Targeting Ferroptosis in Lethal RB1 Deficient Prostate Cancer

项目摘要/摘要 患有转移性去势抵抗前列腺癌(MCRPC)的男性总是屈从于他们的疾病。 因此，迫切需要对晚期前列腺癌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基因发生了约20%的基因突变 前列腺癌病例和70%的神经内分泌/小细胞前列腺癌病例，这些 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rb1基因组改变是与临床不良最密切相关的分子因素。 MCRPC患者的预后，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问题的潜在治疗策略 治疗相当大一部分致命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基因的中断显著增加了前列腺癌的敏感度 细胞发生铁下垂，这是一种可用于癌症治疗的调节细胞死亡形式。从机械上讲， 我们发现，RB1-Lost/E2F激活导致ACSL4上调，ACSL4是铁性下垂的关键决定因素 敏感度。基于这些令人信服的初步发现，我们假设铁性下垂是一种新出现的癌症。 Rb1缺乏引起的脆弱性，并提出靶向铁下垂可能是一种新的治疗方法 致死性RB1基因缺陷型前列腺癌的治疗探讨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 通过病理分析，我们的目标是确定靶向下垂是否代表一种有效的治疗方法 治疗致死性RB1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方法 用两种不同的BUT诱导铁下垂治疗致死性RB1缺陷性前列腺癌的可能性 互补的RB1缺陷前列腺癌模型系统，即患者来源的异种移植模型和 转基因小鼠模型。在目标2中，我们将阐明RB1损失的潜在机制。 与铁性下垂相关的易感性。在目标3中，我们将确定RB和铁性下垂的相关性 MCRPC样本中的标记。 这一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。 系统和功能测试系统和功能测试体内治疗下睑下垂的治疗潜力 致命性的RB1缺陷前列腺癌。成功完成这些调查将勾勒出下游 Rb/E2F途径的效应者，为Rb在铁性下垂中的作用以及 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 针对铁性下垂作为致命的rb1基因缺陷前列腺癌的治疗策略的试验。

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 To this end, we now have exciting unpublished preliminary data demonstrating that RB1 disruptions significantly sensitize prostate cancer cells to ferroptosis, a form of regulated cell death that could be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