Targeting KIF20A, a Kinesin with a Novel, Noncanonical Role in Castration-Resistant Prostate Cancer
Abstract
Rationale: Castration-resistant prostate cancer (CRPC) is currently incurable and presents a formidable obstacle to treatment. With time, CRPC tumors almost always develop the ability to evade the second-generation androgen receptor-targeted drugs, such as enzalutamide, resulting in reinitiation of tumor growth. Androgen receptors are proteins responsible for regulating the effects of androgens (e.g., the hormone testosterone) and for promoting uncontrolled tumor growth in CRPC. To overcome this significant obstacle, new treatment strategies are required to specifically combat CRPC and metastatic CRPC (when tumors have escaped the prostate and initiated growth at remote sites, most commonly the skeleton). By analyzing publicly available data obtained from patients with prostate cancer (PC) and by testing PC samples in our lab, we identified a protein termed KIF20A that is present at high levels in CRPC and even more so in metastatic CRPC (compared to primary early stage PC and normal prostate tissue). In our studies conducted in mice bearing human prostate tumors, we demonstrated that increasing KIF20A (by genetic manipulations) causes primary PC cells to undergo the devastating transition to CRPC tumors. We have also demonstrated that KIF20A can promote lethal PC by causing tumors to secrete yet-to-be-defined biological substances that stimulate tumors to grow under castration-resistant conditions (similar to the conditions experienced by men undergoing androgen-deprivation therapy). Most importantly, our cell-based data showed that blocking KIF20A (either by genetic experiments or by treatment with pre-clinical drugs) stopped the growth of CRPC cells but spared normal cells. Objective and Aims: We hypothesize that KIF20A represents a therapeutic vulnerability in lethal PC. Given the current availability (and planned development) of preclinical drugs that inhibit KIF20A, we propose that targeting KIF20A offers a promising and novel approach for treating CRPC and metastatic CRPC. Study Design: Focusing the expertise of our multi-disciplinary team of scientists, our strategy confronts KIF20A using three powerful approaches. First, we will determine how KIF20A promotes the emergence of CRPC. We will use an array of advanced techniques (including mass spectrometry) to identify the active ingredients in the undefined mixture secreted by PC cells with elevated KIF20A. Equally promising, cataloging these ingredients may identify a circulating biomarker for diagnosing early stages of CRPC. Second, we will examine a preclinical drug known to selectively inhibit KIF20A and its function in a spectrum of aggressive CRPC models. Specifically, we will evaluate the anti-tumor effects of a KIF20A inhibitor both in human CRPC cell lines growing in mouse prostates and in human tumors transplanted to mice (aka, patient-derived xenografts), collectively representing an array of PC features found in men. Using big data to guide our understanding (and frame future clinical research), we will analyze patient-specific variations in KIF20A levels in a large collection (the Prostate Cancer Biorepository Network) of tumor samples from PC patients – focusing on CRPC and metastatic CRPC – to ultimately identify those patients most likely to benefit from drugs that inhibit KIF20A. Third, collaborating with a medicinal chemist and a computational drug modeler, we will generate improved KIF20A inhibitors. PCRP Overarching Challenges: In targeting KIF20A for drug treatment, we advance a therapeutic strategy for those with incurable CRPC, directly addressing the PCRP challenge, Develop treatments that improve outcomes for men with lethal prostate cancer. In defining the specific role of KIF20A in newly emergent CRPC, we advance a more nuanced understanding of CRPC – necessary for optimal clinical use of KIF20A inhibitors and to reveal potential new biomarkers – that explicitly addresses the PCRP challenge, Define the biol
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310369
Entities
People
- Kerry L Burnstein
Organizations
- United States Army
- University of Miami