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Understanding and Targeting Tumor Microenvironment in Prostate Cancer to Inhibit Tumor Progression and Castration Resistance

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Technical Report,30 Sep 2014,29 Sep 2017

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MD Anderson Cancer Center Houston United States

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.A significant fraction of advanced prostate cancer PCa patients treated with androgen deprivation therapy ADT experience relapse with relentless progression to lethal metastatic castration-resistant prostate cancer mCRPC. Immune checkpoint blockade ICB using antibodies against CTLA4 or PD1PD-L1 generates durable therapeutic responses in a significant subset of patients across a variety of cancer types. However, mCRPC showed overwhelming de novo resistance to ICB, motivating a search for targeted therapies that overcome this resistance. Myeloid-derived suppressor cells MDSCs are known to play important roles in tumor immune evasion. Circulating MDSC abundance correlates with PSA levels and metastasis in PCa patients. Mouse models of PCa show that MDSCs CD11b Gr1 promote tumor initiation and progression. These observations prompted us to hypothesize that robust immunotherapy responses in mCRPC may be elicited by the combined actions of ICB agents together with targeted agents that neutralize MDSCs yet preserve T cell function. Here I developed a novel chimeric mouse model of mCRPC to efficiently test combination therapies in an autochthonous setting. Combination of anti-CTLA4 and anti-PD1 engendered only modest efficacy. Targeted therapy against mCRPC-infiltrating MDSCs, using multikinase inhibitors such as cabozantinib and dactolisib, also showed minimal anti-tumor activities. Strikingly, primary and metastatic CRPC showed robust synergistic responses when ICB was combined with MDSC-targeted therapy. Mechanistically, combination therapy efficacy stemmed from the upregulation of IL-1ra and suppression of MDSC-promoting cytokines secreted by PCa cells. These observations illuminate a clinical path hypothesis for combining ICB with MDSC-targeted therapies in the treatment of mCRPC

Subject Categories:

  • Medicine and Medical Research
  • Biochemistry
  • Pharmacology

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