Developing A Novel Combinatorial Therapy for Lethal Neuroendocrine Prostate Cancer

Project Summary/Abstract
Neuroendocrine prostate cancer (NEPC) is a highly aggressive subtype of prostate cancer that can arise de
novo, but more commonly develops after hormone therapies for advanced prostate adenocarcinoma (PADC). It
accounts for up to 25% of deaths related to prostate cancer. Current treatment options for NEPC are only
palliative, and most patients die within several months. Therefore, there is a pressing unmet need to develop
effective targeted therapies for patients with NEPC.
Among molecular events associated with NEPC, loss of retinoblastoma (RB) protein occurs nearly
universally and drives prostate cancer castration resistance, metastasis, lineage plasticity, and lethality, which
suggests that RB1 loss is a pivotal event in the development of NEPC and may be exploited to identify and target
therapeutic vulnerabilities in NEPC. In our recent research into the molecular and genetic events underlying
ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, we discovered that RB1
disruptions significantly sensitize prostate cancer cells to ferroptosis, at least in part, through a RB/E2F/ACSL4
axis, and that ferroptosis inducers preferentially kill RB1-null NEPC cells rather than RB1-intact PADC cells,
implying the therapeutic potential of ferroptosis inducers in the treatment of NEPC. Given that NEPC is
notoriously hard to treat and monotherapy often benefits only a small portion of patients, as is the cases with
other poorly differentiated neuroendocrine tumors such as small-cell carcinoma of the lung, we propose to
develop an effective combinatorial therapy for NEPC based on targeting ferroptosis. Our exciting unpublished
preliminary data has shown that the combination of the ferroptosis inducer with the BCL2 inhibitor strongly
induces synergistic cytotoxicity in NEPC cells both in vitro and in cell line-derived xenograft (CDX) models of
NEPC. Based on these compelling preliminary findings, we hypothesize that ferroptosis inducers and BCL2
inhibitors synergistically promote cell death pathways in NEPC cells, and that co-targeting ferroptosis and BCL2
represents a promising combinatorial approach to treating lethal NEPC. Through a multidisciplinary approach
combining unique prostate cancer model systems, in vivo preclinical studies, and well-established molecular and
cellular assays, we aim to determine whether co-targeting ferroptosis and BCL2 represents a promising
combinatorial approach to treating lethal NEPC. In Aim 1, we will determine the therapeutic efficacy of ferroptosis
induction combined with BCL2 inhibition in patient-derived xenograft models of NEPC. In Aim 2, we will determine
the therapeutic efficacy of ferroptosis induction combined with BCL2 inhibition in genetically engineered mouse
models of NEPC. In Aim 3, we will elucidate the molecular mechanisms underlying the anti-tumor activity of
ferroptosis induction combined with BCL2 inhibition in NEPC.

Grant Number: 5R01CA266510-04
NIH Institute/Center: NIH
Principal Investigator: MING CHEN