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

• 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
• 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

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.

项目摘要/摘要 患有转移性cast割前列腺癌（MCRPC）的男性总是屈服于他们的疾病。 因此，需要对新药和药物组合的临床前测试迫切需要晚期前列腺 癌症。在与MCRPC相关的分子事件中，RB1的遗传像差发生在约20％ 前列腺腺癌病例和70％的神经内分泌/小细胞前列腺癌病例，这些病例 事件驱动前列腺癌去势抗性，谱系可塑性和转移。重要的是，最近的研究 已经确定RB1基因组改变是与临床差最密切相关的分子因子 MCRPC患者的结果，突出了RB的丧失作为前列腺癌的主要驱动力 致死性，并强调识别针对此目标的潜在治疗策略的关键需求 大多数致命的前列腺癌病例的治疗机制。为此，我们现在有 令人兴奋的未发表的初步数据表明RB1中断显着敏感前列腺癌 细胞直至铁凋亡，这是一种受调节的细胞死亡形式，可以用于癌症治疗。机械上， 我们发现RB1-loss/e2f激活导致ACSL4上调，ACSL4是铁铁的关键决定因素 灵敏度。基于这些引人入胜的初步发现，我们假设铁铁作用是一种新兴的癌症 RB1缺乏引起的脆弱性，并提出靶向铁毒剂可能代表一种新颖的治疗性 治疗致死性RB1缺乏的前列腺癌的方法。通过组合的多学科方法 独特的前列腺癌模型系统，体内临床前研究，法学技术和分子和分子 病理分析，我们旨在确定靶向螺旋病是否代表有效的治疗 治疗致命的RB1缺陷前列腺癌的方法。在AIM 1中，我们将在体内确定治疗性 使用两种不同但 互补的RB1缺陷前列腺癌模型系统，即患者衍生的异种移植模型和 基因工程的鼠标模型。在AIM 2中，我们将阐明RB1损坏的基础机制 相关的漏虫病。在AIM 3中，我们将确定RB与铁凋亡之间的相关性 MCRPC样品中的标记。 该建议基于有希望的初步发现，并利用了高度相关的前列腺癌模型 系统和功能测定，以测试诱导体体内的体内治疗潜力 致命的RB1缺陷前列腺癌。这些调查的成功完成将划定下游 RB/E2F途径的效应因素，并提供了对RB对铁铁作用的贡献以及 关于未来临床的合理设计所需的功效，安全性和生物标志物的临床前数据 针对致死性RB1缺陷前列腺癌的治疗策略的试验作为一种治疗策略。