Targeting Ferroptosis in Lethal RB1 Deficient Prostate Cancer

项目总结/摘要 发生转移性去势抵抗性前列腺癌（mCRPC）的男性总是死于疾病。 因此，迫切需要对用于晚期前列腺的新药和药物组合进行临床前测试 癌在与mCRPC相关的分子事件中，约20%发生RB 1遗传畸变 的前列腺癌病例和70%的神经内分泌/小细胞前列腺癌病例， 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 已经确定RB 1基因组改变是与临床表现不佳最密切相关的分子因素， mCRPC患者的结局，强调RB功能丧失是前列腺癌的主要驱动因素 致命性，并强调迫切需要确定针对这一点的潜在治疗策略 前列腺癌是一种常见的恶性肿瘤。为此，我们现在有 令人兴奋的未发表的初步数据表明，RB 1的破坏显着敏化前列腺癌 铁凋亡是一种受调控的细胞死亡形式，可用于癌症治疗。机械地说， 我们发现RB 1缺失/E2 F激活导致ACSL 4上调，ACSL 4是铁凋亡的关键决定因素 灵敏度基于这些令人信服的初步发现，我们假设铁下垂是一种新兴的癌症 RB 1缺陷引起的脆弱性，并提出针对铁凋亡可能代表一种新的治疗方法， 治疗致命的RB 1缺陷型前列腺癌的方法。通过多学科方法， 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 通过病理分析，我们旨在确定靶向铁凋亡是否代表一种有效的治疗方法， 治疗致命的RB 1缺陷型前列腺癌的方法。在目标1中，我们将在体内确定治疗剂 使用两种不同的但不同的方法， 互补的RB 1缺陷型前列腺癌模型系统，即，患者来源的异种移植物模型， 基因工程小鼠模型。在目标2中，我们将阐明RB 1缺失的潜在机制， 相关的易发性铁下垂。在目标3中，我们将确定RB和铁凋亡之间的相关性。 mCRPC样本中的标志物。 该建议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，以测试铁凋亡诱导剂在治疗 致命的RB 1缺陷型前列腺癌成功完成这些调查将划定下游 RB/E2 F途径的效应子，并提供了RB对铁凋亡的贡献以及 关于未来临床合理设计所需的有效性、安全性和生物标志物的临床前数据 针对铁凋亡作为治疗策略对致命的RB 1缺乏前列腺癌的试验。

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 To this end, we now have exciting unpublished preliminary data demonstrating that RB1 disruptions significantly sensitize prostate cancer cells to ferroptosis, a form of regulated cell death that could be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.