Overcoming Androgen Receptor-Mediated Prostate Cancer Resistance to Immunotherapy
Abstract
Metastatic prostate cancer (mPCa) is lethal with limited treatment options. Immunotherapy has significantly improved survival in patients a variety of solid tumors; however, it has only presented marginal efficacy in patients with mPCa. There is a limited understanding of the de novo mechanisms of resistance to immunotherapy in prostate cancer. Thus, there is an unmet need to understand the mechanisms of resistance and to develop effective immunotherapies for mPCa. The overall goal of this proposed study is to address this unmet need. The activated immune cells kill cancer cells through a common “classical” mechanism by secreting a toxic chemical called “granzyme (GRM).” Immune cell itself has a defense mechanism to prevent self-killing by upregulating the GRM inhibitor SerpinB9 in itself once activated. In our preliminary studies, we found that androgen receptor activity can markedly upregulate SerpinB9 in prostate cancer cells, particularly in castration-resistant prostate cancer (CRPC) cells. We have initial proof-of-concept data from animal studies showing that prostate tumor cells engineered to express a lot of SerpinB9 are resistant to immunotherapy compared to the original un-engineered prostate cancer cells that only express low levels of SerpinB9. Furthermore, we found an immune stimulatory antibody B10G5, a “prodrug” antibody that has been shown to revive the immune system tumor host in animal models, sensitizes CRPC cells to immune cell killing through activation of a “non-classical” FasL/Fas cell death pathway. Therefore, in this proposed study, our goal is to understand how androgen receptor activity enhances the expression of SerpinB9 and thus protects CRPC cells from the typical classical immune cell killing and how the immune stimulatory “prodrug” activates the “non-classical” FasL/Fas cell death pathway, as well as to evaluate the synergistic therapeutic efficacy of B10G5 and co-targeting AR in pre-clinical prostate mouse models. Given that androgen-receptor activity is mostly specific to the prostate cancer, our observation would provide a novel and fundamental mechanism that explains why prostate cancer is resistant to immunotherapy. Given that the antibody B10G5 is currently undergoing IND-enabling study as a first-in-class immunotherapy for all solid tumors, our study will have a significant impact on prostate cancer patients battling hormone-resistant diseases in the very near term, such as 3-5 years of term. Our cancer center has planned for clinical trial of using B10G5 to treat mCRPC patients as part of our Prostate SPORE program once IND is approved.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110574
Entities
People
- Jennifer Wu
Organizations
- Northwestern University
- United States Army