Targeting Lipid Kinase PIKfyve in Neuroendocrine Prostate Cancer
Abstract
Rationale, Objective, and Aims of the application: Treatment decisions and prognoses vary across cases of prostate cancer depending on many factors. For instance, prostate cancer confined to the prostate is less aggressive and can be treated with surgery or radiation. More advanced prostate cancer often requires a protein called the androgen receptor (AR) to fuel cancer cell growth and survival, and patients in this setting are prescribed androgen deprivation therapy (ADT) to inhibit AR activity or reduce levels of circulating androgens. However, many patients progress on ADT to a state known as castration-resistant prostate cancer (CRPC). Since AR remains a major driver of CRPC, additional AR inhibitors (e.g., enzalutamide and abiraterone) were developed to decrease remaining AR activity in CRPC. Although these drugs improve CRPC survival, they are not curative, and CRPC cells can develop further mechanisms of resistance. One such type of prostate cancer that can develop from CRPC AR inhibitor treatment is called neuroendocrine prostate cancer (NEPC). NEPC often has no or little AR expression, and the only standard therapy option for NEPC is chemotherapy (e.g., cisplatin). Although many NEPC patients initially respond to chemotherapy, resistance invariably occurs after a short time, and the disease remains incurable. Thus, there is an urgent need to develop new therapies to decrease mortality from NEPC. Through preliminary studies, we have identified a promising new therapeutic target for NEPC called PIKfyve. Using cell lines and patient-derived xenografts (PDXs; tumors removed from patients that are then grown in mice), we found that NEPC is preferentially sensitive to PIKfyve inhibition with the clinical compound ESK981. PIKfyve is known to play essential roles in processes called autophagy and lysosome adaptation that are vital for cell growth and survival in oxygen-depleted (a state known as hypoxia) and nutrient-poor environments, both being settings found in NEPC. We, therefore, hypothesize that PIKfyve is indispensable for NEPC development and progression through maintenance of adaptive lysosome and nutrient recycling pathways under hypoxic and nutrient-deprived conditions, which occur from loss of androgen signaling. Specific Aims: To test this, we propose three specific aims. Aim 1. Determine the role of PIKfyve in NEPC progression. Our preliminary data suggest that NEPC develops an enhanced dependency on PIKfyve during progression from AR-dependent CRPC. We will use genetic and pharmacologic targeting methods in cell lines and animal models to ascertain whether PIKfyve is indeed required for NEPC development and proliferation. Aim 2. Examine the mechanisms by which PIKfyve regulates cell survival in NEPC. The high proliferative rates of NEPC coupled with hypoxia and nutrient depletion requires a coordinated set of responses for tumor survival. We will delineate the pathways through which PIKfyve mediates survival in NEPC by inhibiting PIKfyve and examining activation of key players in nutrient survival pathways (e.g., mTORC1 and TFEB) as well as effects on oxygen consumption and stress on the cellular protein synthesis machinery. Aim 3. Determine whether PIKfyve inhibition combined with standard of care therapies for NEPC and CRPC enhance outcomes in preclinical models. We will perform preclinical animal studies with multiple NEPC models treated with cisplatin, ESK981, or the combination to determine whether PIKfyve inhibition can enhance NEPC response to chemotherapy. Our preliminary data also found that ESK981 and AR inhibitors can synergize in AR-dependent CRPC; thus, we will also employ animal models to determine whether combined ESK981 and standard of care enzalutamide decreases tumor growth of AR-dependent CRPC. Clinical Applicability of the Research: This research addresses two of the FY22 PCRP Overarching Challenges: 1. Define the biology of prostate ca
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310084
Entities
People
- Yuanyuan Qiao
Organizations
- United States Army
- University of Michigan