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：
10588173
负责人：
MING CHEN
金额：
$ 41.17万
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/10588173
关键词：
Affect Automobile Driving Biological Assay Biological Markers Biological Models British Columbia Cancer Patient Castration Cell Death Cell Line Clinic Clinical Clinical Trials Collaborations DNA Sequence Alteration Data Disease Drug Combinations Epithelium Event Family Foundations Future Genetic Genetically Engineered Mouse Immunohistochemistry In Vitro Individual Investigation Iron Knowledge Lipid Peroxidation Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Modeling Molecular 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 biomarker development biomarker identification cancer therapy castration resistant prostate cancer design drug candidate experience improved in vivo in vivo evaluation insight interdisciplinary approach malignant breast neoplasm men mortality mouse model novel novel therapeutic intervention novel therapeutics 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.

项目概要/摘要患有转移性去势抵抗性前列腺癌（mCRPC）的男性总是会死于这种疾病。因此，迫切需要针对晚期前列腺的新药和药物组合进行临床前测试癌症。在与 mCRPC 相关的分子事件中，RB1 的遗传畸变发生率约为 20% 的前列腺腺癌病例和 70% 的神经内分泌/小细胞前列腺癌病例，以及事件驱动前列腺癌去势抵抗、谱系可塑性和转移。重要的是，最近的研究已确定 RB1 基因组改变是与不良临床表现最密切相关的分子因素 mCRPC 患者的结果，强调 RB 功能丧失是前列腺癌的主要驱动因素致死率，并强调迫切需要确定针对此的潜在治疗策略治疗大部分致命性前列腺癌病例的机制。为此，我们现在有令人兴奋的未发表的初步数据表明 RB1 破坏显着使前列腺癌变得敏感细胞铁死亡，这是一种可用于癌症治疗的受调节细胞死亡形式。从机械上来说，我们发现 RB1 丢失/E2F 激活会导致 ACSL4 上调，这是铁死亡的关键决定因素敏感性。基于这些令人信服的初步发现，我们假设铁死亡是一种新出现的癌症 RB1 缺乏引起的脆弱性，并提出针对铁死亡可能代表一种新的治疗方法治疗致命性 RB1 缺陷型前列腺癌的方法。通过多学科方法结合独特的前列腺癌模型系统、体内临床前研究、组学技术以及分子和病理分析，我们的目的是确定靶向铁死亡是否代表一种有效的治疗方法治疗致命性 RB1 缺陷型前列腺癌的方法。在目标 1 中，我们将确定体内治疗方法使用两种不同但不同的方法诱导铁死亡治疗致命性 RB1 缺陷型前列腺癌的潜力互补的 RB1 缺陷型前列腺癌模型系统，即患者来源的异种移植模型和基因工程小鼠模型。在目标 2 中，我们将阐明 RB1-loss- 的潜在机制与铁死亡相关的脆弱性。在目标 3 中，我们将确定 RB 与铁死亡之间的相关性 mCRPC 样本中的标记。该提案基于有希望的初步发现，并利用高度相关的前列腺癌模型系统和功能测定，以测试铁死亡诱导剂在治疗中的体内治疗潜力致命的 RB1 缺陷型前列腺癌。这些调查的成功完成将描绘出下游 RB/E2F 通路的效应子，并为 RB 对铁死亡的贡献以及合理设计未来临床所需的有关功效、安全性和生物标志物的临床前数据针对铁死亡作为针对致命性 RB1 缺陷型前列腺癌的治疗策略的试验。