Developing A Novel Combinatorial Therapy for Lethal Neuroendocrine Prostate Cancer

项目摘要/摘要 神经内分泌前列腺癌(NEPC)是一种侵袭性极强的前列腺癌亚型。 Novo，但更常见的是在激素治疗晚期前列腺癌(PADC)后发展起来的。它 占与前列腺癌有关的死亡人数的25%。目前对NEPC的治疗选择仅限于 姑息治疗，大多数患者在几个月内死亡。因此，有一种迫切的未得到满足的需求需要发展。 针对NEPC患者的有效靶向治疗。 在与NEPC相关的分子事件中，视网膜母细胞瘤(RB)蛋白的丢失几乎发生在 并推动前列腺癌的去势抵抗、转移、谱系可塑性和致命性 提示RB1缺失在NEPC的发展过程中是一个关键事件，可以被利用来识别和靶向 NEPC中的治疗脆弱性。在我们最近对分子和遗传事件的研究中， 铁下垂，一种由铁依赖的脂质过氧化驱动的调节性细胞死亡形式，我们发现RB1 中断至少部分通过Rb/E2F/ACSL4基因使前列腺癌细胞对铁性下垂敏感 而铁下垂诱导剂优先杀死RB1缺失的NEPC细胞，而不是RB1完整的PADC细胞， 提示铁性下垂诱导剂在治疗上睑下垂中的治疗潜力。鉴于NEPC是 出了名的难以治疗，单一疗法通常只对一小部分患者有利，就像患有 其他低分化的神经内分泌肿瘤，如肺小细胞癌，我们建议 开发一种基于靶向下垂的NEPC有效的联合治疗方法。我们激动人心的未出版作品 初步数据显示，铁下垂诱导剂与bcl2抑制剂的结合强烈。 在体外和细胞系来源的异种移植(CDX)模型中诱导对NEPC细胞的协同细胞毒作用 NEPC。基于这些令人信服的初步发现，我们假设铁下垂诱导剂和bcl2 抑制剂协同促进NEPC细胞的死亡途径，并共同靶向铁下垂和bcl2 代表了一种治疗致命性NEPC的有前途的组合方法。通过多学科方法 结合独特的前列腺癌模型系统、体内临床前研究和成熟的分子和 细胞分析，我们的目标是确定共靶向铁下垂和bcl2是否代表一个有希望的 治疗致死性NEPC的组合方法。在目标1中，我们将确定铁性下垂的治疗效果。 诱导联合bcl2抑制患者来源的NEPC异种移植模型。在目标2中，我们将确定 铁诱导下垂联合bcl2抑制对基因工程小鼠的治疗作用 NEPC的模型。在目标3中，我们将阐明其抗肿瘤活性的分子机制。 铁性下垂诱导联合bcl2抑制NEPC。

Project Summary/Abstract Neuroendocrine prostate cancer (NEPC) is a highly aggressive subtype of prostate cancer that can arise de novo, but more commonly develops after hormone therapies for advanced prostate adenocarcinoma (PADC). It accounts for up to 25% of deaths related to prostate cancer. Current treatment options for NEPC are only palliative, and most patients die within several months. Therefore, there is a pressing unmet need to develop effective targeted therapies for patients with NEPC. Among molecular events associated with NEPC, loss of retinoblastoma (RB) protein occurs nearly universally and drives prostate cancer castration resistance, metastasis, lineage plasticity, and lethality, which suggests that RB1 loss is a pivotal event in the development of NEPC and may be exploited to identify and target therapeutic vulnerabilities in NEPC. In our recent research into the molecular and genetic events underlying ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, we discovered that RB1 disruptions significantly sensitize prostate cancer cells to ferroptosis, at least in part, through a RB/E2F/ACSL4 axis, and that ferroptosis inducers preferentially kill RB1-null NEPC cells rather than RB1-intact PADC cells, implying the therapeutic potential of ferroptosis inducers in the treatment of NEPC. Given that NEPC is notoriously hard to treat and monotherapy often benefits only a small portion of patients, as is the cases with other poorly differentiated neuroendocrine tumors such as small-cell carcinoma of the lung, we propose to develop an effective combinatorial therapy for NEPC based on targeting ferroptosis. Our exciting unpublished preliminary data has shown that the combination of the ferroptosis inducer with the BCL2 inhibitor strongly induces synergistic cytotoxicity in NEPC cells both in vitro and in cell line-derived xenograft (CDX) models of NEPC. Based on these compelling preliminary findings, we hypothesize that ferroptosis inducers and BCL2 inhibitors synergistically promote cell death pathways in NEPC cells, and that co-targeting ferroptosis and BCL2 represents a promising combinatorial approach to treating lethal NEPC. Through a multidisciplinary approach combining unique prostate cancer model systems, in vivo preclinical studies, and well-established molecular and cellular assays, we aim to determine whether co-targeting ferroptosis and BCL2 represents a promising combinatorial approach to treating lethal NEPC. In Aim 1, we will determine the therapeutic efficacy of ferroptosis induction combined with BCL2 inhibition in patient-derived xenograft models of NEPC. In Aim 2, we will determine the therapeutic efficacy of ferroptosis induction combined with BCL2 inhibition in genetically engineered mouse models of NEPC. In Aim 3, we will elucidate the molecular mechanisms underlying the anti-tumor activity of ferroptosis induction combined with BCL2 inhibition in NEPC.