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Targeting Ferroptosis in Lethal RB1 Deficient Prostate Cancer

靶向致命性 RB1 缺陷型前列腺癌中的铁死亡

基本信息

批准号：
10413399
负责人：
MING CHEN
金额：
$ 42.01万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10413399
关键词：
Affect Automobile Driving Biological Assay Biological Markers Biological Models British Columbia Cancer Patient Castration Cell Death Cell Line Cells Clinic Clinical Clinical Trials Collaborations DNA Sequence Alteration Data Disease Drug Combinations Epithelial Event Family Foundations Future Genetically Engineered Mouse Immunohistochemistry In Vitro Individual Investigation Iron Knowledge Lipid Peroxidation Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Modeling Molecular Molecular Genetics Neoplasm Metastasis Neurosecretory Systems Outcome Pathologic Pathway interactions Patients Personal Satisfaction Preclinical Testing Prostate Adenocarcinoma RB1 gene Research Resistance Role Safety Sampling Stains Technology Testing Therapeutic Translations Universities Up-Regulation Validation Work Xenograft Model base biomarker development cancer genetics cancer therapy castration resistant prostate cancer design drug candidate experience improved in vivo in vivo evaluation insight interdisciplinary approach malignant breast neoplasm men mortality novel novel drug combination novel therapeutic intervention patient derived xenograft model pre-clinical preclinical study prostate cancer cell prostate cancer model rational design targeted treatment therapeutically effective tumor tumor xenograft

项目摘要

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.

项目总结/文摘