Though initially responsive to hormonal therapy, prostate cancer (PCa) invariably progresses to an incurable metastatic castration-resistant state (mCRPC). Additionally, the proportion of patients with androgen receptor (AR)-indifferent mCRPCe has increased significantly in the post-supracastration (e.g. -enzalutamide/- abiraterone) era in men with late-stage lethal disease. Whether treatment-induced or otherwise, this emphasizes the urgent need to develop innovative non-AR targeted approaches if we want to do more than provide incremental increases in patient survival and combat this emerging highly-aggressive lethal phenotype. Tumor- infiltrating fibroblast activation protein (FAP)-positive cells (i.e. MSCs, CAFs, and TAMs) are recognized as key architects of the pro-tumorigenic and immunosuppressive microenvironment conducive to tumor progression. This is in part through their production of energy-rich nutrients and metabolic intermediates that the cancer cells ?parasitize? from the extracellular fluid to fuel tumor growth and progression. These observations suggest that a FAP-targeted therapy could provide an AR-independent multi-faceted anti-tumor assault by simultaneously disrupting the parasitic dependence on the tumor stroma and eliminating multiple immunosuppressive cell types within the tumor microenvironment (TME). To accomplish this goal, we have synthesized an orally-available small molecule FAP-activated mitochondrial protoxin based on niclosamide, an FDA-approved anti-helminthic that uncouples mitochondrial oxidative phosphorylation with nanomolar potency in a cell cycle-independent manner, making it an ideal warhead for FAP+ stromal cells with a low proliferative index. This proposal is innovative from conceptual and technical perspectives: 1) multiple tumor-infiltrating FAP+ cells in the TME are selectively and simultaneously targeted to overcome the immune barrier and disrupt the ?parasitic cycle? fueling tumor growth; 2) a first-in-class enzymatically-activated lipophilic mitochondrial protoxin designed to increase the therapeutic index of an FDA-approved drug while sparing toxicity to surrounding healthy tissue is synthesized and characterized; 3) FAP expression patterns in a unique series of human prostate tissues, lymph nodes, and metastases as a function of malignancy and treatment status are assessed to identify clinical states most likely to benefit from FAP-targeted therapy; and 4) efficacy, toxicity, and specificity are evaluated using a novel series of patient-derived xenograft (PDX) and syngeneic models that recapitulate key clinical features of human PCa in order to delineate biologically-relevant immune-independent and ?dependent mechanisms underlying the anti-tumor response. Furthermore, this strategy combines agents that have been individually tested in patients, which significantly bolsters potential for near-term patient benefit. More immediately, the proposal will provide important insights into the role of FAP+ cells in PCa pathophysiology particularly with respect to their interaction with the immune system, while providing the necessary preclinical proof-of-principle data needed to translate this innovative therapeutic platform into the clinic.

Public Health Relevance

Prostate cancer (PCa) remains an incurable disease once progression to the metastatic castration-resistant (mCRPC) state occurs, a state in which we have identified fibroblast activation protein (FAP) as a key feature of the PCa-supportive, immunosuppressive tumor microenvironment permissive to disease progression that is upregulated on the surface of tumor-associated macrophages (TAMs), mesenchymal stem cells (MSCs), and carcinoma-associated fibroblasts (CAFs). The objectives of this proposal are to identify PCa disease states most likely to respond to FAP-targeted therapy as well as evaluating the efficacy, specificity, and toxicity of a novel first-in-class FAP-activated mitochondrial protoxin in advanced preclinical model systems that accurately recapitulate key clinical features of human PCa. Short-term benefits include a greater understanding of how FAP+ cells contribute to PCa pathophysiology particularly with respect to their interaction with the immune system, while providing the necessary preclinical proof-of-principal data needed to translate this innovative therapeutic platform into the clinic over the longer-term.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Drug Discovery and Molecular Pharmacology Study Section (DMP)
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Verma, Sharad Kumar
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Johns Hopkins University
Internal Medicine/Medicine
Schools of Medicine
United States
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