Rowena Kannaiyan
Pronouns:
Research Mentor(s): Yang Zheng
Research Mentor School/College/Department: Pathology / Medicine
Program:
Authors: Rowena Kannaiyan, Kyle Garcia-Rogers, Arya Kamat, Yang Zheng, Arul Chinnaiyan
Session: Session 6: 3:40 pm – 4:30 pm
Poster: 35
Abstract
Neuroendocrine Prostate Cancer (NEPC) represents a rare, yet markedly aggressive histological subtype of prostate cancer, characterized by rapid metastasis and resistance to conventional anti-androgen therapies and androgen receptor pathway inhibitors (ARPIs). Often manifesting in advanced stages of the disease, NEPC poses significant clinical challenges with an average life expectancy of merely seven months following diagnosis. Current administered therapies involve platinum-based chemotherapy and radiation, which is largely based on their success in treating small cell lung cancer (SCLC), a cancer phenotypically similar to NEPC. However, these treatments offer limited efficacy in NEPC and pose a risk of severe neutropenia and lethal toxicity. Thus far, effective therapy targeting the specific molecular features of NEPC is yet to be established. This study explores the efficacy of ESK981, originally developed as a multi-tyrosine kinase inhibitor, in targeting tumor growth and cancer proliferation in patients with NEPC. ESK981 operates by selectively targeting PIKfyve, a critical lipid kinase involved in regulating lysosomal homeostasis, a cellular process strongly associated with autophagy. To assess the anti-tumor efficacy of ESK981, subcutaneous patient-derived xenograft (PDX) and cell line-derived xenograft (CDX) tumors were established in severe combined immunodeficiency (SCID) mice. In these models, ESK981 significantly inhibited NEPC tumor growth across all preclinical models by PIKfyve blockade. Combinational therapies targeting both androgen receptor signaling pathway and PIKfyve robustly diminished tumor growth in AR positive prostate cancers. This study highlights ESK981 as a promising therapeutic agent for NEPC, primarily functioning through PIKfyve inhibition. Moreover, its potential to synergize with current stand-of-care, ARPIs, in prostate adenocarcinomas highlights its versatility in clinical applications.
