. Hierarchical cluster analyses revealed distinct sub-clusters of recurrent tumors. Common mechanisms of recurrence include upregulation of angiogenesis pathways and PI3k/Akt/mTOR signaling pathways. Interestingly, recurrent tumors exhibit upregulation of genes involved in cellular metabolism and membrane transport/ potential. The source of heterogeneity in recurrent tumors in both subtypes appears to be due to the diversity in expression of gene sets involved in hallmark of cancer pathways such as cell cycle, Notch and Wnt signaling pathways and heterogeneity in oncogenic signatures and cell states resembling fetal or neural cells. Further research into the recurrent tumor microenvironment by spatial multi-omics approaches using this pre-clinical recurrent GBM model will elucidate the linkage between cellular as well as molecular heterogeneity and enable identification of targets that can help drive therapeutic decisions for recurrent GBM patients.
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Gibson, Justin Tyler, Prabhakara Nagareddy i Lyse A. Norian. "Obesity-induced changes in baseline immune responses to pre-clinical breast cancer". Journal of Immunology 198, nr 1_Supplement (1.05.2017): 204.6. http://dx.doi.org/10.4049/jimmunol.198.supp.204.6.
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Abstract Obesity is known to increase morbidity and mortality in breast cancer patients; however, the immunological mechanisms behind these changes remain unclear. The long-term goal of our study is to investigate the broad impact of obesity on anti-tumor immunity, with a particular focus on better understanding immune alterations that may influence the use of immunotherapeutics in breast cancer patients. We began by utilizing the leptin-deficient ob/ob mouse model of obesity and non-obese age matched C57BL/6 controls, in combination with the syngeneic E0771 mammary carcinoma cell line. Tumor outgrowth was quantified by means of caliper measurements, endpoint tumor weight, and bioluminescent imaging (BLI) via luciferase-expressing E0771 (E0771-fLUC) cells; immune cell populations were evaluated via multi-parameter flow cytometry. Primary and metastatic tumor growth were not significantly different between lean and ob/ob mice. In primary tumors, we found that obesity caused significant decreases in the frequencies of tumor-infiltrating granulocytic myeloid derived suppressor cells (G-MDSCs) and CD19+ B cells, and trending decreases in the frequencies of T (CD3+, CD4+, and CD8+) cells. In spleens, we found that both obesity and breast cancer induced a significant decrease in the frequency of dendritic and natural killer (NK) cell populations. Additionally, obesity induced a significant increase in the frequency of splenic monocytic myeloid-derived suppressor cells (M-MDSCs). Our findings suggest several cellular candidates for future mechanistic investigations into obesity-induced dysfunctions in breast cancer immunity.
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Valter, Ann, Tanel Kordemets, Aydan Gasimova, Noah Waterfield Price, Lutz Freitag, Anil Vachani, David Paul Carbone i Kersti Oselin. "Pre- and post-operative lung cancer recurrence prediction following curative surgery: A retrospective study using European radiomics and clinical data." Journal of Clinical Oncology 42, nr 16_suppl (1.06.2024): 8066. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.8066.
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8066 Background: Accurately estimating the risk of lung cancer recurrence is vital for making informed treatment choices, both before surgery, such as the prescription of neo-adjuvant/peri-operative therapies and the extent of lung resection, and after surgery, such as the prescription of adjuvant therapies and planning follow-up strategies. In this study, we build on previous work demonstrating the predictive power of pre-operative patient demographic and imaging features and develop a machine-learning model using a combination of clinical and tumour radiomic features in the pre- and post-operative setting. Methods: We collected a dataset of 323 clinical stage I-IIIA lung cancer patients who underwent surgical treatment for lung cancer, of which 94 had lung cancer recurrence. This includes retrospectively collected CT images and associated patient demographic and diagnostic data from North Estonia Medical Centre (NEMC). The models were trained to predict the likelihood of recurrence on a diverse set of features, including radiomic features extracted from CT images and relevant clinical variables. Post-operative clinical factors such as pathological staging and tumor histology were only included in the post-operative model. An 8-fold cross-validation strategy was used, where, in each fold, 6 (of the 8 equally sized) subsets were used for training, one for model tuning, and one for validation. As a baseline, we compare the pre- and post-operative models to clinical and pathological staging, respectively. Performance was evaluated using the Area-Under-the-ROC-Curve (AUC) and sensitivity (at a fixed specificity of 90%). Results: Lung cancer recurrence classification results are tabulated below for the pre-operative models. We find that the pre-operative model (AUC=74.1%, Sens=35.29%) performs significantly better than clinical staging alone (AUC=65.4%, Sens=14.71%, p=0.025), and that the post-operative model (AUC=74.4%, Sens=26.47%) performs significantly better than pathological staging alone (AUC=67.3, Sens=22.4%, p=0.045). Top predictive features for both the pre-operative and post-operative models included clinical staging, tumor shape and textural radiomics, tumor size and tumor location. The post-operative model additionally included pathological staging and tumor histology. Conclusions: Based on this retrospective analysis, we find that the model outperforms staging prediction of lung cancer recurrence in pre- and post-operative settings. With further development, these algorithms could prove a valuable tool to aid the management of lung cancer patients. [Table: see text]
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Iaia, Ilenia, Virginia Brancato, David Caballero, Rui L. Reis, Massimo Aglietta, Dario Sangiolo i Subhas C. Kundu. "Fibroblasts Impair Migration and Antitumor Activity of NK-92 Lymphocytes in a Melanoma-on-Chip Model". Bioengineering 10, nr 1 (30.12.2022): 52. http://dx.doi.org/10.3390/bioengineering10010052.
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Adoptive cell therapy in solid tumors, such as melanoma, is impaired, but little is known about the role that the fibroblasts present in the tumor microenvironment could exert. However, the mechanism at play is not well understood, partly due to the lack of relevant pre-clinical models. Three-dimensional culture and microfluidic chips are used to recapitulate the dynamic interactions among different types of cells in the tumor microenvironment in controlled and physiological settings. In this brief report, we propose a reductionist melanoma-on-a-chip model for evaluating the essential role of fibroblasts in the antitumor activity of lymphocytes. To this end, 3D melanoma spheroids were monocultured and co-cultured with human dermal fibroblasts and the NK-92 cell migration towards the tumor compartment was tested in a commercially available microfluidic device. Utilizing confocal microscopy, we observed the different recruitment of NK-92 cells in the presence and absence of fibroblasts. Our results show that fibroblasts’ presence inhibits immune effector recruiting by exploiting a 3D pre-clinical tumor model.
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Ciron, Carine, Françoise Shneiker i Odile Duvaux. "Pre-clinical efficacy of the first glyco-humanized oncolytic polyclonal antibody (XON7) in onco-hematology." Journal of Clinical Oncology 41, nr 16_suppl (1.06.2023): e14519-e14519. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.e14519.
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e14519 Background: Polyclonal antibodies pAb were shown to possess oncolytic properties a century ago with reported clinical responses. More recent pre-clinical models confirmed pAb efficacy though their ability to tackle complex target antigens. The emergence of escape variants could be minimized by multi-targeting of tumor cells with pAb, which would be more efficient than mAb at mediating effector functions for target destruction. However, the use of heterologous pAb is limited by their immunogenicity. Glyco-humanization (GH) solves this issue and allows to reconsider the potential of pAb in oncology. 3 GH-pAb have already been introduced in clinic in non-oncology settings, with a good safety profile. XON7 is a new GH-pAb targeting cancer cells. Methods: Complement dependent cytotoxicity (CDC) and apoptosis against various tumor cell lines and PBMC from healthy donors were tested with XON7 at increasing concentrations (6,25 µg/mL to 400 µg/mL) Specific binding to human tumors was assessed by immunochemistry on tissue micro-array (13 sections of original tumor, 13 healthy tissues). Cross-cancer activity was evaluated on biopsies from patients with solid tumor or blood cancer: CRC (n=63), NSCLC (n=30), Osteosarcoma (n=4), pancreatic (n= 48), GIST (n=2), AML (n=10), DLBCL (n=7). Xenograft mice model: XON7 efficacy was tested in several sub cutaneous xenograft models in NMRI nude mice (n=10 per group) using A549: non-small-cell lung cancer, HCT-116: colon cancer, LnPac: prostate cancer, KMS-12-BM: myeloma, T1301: T cell lymphoma. Treatments (35mg/kg, twice a week) were given for 4 weeks once the tumor reached 50 mm3. Results: XON7 induced specific human tumor cell lines CDC (IC50=50ug/mL) and apoptosis (IC50= 100ug/mL) up to 100% of the cells, without cross-reactivity with healthy human cells. XON7 targets several patients’ tumoral tissues. In vivo, XON7 induces a significant reduction of tumor growth ranging from 40 to 90% across all tested tumors. Conclusions: Immunotherapy with XON7 could be a novel therapeutic approach to fight solid tumors and hematological malignancies. [Table: see text]
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ZHOU, FEIFAN, XIAOSONG LI, SHENG SONG, JOSEPH T. ACQUAVIVA, ROMAN F. WOLF, ERIC W. HOWARD i WEI R. CHEN. "ANTI-TUMOR RESPONSES INDUCED BY LASER IRRADIATION AND IMMUNOLOGICAL STIMULATION USING A MOUSE MAMMARY TUMOR MODEL". Journal of Innovative Optical Health Sciences 06, nr 04 (październik 2013): 1350039. http://dx.doi.org/10.1142/s1793545813500399.
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Anti-tumor immunological response induced by local intervention is ideal for treatment of metastatic tumors. Laser immunotherapy was developed to synergize photothermal interaction with immunological stimulation for cancer treatment. Using an infrared laser, indocyanine green (ICG, as a light absorbing agent), and glycated chitosan (GC, as an immunostimulant), laser immunotherapy has resulted in tumor suppression and anti-tumor responses in pre-clinical as well as clinical studies. To further understand the mechanism of laser immunotherapy, the effects of laser and GC treatment without specific enhancement of laser absorption were studied. Passive adoptive immunity transfer was performed using splenocytes as immune cells. Spleen cells harvested from tumor-bearing mice treated by laser + GC provided 60% immunity in naive recipients. Furthermore, cytotoxicity and TNF-α secretion by splenocytes from treated mice also indicated that laser + G induced immunity was tumor-specific. The high level of infiltrating T cells in tumors after laser + GC treatment further confirmed a specific anti-tumor immune response. Therefore, laser + GC could prove to be a promising selective local treatment modality that induces a systemic anti-tumor response, with appropriate laser parameters and GC doses.
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Mihaylov, Ivaylo B., Tulasigeri M. Totiger, Teresa M. Giret, Dazhi Wang, Benjamin Spieler i Scott Welford. "Toward prediction of abscopal effect in radioimmunotherapy: Pre-clinical investigation". PLOS ONE 16, nr 8 (24.08.2021): e0255923. http://dx.doi.org/10.1371/journal.pone.0255923.
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Purpose Immunotherapy (IT) and radiotherapy (RT) can act synergistically, enhancing antitumor response beyond what either treatment can achieve separately. Anecdotal reports suggest that these results are in part due to the induction of an abscopal effect on non-irradiated lesions. Systematic data on incidence of the abscopal effect are scarce, while the existence and the identification of predictive signatures or this phenomenon are lacking. The purpose of this pre-clinical investigational work is to shed more light on the subject by identifying several imaging features and blood counts, which can be utilized to build a predictive binary logistic model. Materials and methods This proof-of-principle study was performed on Lewis Lung Carcinoma in a syngeneic, subcutaneous murine model. Nineteen mice were used: four as control and the rest were subjected to combined RT plus IT regimen. Tumors were implanted on both flanks and after reaching volume of ~200 mm3 the animals were CT and MRI imaged and blood was collected. Quantitative imaging features (radiomics) were extracted for both flanks. Subsequently, the treated animals received radiation (only to the right flank) in three 8 Gy fractions followed by PD-1 inhibitor administrations. Tumor volumes were followed and animals exhibiting identical of better tumor growth delay on the non-irradiated (left) flank as compared to the irradiated flank were identified as experiencing an abscopal effect. Binary logistic regression analysis was performed to create models for CT and MRI radiomics and blood counts, which are predictive of the abscopal effect. Results Four of the treated animals experienced an abscopal effect. Three CT and two MRI radiomics features together with the pre-treatment neutrophil-to-lymphocyte (NLR) ratio correlated with the abscopal effect. Predictive models were created by combining the radiomics with NLR. ROC analyses indicated that the CT model had AUC of 0.846, while the MRI model had AUC of 0.946. Conclusions The combination of CT and MRI radiomics with blood counts resulted in models with AUCs of 1 on the modeling dataset. Application of the models to the validation dataset exhibited AUCs above 0.84, indicating very good predictive power of the combination between quantitative imaging and blood counts.
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Bangiev-Girsh, Einav, Amir Basis, Paul Zannou, Inna Naroditsky, Asaf Aizic, Ami Aronheim, Liron Berger i Ruth Perets. "Abstract A067: A novel genetically engineered mouse model of ovarian carcinosarcoma". Cancer Research 84, nr 5_Supplement_2 (4.03.2024): A067. http://dx.doi.org/10.1158/1538-7445.ovarian23-a067.
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Abstract Ovarian carcinosarcoma (OCS) is a rare and extremely lethal gynecological cancer, accounting for less than 1% of all ovarian cancers, and harboring an unfavorable prognosis compared to the common subtype. There are no efficient treatments available, highlighting the need for a reliable pre-clinical model as a tool to study this disease. Our goal was to generate a genetically engineered mouse model (GEMM) of OCS, carrying relevant genetic alterations, in order to study OCS pathogenesis. To generate the model, we used a Cre-Lox system for targeted knockout of three relevant tumor suppressor genes: Trp53, Brca2 and Pten. Mice in our model also carry a Lox-stop-Lox-TdTomato transgene, which results in fluorescent TdTomato protein expression in all recombined cells. Gene knockout in our model was achieved via injections of adenoviral particles coding for CRE recombinase into the ovarian bursa. Female mice in our model developed tumors arising from the ovary with an admixture of malignant epithelial and stromal elements, successfully mimicking human OCS. Tumors often metastasized to the abdominal cavity and at times generated ascites. The tumors showed patchy staining for PAX8, ER, Cytokeratin and Vimentin, further confirming their resemblance to human OCS. Mice harboring homozygous deletions of all three tumor suppressor genes developed tumors rapidly, first imaged 7 weeks after induction, and euthanized at a humane end point 11-14 weeks after CRE injection (average 11.4±0.95 weeks). This rapid timeline, together with high Ki-67 expression, suggest that tumor development in our model mimics the highly aggressive nature of the human disease. Interestingly, homozygous deletion of Trp53 and Pten and heterozygous deletion of Brca2 did not significantly alter time to tumor formation or tumor morphology, compared to the original model, suggesting that homozygous deletion of Brca2 is not essential or OCS development in our model. On the other hand, heterozygous deletion of either Trp53 or Pten, maintaining homozygous deletion of the other alleles, significantly delayed tumor formation and reduced tumor penetration, suggesting that Trp53 and Pten play a significant role in this model. Finally, harvesting mouse ovaries at very early time points, prior to tumor development, showed early pre-malignant lesions emerging from the ovarian surface epithelium, implicating ovarian surface epithelial cells as a potential OCS cell of origin of in our model. In conclusion, we have developed a reproducible model of OCS arising from the ovarian surface epithelium, correctly mimicking human disease in terms of clinical course, morphology, and tumor markers. This novel pre-clinical model, together with the mouse OCS cell lines we have generated from the model, will allow studies of disease pathogenesis, development of early detection and prevention tools, and studies of new OCS treatments. Citation Format: Einav Bangiev-Girsh, Amir Basis, Paul Zannou, Inna Naroditsky, Asaf Aizic, Ami Aronheim, Liron Berger, Ruth Perets. A novel genetically engineered mouse model of ovarian carcinosarcoma [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A067.
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Carr-Ascher, Janai R. "Abstract PR010: Development of a pre-clinical metastatic model of human sarcoma to identify therapeutic targets". Clinical Cancer Research 28, nr 18_Supplement (15.09.2022): PR010. http://dx.doi.org/10.1158/1557-3265.sarcomas22-pr010.
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Abstract Targeted therapies have led to significant advances in the treatment of multiple tumor types resulting in more effective and often, less toxic therapeutic options. In sarcomas, the development of targeted therapies has been met limited success. There are more than 70 sarcoma subtypes that vary in histology, clinical course and patient demographics. Despite these clear differences, clinically, sarcomas are treated similarly with variable efficacy. Patients with localized disease are treated with surgery, radiation, and often chemotherapy. Even with this aggressive multimodality treatment, 35% of patients will develop incurable metastatic disease. This highlights the need for additional therapies targeting micrometastatic disease or cells within the primary tumor with a high propensity for metastasis. Understanding the pathways driving the formation of sarcoma metastasis would allow for the development of new therapies. Targeted treatments are limited due to the heterogeneity of the disease and the paucity of pre-clinical models that accurately reflect the human disease. We have focused on creating in vivo models of sarcoma development and metastasis that can be used as the basis of further studies and to test potential therapeutic targets. Mesenchymal stem cells (MSCs) are the presumed cell of origin for sarcomas and therefore, the starting cell for our investigations. We hypothesized that by recreating key genetic events in human MSCs, we could generate sarcomas in vivo that are reflective of the human disease. RB1 and P53, tumor suppressors that are often mutated or functionally inactive in sarcomas were first targeted using CRISPR-Cas9 technology in MSCs that have been immortalized by human telomerase (hTERT). Genes that are overexpressed or amplified in The Cancer Genome Atlas (TCGA) data were identified and a library of potential oncogenes was generated. This library was then added to RB1-/-P53+/- cells through lentiviral transduction. Targeting of key tumor suppressors and adding oncogenic drivers resulted in the formation of high-grade human sarcomas subcutaneously. We then sought to investigate the ability of these cells to metastasize. Injection of cells intramuscularly (into the thigh) in immunocompromised mice resulted in the formation of spontaneous lung metastasis without clear evidence of disease in other organs. This pattern clinically reflects that of human disease. Comparing oncogenic genes from metastatic outgrowths to primary tumors identified KLF4, DDIT3, JUN, and KRAS as being enriched in metastatic cells. This system allows for reproducible and robust genetic manipulation of tumor cells to characterize key drivers of metastatic growth. This will result in the identification and validation of new therapeutic targets to treat or prevent metastatic disease in our patients. Citation Format: Janai R. Carr-Ascher. Development of a pre-clinical metastatic model of human sarcoma to identify therapeutic targets [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr PR010.
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Kines, Rhonda, Reema S. Railkar, Piyush K. Agarwal i John T. Schiller. "Targeting urothelial neoplasia using an investigational virus-like drug conjugate." Journal of Clinical Oncology 40, nr 6_suppl (20.02.2022): 514. http://dx.doi.org/10.1200/jco.2022.40.6_suppl.514.
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514 Background: Human papillomavirus virus-like particles (HPV VLP) preferentially target tumor cells via cell surface modified heparan-sulfate proteoglycans (HSPG). The investigational virus-like drug conjugate, belzupacap sarotalocan (AU-011), is currently in phase 2 clinical trials for treatment of primary choroidal melanoma. We previously demonstrated AU-011’s in vivo tumor acute cytotoxicity upon activation with near-infrared light (nIR), resulting in tumor-free survival for at least 100 days and protection from tumor re-challenge in the MB49 murine flank model of bladder cancer. Here we provide additional data supporting further clinical development in urothelial neoplasia as an additional oncology indication. Methods: We examined the cytotoxicity of AU-011 in a panel of six human bladder cancer cell lines in vitro and binding and distribution in human tumor biopsy samples ex vivo. Tumor distribution of AU-011 was also assessed in vivo after intravesical instillation in the orthotopic MB49 murine model. In consideration of the glycocalyx layer often found coating the interior of the bladder wall and the surface of bladder tumors, pre-treatment with hyauronidase was tested both on human biopsy samples and in the murine orthotopic model. Lastly, tumor distribution of AU-011 was evaluated when formulated with the polyamide Syn3. Results: When tested in vitro on a panel of human bladder tumor cell lines representing grades I-IV carcinomas, we found AU-011’s potency to be in the picomolar range (EC50 range 16.6 pM – 62.75 pM). We assessed the VLPs ability to bind ex vivo to a panel of human urothelial tumor biopsies and observed binding in samples representing both invasive T2 and non-invasive Ta papillary tumors. Tumor biopsy samples were pre-treated with hyaluronidase to break down the glycocalyx layer surrounding the tumor, and an increase in signal was observed in the Ta biopsy sample. Similarly, using the orthotopic MB49 murine tumor model with intravesical delivery of AU-011, we observed an enhancement of AU-011 distribution into the tumor when the bladders were pre-treated with hyaluronidase. Additionally, when formulated with Syn3, AU-011 distribution throughout the tumors was augmented without the need for hyaluronidase pre-treatment. Conclusions: We have demonstrated AU-011 targeted cytotoxicity in vitro using a panel of human bladder cancer cell lines indicating that its binding to bladder cancer cells is tumor grade and genetic mutation agnostic. Additionally, tumor binding and distribution was observed ex vivo using human bladder cancer biopsy samples and in vivo in the murine MB49 orthotopic model. Human and murine tumor distribution was improved with a pre-treatment of hyaluronidase or when formulated with Syn3. Collectively, these data support the further investigation of the use of AU-011 for the indication of uroepithelial cancer.
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Singh, Naresh, Samantha Sharma, Kevin Van Der Jeught, Zhuolong Zhou, Xinna Zhang i Xiongbin Lu. "Abstract 119: A non-surgical method for developing a pre-clinical orthotopic mouse model for colorectal cancer". Cancer Research 84, nr 6_Supplement (22.03.2024): 119. http://dx.doi.org/10.1158/1538-7445.am2024-119.
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Abstract Recapitulating physiologically relevant tumor microenvironment is important yet a significant challenge in modeling colorectal cancer (CRC) for basic and translational studies. Among the different methods, using the cecal-wall injection technique is the most common way to create animal models of colorectal cancer (CRC). However, this approach requires complex surgery, and its unnatural placement creates a significant obstacle for developing treatments. Here, we report a non-surgical procedure for establishing orthotopic CRC mouse models, reflecting the appropriate tumor microenvironment to better model the disease development and facilitate translational studies including drug identification and validation. In this procedure, anesthesia is induced in overnight fasted study immunocompetent or immunodeficient mice while placed on a thermostat-controlled heating blanket. A specialized catheter is inserted and distended into the mouse colon to gently block the colon and ensure the localization for tumor development. Hereafter, the colonic epithelium is treated with proteases and mechanical abrasion to cause mild disruption. Following the local gut inflammation, the targeted colon region is incubated with tumor cells, leading to the adhesion of tumor cells to the colonic epithelium. Based on the animal background and the cell line used, the tumor developed within 3-4 weeks. The stages of tumor development at different time points were successfully confirmed using hematoxylin and eosin stain. Tumor microenvironment data revealed a significant increase in the immune cell infiltration specifically CD4+ T-cells and tumor-associated macrophages in the non-surgical procedure as compared to the cecal-wall injection. Furthermore, a significant increase in the PD-1 expression of the CD8+ T-cells in the cecal-wall injection as compared to the non-surgical procedure, suggests that the precise location of the tumor site may exert a substantial influence on pre-clinical therapeutic outcomes of immune-checkpoint inhibitors, thereby potentially hampering the clinical efficacy of drug treatments. Additional adaptations of this procedure may include: i) tumor development in different mouse strains, ii) local delivery of adeno-Cre in transgenic mice for CRC, and iii) delivering tumor organoids and patient-derived xenografts in immuno-deficient mice. Overall, our non-surgical procedure overcomes the technical difficulties of surgery and offers several advantages like ease of handling, cost-effectiveness, pain-free with nearly no procedure-associated mortality and adaptability to several strains. In conclusion, this procedure provides novel and promising alternative to conventional surgical orthotopic CRC mouse models for therapeutic interventions. Citation Format: Naresh Singh, Samantha Sharma, Kevin Van Der Jeught, Zhuolong Zhou, Xinna Zhang, Xiongbin Lu. A non-surgical method for developing a pre-clinical orthotopic mouse model for colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 119.
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Furst, Liam M., Enola M. Roussel, Ryan F. Leung, Ankita M. George, Sarah A. Best, James R. Whittle, Ron Firestein, Maree C. Faux i David D. Eisenstat. "The Landscape of Pediatric High-Grade Gliomas: The Virtues and Pitfalls of Pre-Clinical Models". Biology 13, nr 6 (7.06.2024): 424. http://dx.doi.org/10.3390/biology13060424.
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Pediatric high-grade gliomas (pHGG) are malignant and usually fatal central nervous system (CNS) WHO Grade 4 tumors. The majority of pHGG consist of diffuse midline gliomas (DMG), H3.3 or H3.1 K27 altered, or diffuse hemispheric gliomas (DHG) (H3.3 G34-mutant). Due to diffuse tumor infiltration of eloquent brain areas, especially for DMG, surgery has often been limited and chemotherapy has not been effective, leaving fractionated radiation to the involved field as the current standard of care. pHGG has only been classified as molecularly distinct from adult HGG since 2012 through Next-Generation sequencing approaches, which have shown pHGG to be epigenetically regulated and specific tumor sub-types to be representative of dysregulated differentiating cells. To translate discovery research into novel therapies, improved pre-clinical models that more adequately represent the tumor biology of pHGG are required. This review will summarize the molecular characteristics of different pHGG sub-types, with a specific focus on histone K27M mutations and the dysregulated gene expression profiles arising from these mutations. Current and emerging pre-clinical models for pHGG will be discussed, including commonly used patient-derived cell lines and in vivo modeling techniques, encompassing patient-derived xenograft murine models and genetically engineered mouse models (GEMMs). Lastly, emerging techniques to model CNS tumors within a human brain environment using brain organoids through co-culture will be explored. As models that more reliably represent pHGG continue to be developed, targetable biological and genetic vulnerabilities in the disease will be more rapidly identified, leading to better treatments and improved clinical outcomes.
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Muqbil, Irfana, Mahmoud Chaker, Amro Aboukameel, Ramzi M. Mohammad, Asfar S. Azmi i Radhakrishanan Ramchandren. "Pre-clinical anti-tumor activity of Bruton's Tyrosine Kinase inhibitor in Hodgkin's Lymphoma cellular and subcutaneous tumor model". Heliyon 5, nr 8 (sierpień 2019): e02290. http://dx.doi.org/10.1016/j.heliyon.2019.e02290.
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Gibson, Justin Tyler, Prabhakara Nagareddy i Lyse Norian. "Obesity-induced changes in baseline immune responses to pre-clinical breast cancer". Journal of Immunology 200, nr 1_Supplement (1.05.2018): 177.15. http://dx.doi.org/10.4049/jimmunol.200.supp.177.15.
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Abstract Obesity is known to increase morbidity and mortality in breast cancer patients; however, the immunological contributions to such changes remain incompletely understood. Our long-term goal is to investigate the broad impact of obesity on anti-tumor immunity, with a particular focus on understanding the mechanisms underlying obesity-induced immune alterations and how these alterations may influence the use of immunotherapeutics in breast cancer patients. For our studies, we utilized a diet-induced model of obesity (DIO) in which mice were fed either a high-fat or low-fat diet to generate DIO or age-matched lean controls, respectively, then challenged with the syngeneic E0771 mammary carcinoma cell line. Tumor outgrowth was quantified by caliper measurements, bioluminescent imaging (BLI) via firefly luciferase-expressing E0771 (E0771-fLUC) cells, and endpoint tumor weights. Immune populations were evaluated via multi-parameter flow cytometry. BLI revealed that obesity increases primary tumor outgrowth and significantly alters intra-tumoral immune populations. Changes include decreases in the frequency of CD4+ and CD8+ T cells, increases in granulocytic myeloid-derived suppressor cells (G-MDSCs) and dendritic cells (DCs), and a trending decrease in total CD45+ tumor infiltrating leukocytes. These alterations were specific to the tumor environment, as they were not present in the spleens of tumor-bearing mice. Collectively these data implicate obesity as a causal agent in impairing anti-tumor immune responses to murine breast cancer. Furthermore, they suggest several cellular candidates for mechanistic investigations into obesity-induced dysfunction in breast cancer immunity.
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Modzelewska, K., D. Picard, E. Boer, R. Miles, R. Jensen, T. Pysher, J. Schiffman, C. Jette, A. Huang i R. Stewart. "PM-12 * USING A ZEBRAFISH PEDIATRIC BRAIN TUMOR MODEL FOR PRE-CLINICAL DRUG SCREENING". Neuro-Oncology 17, suppl 3 (23.04.2015): iii33. http://dx.doi.org/10.1093/neuonc/nov061.134.
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Sypniewska, Roza K., Lieve Hoflack, David J. Bearss i Claudia Gravekamp. "Potential Mouse Tumor Model for Pre-Clinical Testing of Mage-Specific Breast Cancer Vaccines". Breast Cancer Research and Treatment 74, nr 3 (sierpień 2002): 221–33. http://dx.doi.org/10.1023/a:1016367104015.
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Kimler, Bruce F. "The 9L rat brain tumor model for pre-clinical investigation of radiation-chemotherapy interactions". Journal of Neuro-Oncology 20, nr 2 (1994): 103–9. http://dx.doi.org/10.1007/bf01052721.
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Gough, Michael J., Lauren Zebertavage, Shelly Bambina, Gwen Kramer, David J. Friedman, Victoria Troesch, Tiffany Blair, Jason R. Baird, Alejandro Alice i Marka R. Crittenden. "Anti-tumor immunity generated as an artifact of tumor implantation determines the response to immunotherapy in murine models". Journal of Immunology 200, nr 1_Supplement (1.05.2018): 178.17. http://dx.doi.org/10.4049/jimmunol.200.supp.178.17.
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Abstract Cancer cell lines grown in vitro and implanted into mice are a centerpiece of preclinical modeling. However, tumor implantation is an in vivo vaccination event that can impact tumor growth. Checkpoint inhibitors targeting PD1 or CTLA4 interactions are effective at unleashing suppressed pre-existing immunity in murine models, but do not generate new immune responses. We hypothesized that tumor control by checkpoint inhibitor immunotherapies was dependent on pre-existing immunity generated at tumor implantation. Using cancer cells engineered to express model antigens, spontaneous tumor models with defined trackable antigens, or unmodified cancer cells, we demonstrate that tumor implantation results in initial T cell mediated immunity. As the tumors progress, these cells become undetectable in the periphery and accumulate in the tumor, but do not prevent tumor progression. While tumors respond to checkpoint inhibitors administered closely following implantation, delayed administration results in a loss of efficacy. This efficacy can be recovered by the addition of radiation therapy to checkpoint inhibitors, permitting cure of established murine tumors that are not controlled by either therapy alone. However, blocking the immune response at tumor implantation using a range of approaches results in a complete loss of efficacy of tumor control by all therapies based around checkpoint inhibitors. We demonstrate an approach to ‘silently’ establish tumors in mice to test therapies that can initiate de novo immunity to tumors. These data have significant implications for current clinical attempts to use checkpoint inhibitors, which may not be a solution for patients without pre-existing immunity to their tumor.
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Ramachandran, Indu R., Cindy Lin, Tess Chase, Dmitry Gabrilovich i Yulia Nefedova. "A Novel Agent Tasquinimod Demonstrates a Potent Anti-Tumor Activity in Pre-Clinical Models of Multiple Myeloma". Blood 124, nr 21 (6.12.2014): 5729. http://dx.doi.org/10.1182/blood.v124.21.5729.5729.
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Abstract Multiple myeloma (MM) is a devastating bone marrow (BM) cancer characterized by clonal proliferation of plasma cells. Despite the emergence of novel therapeutics MM remains a fatal disease. The tumor microenvironment plays a critical role in promoting MM growth. We have recently demonstrated that a population of BM myeloid-derived suppressor cells is involved in regulation of MM progression. These cells abundantly produce the pro-inflammatory protein S100A9. Tasquinimod (ABR-215050, Active Biotech/IPSEN) is a quinoline-3-carboxamide derivative that binds to S100A9 and blocks its interaction with receptors TLR4, RAGE, and CD147. Here we investigated whether pharmacological inhibition of S100A9 with tasquinimod inhibits MM progression. A panel of MM murine (DP42) and human (RPMI-8226, H929, and U266) cell lines was cultured in the presence of tasquinimod or vehicle control and cell viability was determined using MTT assay. Treatment with tasquinimod did not affect MM cell viability. We then evaluated the anti-tumor effect of tasquinimod in vivo in a MM syngeneic model. In this model, murine MM DP42 cells are injected i.v., home to the BM, and grow as MM that closely resembles the human disease. On day 2 after tumor cell injection mice were randomly assigned to the treatment or control groups. Treatment group received tasquinimod at a dose of 30 mg/kg/day in drinking water for 28 days. We found that tasquinimod significantly improved survival of MM-bearing mice (p<0.005). To exclude a B and T-cell driven mechanism for tasquinimod’s pro-survival effect, we tested whether this compound has an anti-tumor effect in immunodeficient mice. A xenograft model of H929 human MM cells was established in SCID-beige mice. Treatment with tasquinimod significantly (p<0.0001) reduced tumor growth in this model. Similar results were obtained for RPMI-8226 human MM tumor. We next tested whether the anti-tumor effect of tasquinimod is indeed mediated through inhibition of S100A9. MM DP42 tumors were established in syngeneic S100A9 knockout (KO) mice. Treatment of S100A9KO mice with tasquinimod did not improve their survival from MM.These data suggest that the anti-MM effect of tasqunimod is indeed mediated through inhibition of S100A9. BM angiogenesis plays a critical role in MM progression. We evaluated whether inhibition of S100A9 with tasquinimod would block angiogenesis in MM. Immunohistochemical staining with anti-CD31 antibody demonstrated increased angiogenesis in the BM of MM-bearing mice as compared with control tumor-free mice, and treatment with tasquinimod significantly reduced angiogenesis (p<0.005). Serum collected from tasquinimod or vehicle control treated MM DP42-bearing mice two weeks after tumor cell inoculation, was subjected to Mouse Angiogenesis Proteome Profiler Antibody Array (R&D). A significant decrease in serum levels of pro-angiogenic factors including VEGF, FGF2, tissue factor, and endoglin was detected in tasquinimod-treated mice. Taken together, our data indicate that targeting S100A9 with tasquinimod results in strong anti-tumor effect in preclinical models of MM. This effect is associated with a reduced angiogenesis in the BM. Therefore, tasquinimod could be therapeutically beneficial for patients with MM. Disclosures No relevant conflicts of interest to declare.
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Haddad, Alexander, Jordan Spatz, Sara Collins, Matheus Pereira, Sabraj Gill, Megan Montoya, Polly Chuntova i in. "EXTH-17. LOCAL DELIVERY OF CYTOKINES AND SYNTHETIC IMMUNOMODULATORS INCREASES T CELL INFILTRATION AND SIGNIFICANTLY IMPROVES SURVIVAL IN A POORLY IMMUNOGENIC MODEL OF GLIOBLASTOMA". Neuro-Oncology 22, Supplement_2 (listopad 2020): ii90. http://dx.doi.org/10.1093/neuonc/noaa215.371.
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Abstract BACKGROUND Severe local and systemic immune suppression in glioblastoma (GBM) contributes to the failure of single-agent immunotherapies in clinical trials. In this study, we evaluated the efficacy of locally delivered combination immunotherapy in a poorly immunogenic murine GBM model. METHODS Immunomodulators used in these studies included: IL-15 and IL-7 (T cell activation), LIGHT (T cell tumor infiltration), FLT3L (dendritic cell maturation/proliferation), a surface T cell engager (T cell killing of tumor cells), and a bispecific PD-L1/T cell engager (T cell killing targeted to PD-L1-expressing cells). We first assessed T cell-mediated cytotoxicity in vitro against SB28, a poorly immunogenic murine GBM cell line, after expressing these immunomodulators in combination. Next, tumor growth inhibition in vivo was evaluated in syngeneic C57BL/6 mice, initially by establishment of intracranial tumors with pre-transduced SB28 cells, and subsequently by delivering these immunomodulators to pre-established naïve SB28 tumors using neural stem cells (NSCs) and retroviral replicating vectors (RRV). RESULTS SB28 cells transduced with immunomodulators activated dose-dependent T cell-mediated cytotoxicity in vitro. Mice with pre-transduced intracranial SB28 gliomas showed significantly longer survival (minimum survival: 60 days, long-term survival in 57% of mice) vs. control mice (median survival: 20 days) (p< 0.001), and significantly increased tumor infiltration of CD4+ and CD8+ T cells. NSC- and RRV-mediated immunomodulator delivery to pre-established SB28 gliomas also resulted in significantly increased survival of treated mice vs. controls (median survival: 31 days vs. 22 days, p< 0.001). Immunomodulator-treated tumors again showed significantly increased infiltration of CD4+ and CD8+ T cells, along with decreased CD11b+ cell infiltration. CONCLUSIONS A novel combination therapy for GBM immunotherapy activated T cell killing of SB28 GBM cells in vitro and achieved a significant survival benefit in vivo, associated with anti-tumor alterations to the GBM tumor microenvironment. Further studies to optimize the efficiency of combinatorial immunomodulator delivery are currently underway.
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Huang, Wentao, Zhifang Liu, Yifan Li, Heng Pan, Xia Qin, Da Fei i Runsheng Li. "Abstract 5907: Pre-clinical evaluation of a novel antibody drug conjugate (ADC) LM-317 targeting NaPi2b". Cancer Research 84, nr 6_Supplement (22.03.2024): 5907. http://dx.doi.org/10.1158/1538-7445.am2024-5907.
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Abstract Introduction: NaPi2b is a multi-transmembrane type II sodium-dependent phosphate transporters that regulates phosphate homeostasis in normal physiological condition [1]. It is highly expressed in ovarian cancer (OC), non-small-cell lung cancer (NSCLC), and papillary thyroid cancer, with limited expression in normal tissue, making it a promising target for antibody-drug conjugates (ADCs) [2,3]. LM-317 is a novel NaPi2b targeted humanized monoclonal antibody LM-117 conjugated to the next-generation topoisomerase I inhibitor LDX2 via a cleavable linker, with antibody-drug ratio of 8. Here, we present the preclinical in vivo and in vitro results of LM-317. Results: LM-317 is highly specific cross-reactive with rhesus monkeys, cynomolgus monkeys, mouse, and rat NaPi2b. Concentration-dependent cell binding and internalization effects of LM-317 were observed in human NaPi2b-expressing cells, and OC and NSCLC cells expressing NaPi2b, with EC-50 of 0.92 - 9.7 nM and 1.51 - 4.76 nM, respectively. The cytotoxicity effect of LM-317 in NaPi2b -positive tumor cells was superior to LM-117-DXD, with IC-50 of 0.002 - 0.52nM. The in vivo studies showed that 1 mg/kg of LM-317 almost completely eradicated tumors in the OVCAR-3 xenograft mice model of OC, and similar antitumor activity was observed in the NCI-H175-xenograft mice model of NSCLC at the dose of 3 mg/kg. Single dose of 6 mg/kg of LM-317 showed sustained tumor eradication in the NSCLC xenograft -mouse model. LM-317 also exhibited potent tumor regression in the PDX model of OC and NSCLC. The tumor growth inhibition (TGI) value was 80%-100% in OC and NSCLC PDX models with different expression degree of NaPi2b after treatment with LM-317. The antitumor activity of LM-317 in cell line- and PDX models of OC and NSLCL was comparable to those of LM-117-DXD. Conclusion: The novel ADC LM-317 targeting NaPi2b showed robust antitumor activity in vitro, and in the OC and NSCLC cell line derived models and PDX models. LM-317 could potentially provide therapeutic benefit to treat NaPi2b-positive tumors including OC and NSCLC in the future. Reference: 1.S. Banerjee et al. Cancer Treatment Reviews 112 (2023) 1024892.Finstad CL, Lloyd KO, Federici MG, et al. Clin. Cancer Res. 1997;3(8):1433-14423.Zhang et al. Tumor Biology July 2017: 1-7. Citation Format: Wentao Huang, Zhifang Liu, Yifan Li, Heng Pan, Xia Qin, Da Fei, Runsheng Li. Pre-clinical evaluation of a novel antibody drug conjugate (ADC) LM-317 targeting NaPi2b [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5907.
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Lindberg, James M., Dustin M. Walters, Sara J. Adair, Catharine R. Cowan, Jayme B. Stokes, Cheryl A. Borgman, Edward B. Stelow i in. "Acquired resistance to combination therapy with lapatinib and MEK 1/2 inhibitor GSK1120212 in an in vivo murine model of pancreatic cancer." Journal of Clinical Oncology 30, nr 4_suppl (1.02.2012): 208. http://dx.doi.org/10.1200/jco.2012.30.4_suppl.208.
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208 Background: Mutations of the oncogene KRAS and activation of cell-surface receptor tyrosine kinases are important and preserved mechanisms of tumorgenicity in pancreatic cancer. Dual inhibition of the downstream KRAS effector MEK 1/2 and tyrosine kinases EGFR and Her2 results in effective inhibition of patient-derived tumor growth in a murine orthotopic transplantation model. Because combinatorial therapies are moving rapidly into clinical trials, we sought to develop a model of acquired tumor resistance to this combination therapy. Methods: Patient-derived pancreatic tumor xenografts MAD 09-366 (KRAS mut), MAD 08-608 (KRAS mut) and MAD 08-738 (KRAS wt) were implanted orthotopically in nude mice and treated with combination lapatinib (EGFR/Her2 inhibitor) and GSK1120212 (MEK1/2 inhibitor) and tumor volume was measured by MRI. Following 4-6wks of treatment, tumors were reimplanted in second and third generation mice and retreated. Tumors were evaluated by phospho-RTK and phospho-MAPKinase array. Results: Acquired resistance developed in all three tumor xenografts. Treated tumors demonstrated a relative volume decrease in the original (F0) generation. All second re-implantation (F2) tumors, demonstrated relative tumor volume increases despite treatment. A comparison of pre-treatment mean tumor volumes showed a significant decrease in tumor size from the F0 to F2 generations suggesting selection for slower growing tumors. Array data demonstrated increased activation of FGFR1, VEGFR1/3, GSK-3β, p38, and Akt in resistant tumors as compared to their pre-treatment controls. These may represent mechanisms of tumor resistance and warrant further investigation. Conclusions: Repeated tumor exposure in vivo to combination treatment with GSK1120212 and lapatinib was used to develop a preclinical, orthotopic murine model of acquired drug resistance in patient-derived pancreatic cancers. This model provides the opportunity to define the mechanism of resistance in an appropriate tumor microenvironment and to develop alternative strategies for treating tumors resistant to this and other emerging therapies.
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Hagar, A., i J. Aponte Serrano. "P05.02 An integrated virtual tissue platform for incorporating exercise oncology into immunotherapy". Journal for ImmunoTherapy of Cancer 8, Suppl 2 (październik 2020): A41.1—A41. http://dx.doi.org/10.1136/jitc-2020-itoc7.79.
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We introduce a novel in silico platform for simulating solid tumor growth and anti-tumor immune response. We present the model, test the sensitivity and robustness of its parameters, and calibrate it with pre-clinical and clinical data from exercise oncology experiments which offer a natural biological backdrop for modulation of anti-tumor immune response. We then perform two virtual experiments with the model that demonstrate its usefulness in guiding pre-clinical and clinical studies on immunotherapy. The first virtual experiment probes the intricate dynamics in the tumor microenvironment between the tumor and the infiltrating immune cells. Such dynamics is difficult to probe during a pre-clinical study as it requires significant of redundancy in lab animals and is time and labor intensive. The result is a time series of spatiotemporal observational ‘windows’ into the tumor microenvironment that can serve as a platform to test several mechanistic hypotheses on the role and dynamics of different immune cells in ant-tumor immune response. The second virtual experiment shows how dosage and frequency of immunotherapy drugs can be optimized based on the aerobic fitness of the patient, so that possible adverse side effects of the treatment can be minimized.Disclosure InformationA. Hagar: None. J. Aponte Serrano: None.
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Bownes, Laura, Raoud Marayati, Colin Quinn, Andee Beierle, Sara Hutchins, Janet Julson, Michael Erwin i in. "Pre-Clinical Study Evaluating Novel Protein Phosphatase 2A Activators as Therapeutics for Neuroblastoma". Cancers 14, nr 8 (13.04.2022): 1952. http://dx.doi.org/10.3390/cancers14081952.
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Background: Protein phosphatase 2A (PP2A) functions as an inhibitor of cancer cell proliferation, and its tumor suppressor function is attenuated in many cancers. Previous studies utilized FTY720, an immunomodulating compound known to activate PP2A, and demonstrated a decrease in the malignant phenotype in neuroblastoma. We wished to investigate the effects of two novel PP2A activators, ATUX-792 (792) and DBK-1154 (1154). Methods: Long-term passage neuroblastoma cell lines and human neuroblastoma patient-derived xenograft (PDX) cells were used. Cells were treated with 792 or 1154, and viability, proliferation, and motility were examined. The effect on tumor growth was investigated using a murine flank tumor model. Results: Treatment with 792 or 1154 resulted in PP2A activation, decreased cell survival, proliferation, and motility in neuroblastoma cells. Immunoblotting revealed a decrease in MYCN protein expression with increasing concentrations of 792 and 1154. Treatment with 792 led to tumor necrosis and decreased tumor growth in vivo. Conclusions: PP2A activation with 792 or 1154 decreased survival, proliferation, and motility of neuroblastoma in vitro and tumor growth in vivo. Both compounds resulted in decreased expression of the oncogenic protein MYCN. These findings indicate a potential therapeutic role for these novel PP2A activators in neuroblastoma.
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Chen, Chao-Yi, Yi-Feng Yang, Paul C. Wang, Liang Shan, Stephen Lin, Po-Jung Chen, Yi-Jung Chen i in. "Simvastatin Attenuated Tumor Growth in Different Pancreatic Tumor Animal Models". Pharmaceuticals 15, nr 11 (14.11.2022): 1408. http://dx.doi.org/10.3390/ph15111408.
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Newly diagnosed pancreatic cancer increases year by year, while the prognosis of pancreatic cancer has not been very good. Statin drugs were found to have protective effects against a variety of cancers, but their association with pancreatic cancer remains to be clarified. This study used different pancreatic cancer cell lines and in different animal models to confirm the relationship between simvastatin and pancreatic cancer. Flow cytometry and luciferase-based bioluminescent images were used to investigate the cell cycle and tumor growth changes under simvastatin treatment. Simvastatin decreased the MIA PaCa-2 cells, PANC-1 cells, and BxPC-3 cell viability significantly and may arrest the cell cycle in the G0 phase. During in vivo study, subcutaneously implanted simvastatin pre-treated pancreatic cancer cells and intraperitoneally treated simvastatin continuously demonstrated a slower tumor growth rate and decreased the tumor/body weight ratio significantly. In intravenous implant models, implanted simvastatin-pre-treated BxPC-3 cells and cells treated along with simvastatin significantly decreased the tumor growth curve. Implanting the simvastatin-pre-treated pancreatic cells in the subcutaneous model showed better growth inhibition than the intravenous model. These results suggest simvastatin treatment may relate to different signaling pathways in local growth and metastasis. Pancreatic cancer cells presented different growth patterns in different animal-induced models, which could be important for clinical reference when it comes to the relationship of long-term statin use and pancreatic cancer.
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Nayyar, Naema, Magali de Sauvage, Emily Sullivan, Jane Chuprin, Erika Yamazawa, Brehm Michael i Priscilla Brastianos. "DDDR-02. CDK4/6 INHIBITION WITH ABEMACICLIB SENSITIZES INTRACRANIAL TUMORS TO CHECKPOINT BLOCKADE IN PRE-CLINICAL MODELS OF BRAIN METASTASIS". Neuro-Oncology 24, Supplement_7 (1.11.2022): vii98. http://dx.doi.org/10.1093/neuonc/noac209.367.
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Abstract Although immune checkpoint inhibitors (ICI) have become a useful tool in the management of central nervous system (CNS) metastases, only a subset of patients experience durable clinical responses and prognosis continues to remain poor. In particular, the role of ICI for CNS metastases from breast cancer has also not been adequately explored. CDK4/6 inhibition has been shown to sensitize extracranial tumors to ICI, and we previously reported intracranial efficacy of combination CDK4/6 inhibition with abemaciclib and anti-PD-1 in preclinical models of melanoma brain metastasis. We have now investigated this combination strategy further in a mouse model of triple negative breast cancer brain metastasis. 4T1 mammary carcinoma cells were first injected into the mammary fat pad and then intracranially 3 days later. While single agent anti-PD-1 antibody or abemaciclib were both ineffective at reducing tumor growth, we found a significant reduction in intracranial and extracranial tumor burden when abemaciclib was combined with anti-PD-1. Immunofluorescence for CD8 and CD3 revealed a significant increase in tumor-infiltrating CD8+ T cells with abemaciclib monotherapy as well as combination therapy in intracranial 4T1 tumors. We observed a similar increase in intracranial tumor-infiltrating CD8+ T cells in two melanoma brain metastasis models, YUMM1.7 and B16-F10, following combination therapy. We conclude that combination with abemaciclib can improve intracranial efficacy of ICI by driving CD8+ T cell infiltration into intracranial tumors. Future work will focus on investigating additional treatment-induced changes in the tumor immune microenvironment and dissecting the effect of CDK4/6 inhibition on T cell activation and function.
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Sauvage, Delphine, Manon Bosseler, Elodie Viry, Georgia Kanli, Anais Oudin, Guy Berchem, Olivier Keunen i Bassam Janji. "The BET Protein Inhibitor JQ1 Decreases Hypoxia and Improves the Therapeutic Benefit of Anti-PD-1 in a High-Risk Neuroblastoma Mouse Model". Cells 11, nr 18 (6.09.2022): 2783. http://dx.doi.org/10.3390/cells11182783.
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Anti-programmed death 1 (PD-1) is a revolutionary treatment for many cancers. The response to anti-PD-1 relies on several properties of tumor and immune cells, including the expression of PD-L1 and PD-1. Despite the impressive clinical benefit achieved with anti-PD-1 in several cancers in adults, the use of this therapy for high-risk neuroblastoma remains modest. Here, we evaluated the therapeutic benefit of anti-PD-1 in combination with JQ1 in a highly relevant TH-MYCN neuroblastoma transgenic mouse model. JQ1 is a small molecule inhibitor of the extra-terminal domain (BET) family of bromodomain proteins, competitively binding to bromodomains. Using several neuroblastoma cell lines in vitro, we showed that JQ1 inhibited hypoxia-dependent induction of HIF-1α and decreased the expression of the well-known HIF-1α downstream target gene CA9. Using MRI relaxometry performed on TH-MYCN tumor-bearing mice, we showed that JQ1 decreases R2* in tumors, a parameter associated with intra-tumor hypoxia in pre-clinical settings. Decreasing hypoxia by JQ1 was associated with improved blood vessel quality and integrity, as revealed by CD31 and αSMA staining on tumor sections. By analyzing the immune landscape of TH-MYCN tumors in mice, we found that JQ1 had no major impact on infiltrating immune cells into the tumor microenvironment but significantly increased the percentage of CD8+ PD-1+, conventional CD4+ PD-1+, and Treg PD-1+ cells. While anti-PD-1 monotherapy did not affect TH-MYCN tumor growth, we showed that combinatorial therapy associating JQ1 significantly decreased the tumor volume and improved the therapeutic benefit of anti-PD-1. This study provided the pre-clinical proof of concept needed to establish a new combination immunotherapy approach that may create tremendous enthusiasm for treating high-risk childhood neuroblastoma.
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McKenna, Mary K., Amanda Rosewell-Shaw i Masataka Suzuki. "Modeling the Efficacy of Oncolytic Adenoviruses In Vitro and In Vivo: Current and Future Perspectives". Cancers 12, nr 3 (7.03.2020): 619. http://dx.doi.org/10.3390/cancers12030619.
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Oncolytic adenoviruses (OAd) selectively target and lyse tumor cells and enhance anti- tumor immune responses. OAds have been used as promising cancer gene therapies for many years and there are a multitude of encouraging pre-clinical studies. However, translating OAd therapies to the clinic has had limited success, in part due to the lack of realistic pre-clinical models to rigorously test the efficacy of OAds. Solid tumors have a heterogenous and hostile microenvironment that provides many barriers to OAd treatment, including structural and immunosuppressive components that cannot be modeled in two-dimensional tissue culture. To replicate these characteristics and bridge the gap between pre-clinical and clinical success, studies must test OAd therapy in three-dimensional culture and animal models. This review focuses on current methods to test OAd efficacy in vitro and in vivo and the development of new model systems to test both oncolysis and immune stimulatory components of oncolytic adenovirotherapy.
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Connor, Kate, Emer Conroy, Kieron White, Liam Shiels, William Gallagher, Simon Keek, Abdalla Ibrahim i in. "EXTH-30. EXPANDING THE UTILITY OF PRE-CLINICAL CONTRAST ENHANCED CT (CE-CT) FOR TUMOR DETECTION IN ORTHOTOPIC GBM MODELS USING RADIOMICS". Neuro-Oncology 22, Supplement_2 (listopad 2020): ii93. http://dx.doi.org/10.1093/neuonc/noaa215.384.
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Abstract Despite magnetic resonance imaging (MRI) being the gold-standard imaging modality in the glioblastoma (GBM) setting, the availability of rodent MRI scanners is relatively limited. CT is a clinically relevant alternative which is more widely available in the pre-clinic. To study the utility of contrast-enhanced (CE)-CT in GBM xenograft modelling, we optimized CT protocols on two instruments (IVIS-SPECTRUM-CT;TRIUMPH-PET/CT) with/without delivery of contrast. As radiomics analysis may facilitate earlier detection of tumors by CT alone, allowing for deeper analyses of tumor characteristics, we established a radiomic pipeline for extraction and selection of tumor specific CT-derived radiomic features (inc. first order statistics/texture features). U87R-Luc2 GBM cells were implanted orthotopically into NOD/SCID mice (n=25) and tumor growth monitored via weekly BLI. Concurrently mice underwent four rounds of CE-CT (IV iomeprol/iopamidol; 50kV-scan). N=45 CE-CT images were semi-automatically delineated and radiomic features were extracted (Pyradiomics 2.2.0) at each imaging timepoint. Differences between normal and tumor tissue were analyzed using recursive selection. Using either CT instrument/contrast, tumors > 0.4cm3 were not detectable until week-9 post-implantation. Radiomic analysis identified three features (waveletHHH_firstorder_Median, original_glcm_Correlation and waveletLHL_firstorder_Median) at week-3 and -6 which may be early indicators of tumor presence. These features are now being assessed in CE-CT scans collected pre- and post-temozolomide treatment in a syngeneic model of mesenchymal GBM. Nevertheless, BLI is significantly more sensitive than CE-CT (either visually or using radiomic-enhanced CT feature extraction) with luciferase-positive tumors detectable at week-1. In conclusion, U87R-Luc2 tumors > 0.4cm3 are only detectable by Week-8 using CE-CT and either CT instrument studied. Nevertheless, radiomic analysis has defined features which may allow for earlier tumor detection at Week-3, thus expanding the utility of CT in the preclinical setting. Overall, this work supports the discovery of putative prognostic pre-clinical CT-derived radiomic signatures which may ultimately be assessed as early disease markers in patient datasets.
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Severe, Nicolas, Amanda Facklam, Liz McMichael, Biplab Das, Sara Lewandowski, Justin Trickett, Liyang Diao i in. "Abstract 742: PYX-201, a stroma-targeting ADC composed of an anti-EDB+FN antibody conjugated to Auristatin0101, demonstrates strong anti-tumor efficacy across multiple human cancer indications in pre-clinical PDX tumor models". Cancer Research 84, nr 6_Supplement (22.03.2024): 742. http://dx.doi.org/10.1158/1538-7445.am2024-742.
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Abstract Stroma is crucial to support solid tumor growth, metastasis and resistance to treatment. While most antibody-drug conjugates (ADCs) directly bind to cancer cells, PYX-201, an investigational drug, is designed to target tumor stroma by binding to the extra-domain B splice variant of fibronectin (EDB+FN), a matrix protein abundantly expressed in the tumor microenvironment of many solid tumors with absent or low expression in normal adult tissues. In vitro studies demonstrated PYX-201 was strongly cytotoxic to EDB+FN positive Caki2 cells, but not to EDB+FN negative HT29 cells. In addition, PYX-201 was 30-times more potent than a non-targeted ADC control, demonstrating PYX-201 cytotoxic effects were EDB+FN dependent. Furthermore, when Caki2 and HT29-luciferase cancer cells were co-cultured, the luciferase activity was used to quantify the amount of EDB+FN negative HT29 cells only. Interestingly, PYX-201 was able to kill EDB+FN negative cancer cells in a co-culture assay as shown by a decrease in luciferase activity, demonstrating PYX-201 bystander activity. Pre-clinical mouse model studies were conducted to evaluate PYX-201 anti-tumor efficacy and pharmacokinetic (PK) properties. First, a comprehensive patient-derived xenograft (PDX) mouse model trial was designed to evaluate the anti-tumor efficacy of PYX-201. To fully represent the diversity and characteristics of human tumors, PDX models were pre-selected from ten solid tumor indications based on different levels of EDB+FN protein expression and stromal density. PYX-201 (Q4D × 4 at 3mg/kg) was well tolerated, and strong anti-tumor responses (% Tumor Growth Inhibition [TGI] >90%) were observed in PDX models across various cancer indications. Potential correlations between EDB+FN protein expression with anti-tumor activity will be evaluated. Remarkably, long-term anti-tumor efficacy of PYX-201 was observed as tumors did not relapse even after >100 days in a breast cancer PDX model. Additionally, plasma samples were analyzed from a cell line derived xenograft mouse model after a single dose of PYX-201 to determine its PK profile. At 3 mg/kg, the maximum concentration (Cmax) was 28.1 μg/mL, area under the curve (AUC) was 1,732.7 h*μg/mL, with a low clearance of 1.5 mL/h/kg, and the half-life of the mAb from PYX-201 was calculated at 81.2 h. These PK parameters were associated with strong PYX-201 anti-tumor efficacy (% TGI >90%) in the H1975 xenograft model. Altogether, PYX-201 was well tolerated and demonstrated strong anti-tumor efficacy in a variety of pre-clinical human PDX models. PYX-201 is a promising and innovative ADC which is currently under investigation in a Phase I clinical trial (NCT05720117). Citation Format: Nicolas Severe, Amanda Facklam, Liz McMichael, Biplab Das, Sara Lewandowski, Justin Trickett, Liyang Diao, Chengfeng Merriman, Chuan Shen, Jianwen Feng, Shawn Harriman, Marsha Crochiere, Philipp Steiner, Jan Pinkas. PYX-201, a stroma-targeting ADC composed of an anti-EDB+FN antibody conjugated to Auristatin0101, demonstrates strong anti-tumor efficacy across multiple human cancer indications in pre-clinical PDX tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 742.
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Pishali Bejestani, Elham, Marc Cartellieri, Ralf Bergmann, Armin Ehninger, Simon Loff, Michael Kramer, Johannes Spehr i in. "Characterization of a switchable chimeric antigen receptor platform in a pre-clinical solid tumor model". OncoImmunology 6, nr 10 (20.06.2017): e1342909. http://dx.doi.org/10.1080/2162402x.2017.1342909.
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Shelton, Laura M., Purna Mukherjee, Leanne C. Huysentruyt, Ivan Urits, Joshua A. Rosenberg i Thomas N. Seyfried. "A novel pre-clinical in vivo mouse model for malignant brain tumor growth and invasion". Journal of Neuro-Oncology 99, nr 2 (13.01.2010): 165–76. http://dx.doi.org/10.1007/s11060-010-0115-y.
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Han, Chenglong, Jie Shen, Hao Wang, Lixia Yu, Xiaoping Qian, Baorui Liu i Wenxian Guan. "Personalized primary tumor xenograft model established for the pre-clinical trial to guide postoperative chemotherapy". Medical Hypotheses 79, nr 6 (grudzień 2012): 705–8. http://dx.doi.org/10.1016/j.mehy.2012.06.009.
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Tatalick, Laurie, Kevin Yu, Justin Huard, Justin Huard, Marianne Riley, Ryan Swanson i Carl Walkey. "898 Intratumoral administration of NL-201, an alpha-independent IL-2/15 receptor agonist, inhibits the growth of both injected and uninjected tumors in preclinical models". Journal for ImmunoTherapy of Cancer 9, Suppl 2 (listopad 2021): A942. http://dx.doi.org/10.1136/jitc-2021-sitc2021.898.
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BackgroundNL-201 is a potent, selective, and long-acting computationally designed alpha-independent agonist of the IL-2 and IL-15 receptors that is being developed as an immunotherapy for cancer. Intravenous NL-201 administration is active in numerous pre-clinical tumor models. Here, we report data demonstrating favorable tolerability, pharmacokinetics, and antitumor activity of NL-201 after intratumoral (IT) administration in syngeneic murine tumor models.MethodsMice were implanted with syngeneic colorectal tumors in a single tumor (right flank) or bilateral tumor model (right and left flank). Once tumors were established, mice were randomized to receive IT or intravenous (IV) NL-201, or IV vehicle as control. Tumor volumes (mm3) and bodyweights were measured twice weekly, and mice were monitored for abnormal clinical signs. Blood samples were collected at pre-specified time points, and serum was analyzed for NL-201 concentration using a ligand-binding assay. Toxicokinetic parameters were determined using a non-compartmental model consistent with the IT and IV routes. Animals were sacrificed if tumor sizes reached 2000 mm3 or if body weight loss was >20%. In the bilateral tumor models, surviving tumor-free animals from both the IT and IV treatment arms were rechallenged with tumor cells after a washout period to assess antitumor immune responses.ResultsIT NL-201 demonstrated dose-dependent antitumor activity and was well tolerated based on a lack of clinical observations and body weight changes at doses up to 10 µg/mouse. Comparable antitumor activity was observed in mice receiving 3 μg/mouse NL-201 via IV or IT routes, but reduced systemic exposure and better tolerability were observed after IT administration. The estimated absolute bioavailability following 3 µg/mouse IT administration was 19.4%–66.5% of the NL-201 IV exposure. In the bilateral tumor model, IT NL-201 resulted in significant antitumor activity in both the treated and untreated tumors. Surviving animals from both IT and IV groups in which the initial tumors regressed rejected engraftment of the same tumor cell line upon rechallenge.ConclusionsIT NL-201 administration resulted in dose-dependent antitumor activity in both injected and uninjected tumors while demonstrating markedly reduced systemic exposure and improved tolerability compared to systemic administration at equivalent dose levels. Rechallenged animals failed to develop tumors, demonstrating durable tumor-specific immunity after IT NL-201 treatment. Results of this study support planned clinical investigation of IT NL-201 administration to increase NL-201 concentrations in accessible lesions.Ethics ApprovalThis study was approved by the Institutional Animal Care and Use Committee (IACUC) of CrownBio.
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Roth, Daniel, Marcella Safi, Oskar Vilhelmsson Timmermand, Evangelia Sereti, Malwina Molendowska, Michael Gottschalk, Anders Bjartell, Crister Ceberg, Filip Szczepankiewicz i Joanna Strand. "Evaluation of superficial xenograft volume estimation by ultrasound and caliper against MRI in a longitudinal pre-clinical radiotherapeutic setting". PLOS ONE 19, nr 7 (25.07.2024): e0307558. http://dx.doi.org/10.1371/journal.pone.0307558.
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Background Accurate tumor volume estimation is important for evaluating the response to radionuclide therapy and external beam radiotherapy as well as to other pharmaceuticals. A common method for monitoring the growth of subcutaneous tumors in pre-clinical models and assessing the treatment response is to measure the tumor length and width by external calipers to estimate its volume. This procedure relies on an assumption of a spheroidal tumor shape wherein the tumor depth equals the width and can yield considerably inaccuracies. Ultrasound imaging is a non-invasive technique that can measure all three axes of the tumor and might be an alternative to caliper measurement with potentially greater accuracy and comparable ease-of-use and throughput. Both 2D and 3D ultrasound imaging are possible, the former offering short scan times without the need for anesthesia and heating—valuable factors for longitudinal studies in large animal cohorts. Nevertheless, tumor volume estimation accuracy by 2D ultrasound imaging has seen limited investigation. In this study we have evaluated the accuracy of tumor volume estimation by caliper and 2D ultrasound with comparisons to reference measurements by magnetic resonance imaging (MRI) in a pre-clinical model of prostate cancer treated with either external beam radiotherapy, radionuclide therapy, or no treatment. Results Tumor volumes were measured longitudinally in 29 mice by caliper, ultrasound, and MRI before and after external beam radiotherapy, [177Lu]Lu-PSMA-617 radionuclide therapy, or no treatment. Caliper measurements had a marked bias, overestimating the tumor volumes by a median of 150% compared to MRI. Ultrasound measurements were markedly more accurate, with a median bias of -21% compared to MRI. Conclusion Ultrasound imaging is a reliable and accurate method for tumor volume estimation in pre-clinical models of radiotherapy, whereas caliper measurements are prone to overestimation.
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McCully, Cynthia Lester, Katherine Warren, Sara Zimmerman, Cody Peer, Cruz Garcia Rafael, Joshua Kramer, Matthew Breed, William Douglas Figg, Nathalie Agar i Brigitte Widemann. "EXTH-64. COMPARISON OF PANOBINOSTAT CSF PENETRATION WITH CNS PENETRATION FOLLOWING SYSTEMIC ADMINISTRATION IN A PRE-CLINICAL NON-HUMAN PRIMATE MODEL". Neuro-Oncology 23, Supplement_6 (2.11.2021): vi177—vi178. http://dx.doi.org/10.1093/neuonc/noab196.703.
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Abstract Targeted therapies developed for diffuse midline gliomas (DMG) expressing H3K27M have focused on histone deacetylase inhibitors (HDACi). High-throughput drug screening with patient derived DMG cell lines identified the HDACi panobinostat as a prominent clinical agent as well as pre-clinical studies with orthotopic mouse tumors models proving efficacious. Diametrically there is a pronounced lack of measurable panobinostat CSF concentrations in a non-human primate (NHP) non-tumor bearing pre-clinical model and in pediatric brain tumor patients. Notwithstanding, adult and pediatric glioma clinical trials and clinical observation with panobinostat alone or in combination have demonstrated minor responses. Pharmacokinetic models utilize the premise that CSF drug penetration is a surrogate of CNS drug penetration. However, the direct correlation between CSF and CNS drug levels is undefined especially in lieu of geographic CNS extracellular fluid drug variability previously demonstrated in the same NHP pre-clinical model. Utilizing the same NHP model, this study sought to compare panobinostat CSF penetration to CNS penetration via analysis of homogenized normal cerebrum, cerebellum, and brainstem tissue utilizing LC-MS/MS. METHODS: Panobinostat was administered orally as a single dose to three non-human primates. Pre panobinostat plasma and CSF were collected. Following panobinostat administration (1-hr Tmax) CSF, cerebrum, cerebellum, and brain stem tissue were collected as well as plasma to confirm the presence of panobinostat. Tissue slices were individually homogenized and panobinostat extracted via protein precipitation. Plasma, CSF, and tissue panobinostat concentrations were quantified using a LC-MS/MS assay. The lower limit of quantitation (LLOQ) for plasma-0.1 ng/ml, CSF-0.5 ng/ml, and tissue-10.0 pg/mg. RESULTS: Panobinostat was quantifiable in plasma (n=2) at the 1 hour (20.033 ng/mL and 0.153 ng/mL). CSF and CNS tissue samples were below the LLOQ for panobinostat in all samples. CONCLUSIONS: Panobinostat was not measurable from CSF and homogenized brain tissue in a non-tumor bearing NHP model at 1-hour post-administration using LC-MS/MS.
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Patton, John, Emily Smith, Zahary Smith, Andrew Stiff, A. Douglas Kinghorn, Yiping Yang, Michael R. Grever, David M. Lucas i Robert Baiocchi. "Characterization of Cytotoxic Macrophages in a Pre-Clinical Model of Epstein-Barr Virus (EBV)-Driven Lymphoproliferative Disease". Blood 138, Supplement 1 (5.11.2021): 3502. http://dx.doi.org/10.1182/blood-2021-154161.
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Abstract Epstein-Barr Virus (EBV) is an oncogenic herpes virus associated with the development of malignancies associated with poor outcomes. Current treatments lead to further immune suppression, increasing the risk of EBV reactivation and other opportunistic infections. Strategies aimed at reversing the immune-suppressive microenvironment are likely to result in more durable responses while avoiding deleterious effects of chemotherapy. It is well-established that macrophages play an important role in inhibiting the anti-tumor response as evidenced by poor prognosis associated with increasing tumor-associated macrophage (TAM) density or lower ratio of cytotoxic T lymphocytes. Here we describe a pre-clinical model showing the expansion of cytotoxic TAMs and potential mechanisms to prevent this immunosuppressive environment. To assess soluble factors produced by the interaction of tumor on immune effector cells, we used a co-culture (CoCx) system of EBV-transformed human B cell lymphoblastoid cell lines (LCL) cultured with autologous peripheral blood mononuclear cells (PBMC). Serum-free medium collected after 48 hrs showed increased myeloid-associated factors which were absent from either the LCL or PBMC cultures, suggesting the interaction of tumor cells with immune effectors was leading to the production of chemokines known to attract myeloid cells. When purified autologous CD14+ monocytes were incubated in the presence of CoCx conditioned medium (CM) they generated proliferative foci that were absent in the LCL or PBMC CM alone. To better understand which cellular subsets were necessary for the release of these soluble factors, immune subsets were removed from PBMC prior to incubation with LCL or purified and incubated with LCL. We found that T cells, (CD8+ and CD4+), when incubated in the presence of LCL were necessary and sufficient to stimulate the proliferation of myeloid cells. CD56+, CD14+, or CD19+ subsets within the CM did not appear to contribute to the proliferation of purified myeloid cells. We next used flow cytometry to characterize the monocyte-derived population that expanded when introduced to CoCx CM. We again isolated autologous CD14+ monocytes from PMBC and incubated them for 6 days with CoCx CM followed by immunophenotyping. The monocyte-derived population retained CD14 and CD11b in addition to showing pronounced increases in both canonical M1 and M2 macrophage markers (HLA-DR, and CD163 respectively), and PD-L1, indicating activation consistent with a TAM phenotype. To characterize the functional consequence of this cell population, CoCx CM-derived macrophages were incubated with autologous T cells that were either activated non-specifically with anti-CD3/C28 or left inactivated. Surprisingly, we noted a marked decrease in viable activated T cells (both CD4+ and CD8+) when exposed to conditioned macrophages. However, the inactivated T cell populations were only mildly effected. Together, with previously described experiments, this suggests a mechanism by which exposure of T cells to EBV+ lymphoblastic tumor lines results in cytokine release, polarizing monocytes to TAMs that, in turn, exhibit cytotoxic activity to tumor-specific T cells. The precise mechanism of cytotoxicity is under investigation. We previously reported the eIF4A translational inhibitor silvestrol potentiated a potent immune-mediated anti-tumor response against EBV-driven lymphoma mainly by promoting expansion and activity of EBV-specific cytotoxic T cells. We next questioned if macrophages were important to this mechanism. We found that with silvestrol, when added to CoCx, the resultant CM did not drive the proliferation of TAMs, and Immunophenotype of CoCx showed silvestrol treatment to result in the ablation of CD14+ cells from culture. Interrogation by transcriptome analysis indicated a potential role of aryl hydrocarbon receptor (AhR). Protein analysis by western blotting indicated an increase of AhR in isolated monocytes when exposed to CoCx CM, which was abrogated by addition of silvestrol. Together these results suggest AhR may play a role in the polarization of macrophages within the tumor microenvironment leading to elimination of tumor-specific T cells. While full mechanistic characterization is ongoing, these preliminary results provide a potentially novel approach to modulate tumor specific immunity in this challenging group of EBV-related malignancies. Disclosures Baiocchi: Prelude Therapeutics: Consultancy; viracta: Consultancy, Current holder of stock options in a privately-held company; Codiak Biosciences: Research Funding; Atara Biotherapeutics: Consultancy.
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Joseph, Sydney C., Samson Eugin Simon, Margaret S. Bohm, Minjeong Kim, Madeline E. Pye, Boston W. Simmons, Dillon G. Graves i in. "FXR Agonism with Bile Acid Mimetic Reduces Pre-Clinical Triple-Negative Breast Cancer Burden". Cancers 16, nr 7 (30.03.2024): 1368. http://dx.doi.org/10.3390/cancers16071368.
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Bariatric surgery is associated with improved outcomes for several cancers, including breast cancer (BC), although the mechanisms mediating this protection are unknown. We hypothesized that elevated bile acid pools detected after bariatric surgery may be factors that contribute to improved BC outcomes. Patients with greater expression of the bile acid receptor FXR displayed improved survival in specific aggressive BC subtypes. FXR is a nuclear hormone receptor activated by primary bile acids. Therefore, we posited that activating FXR using an established FDA-approved agonist would induce anticancer effects. Using in vivo and in vitro approaches, we determined the anti-tumor potential of bile acid receptor agonism. Indeed, FXR agonism by the bile acid mimetic known commercially as Ocaliva (“OCA”), or Obeticholic acid (INT-747), significantly reduced BC progression and overall tumor burden in a pre-clinical model. The transcriptomic analysis of tumors in mice subjected to OCA treatment revealed differential gene expression patterns compared to vehicle controls. Notably, there was a significant down-regulation of the oncogenic transcription factor MAX (MYC-associated factor X), which interacts with the oncogene MYC. Gene set enrichment analysis (GSEA) further demonstrated a statistically significant downregulation of the Hallmark MYC-related gene set (MYC Target V1) following OCA treatment. In human and murine BC analyses in vitro, agonism of FXR significantly and dose-dependently inhibited proliferation, migration, and viability. In contrast, the synthetic agonism of another common bile acid receptor, the G protein-coupled bile acid receptor TGR5 (GPBAR1) which is mainly activated by secondary bile acids, failed to significantly alter cancer cell dynamics. In conclusion, agonism of FXR by primary bile acid memetic OCA yields potent anti-tumor effects potentially through inhibition of proliferation and migration and reduced cell viability. These findings suggest that FXR is a tumor suppressor gene with a high potential for use in personalized therapeutic strategies for individuals with BC.