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exciting unpublished preliminary data demonstrating that RB1 disruptions significantly sensitize prostate cancer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.

Grant Number: 5R01CA269211-05
NIH Institute/Center: NIH
Principal Investigator: MING CHEN