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Using a rhabdomyosarcoma patient-derived xenograft to examine precision medicine approaches and model acquired resistance

ABSTRACT: Original patient tumor is directly implanted in mice xenografts. Tumor is propagated to multiple mice for conduct of 6 arm treatment trials and control. Therapies are selected based on T0 and F0 genomic profiles. ICE-T refractory tumor are implanted and additional 6 arm treatment trial and control conducted based on genomic profiles of F2 generation mice to suggested therapies

ORGANISM(S): Homo sapiens

PROVIDER: GSE51130 | GEO | 2014/07/22

SECONDARY ACCESSION(S): PRJNA221341

REPOSITORIES: GEO

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Project description:Cellular senescence is a common outcome of many standard-of-care cytostatic and cytotoxic cancer therapies. Whereas is some contexts therapy-induced senescence can drive tumor growth suppression and anti-tumor immune surveillance through the senescence-associated secretory phenotype (SASP), in others it can promote tumor progression, metastatic dissemination, and immune suppression. How the heterogeneous senescent phenotypes induced by different classes of cancer therapies directly impact tumor and immune responses, and whether understanding those mechanisms could be leveraged for effective combination therapies, has yet to be evaluated in a systematic manner. Here we compared the effects of various CDK inhibitor combinations, chemotherapies, and other DNA damaging agents commonly used in the treatment of advanced prostate cancer on senescence phenotypes in human and mouse prostate tumor models. We observed that while CDK inhibitors could induce senescence in MYC-driven prostate tumor cells, DNA-damaging chemotherapies and Aurora kinase inhibitors mediated a more robust senescence-mediated growth arrest and SASP program, which was paradoxically enhanced in the context of p53 and Rb tumor suppressor losses. The SASP produced by chemotherapy-induced senescence, and in particular with docetaxel, contained not only inflammatory factors that could influence innate immune responses, but also ECM remodeling factors that could facilitate tumor cell dissemination. Though docetaxel treatment could induce senescence and reduce tumor growth in syngeneic prostate cancer mouse models, it was not sufficient to activate anti-tumor immune surveillance or prevent metastatic dissemination. Use of senolytic therapies targeting anti-apoptotic BCL2 and IAP pathways upregulated after docetaxel-induced senescence could effectively clear senescent tumor cells. SMAC mimetic LCL-161 also induced immunogenic cell death capable to remodeling the inflammatory SASP to confer CD8+ T cell activation to further reduce tumor growth and even prevent metastasis in vivo. Our results suggest that combining senescence-inducing chemotherapies with senolytic agents can enhance the immunogenicity and anti-metastatic potential of standard-of-care chemotherapy used for treating prostate cancer patients.

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Using a rhabdomyosarcoma patient-derived xenograft to examine precision medicine approaches and model acquired resistance

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