Friday, May 16, 2025
5/16/2025
Targeting Ferroptosis in Lethal RB1 Deficient Prostate Cancer - Project Summary/Abstract Men who develop metastatic castration-resistant prostate cancer (mCRPC) invariably succumb to their disease. Thus there is a pressing need for preclinical testing of new drugs and drug combinations for late-stage prostate cancer. Among the molecular events associated with mCRPC, genetic aberrations in RB1 occur in about 20% of prostate adenocarcinoma cases and 70% of neuroendocrine/small cell prostate cancer cases, and these events drive prostate cancer castration resistance, lineage plasticity, and metastasis. Importantly, recent studies have identified RB1 genomic alteration as the molecular factor most strongly associated with poor clinical outcomes in patients with mCRPC, highlighting loss of RB function as a dominant driver of prostate cancer lethality, and underscoring the critical need for the identification of potential therapeutic strategies targeting this mechanism for the treatment of a sizable majority of lethal prostate cancer cases. To this end, we now have exciting unpublished preliminary data demonstrating that RB1 disruptions significantly sensitize prostate cancer cells to ferroptosis, a form of regulated cell death that could be harnessed for cancer therapy. Mechanistically, we have found that RB1-loss/E2F activation leads to upregulation of ACSL4, a key determinant of ferroptosis sensitivity. Based on these compelling preliminary findings, we hypothesize that ferroptosis is an emerging cancer vulnerability elicited by RB1 deficiency, and propose that targeting ferroptosis could represent a novel therapeutic approach to the treatment of lethal RB1-deficient prostate cancer. Through a multidisciplinary approach combining unique prostate cancer model systems, in vivo preclinical studies, omics technologies, and molecular and pathological analyses, we aim to determine whether targeting ferroptosis represents an effective therapeutic approach to treating lethal RB1-deficient prostate cancer. In Aim 1, we will determine in vivo the therapeutic potential of ferroptosis induction in the treatment of lethal RB1-deficient prostate cancer using two distinct but complementary RB1-deficient prostate cancer model systems, i.e., patient-derived xenograft models and genetically engineered mouse models. In Aim 2, we will elucidate the mechanisms underlying RB1-loss- associated vulnerability to ferroptosis. In Aim 3, we will determine the correlation between RB and ferroptosis markers in mCRPC samples. This proposal is based on promising preliminary findings, and utilizes highly relevant prostate cancer model systems and functional assays to test the in vivo therapeutic potential of ferroptosis inducers in the treatment of lethal RB1-deficient prostate cancer. Successful completion of these investigations will delineate downstream effectors of the RB/E2F pathway and provide novel insights into the contributions of RB to ferroptosis as well as the preclinical data regarding efficacy, safety, and biomarkers required for the rational design of future clinical trials targeting ferroptosis as a therapeutic strategy against lethal RB1-deficient prostate cancer.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).