Developing A Novel Combinatorial Therapy for Lethal Neuroendocrine Prostate Cancer

开发一种针对致命性神经内分泌前列腺癌的新型组合疗法

• 批准号: 10664011
• 负责人: MING CHEN
• 金额: $ 37.77万
• 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: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664011
• 关键词: Adenocarcinoma Cell; Architecture; BCL2 gene; Biological Assay; Biological Markers; Biological Models; British Columbia; Castration; Cell Death; Cell Line; Cellular Assay; Cessation of life; Characteristics; Clinic; Clinical; Clinical Trials; Collaborations; Data; Development; Drug Combinations; Event; Future; Genetic; Genetically Engineered Mouse; Heterogeneity; Human; Immunodeficient Mouse; In Vitro; Iron; Lipid Peroxidation; Malignant Neoplasms; Malignant neoplasm of prostate; Metastatic Prostate Cancer; Molecular; Neoplasm Metastasis; Neuroendocrine Prostate Cancer; Neuroendocrine Therapy; Neuroendocrine Tumors; Pathway interactions; Patients; Preclinical Testing; Prostate Adenocarcinoma; Prostatic; RB1 gene; Research; Resistance; Retinoblastoma; Retinoblastoma Protein; Safety; Small Cell Carcinoma; Specimen; Testing; Therapeutic; Tissues; Translations; Treatment Efficacy; Universities; Validation; Visceral metastasis; Work; Xenograft Model; Xenograft procedure; combinatorial; cytotoxicity; design; hormone therapy; implantation; in vivo; in vivo evaluation; inhibitor; insight; interdisciplinary approach; loss of function; lung Carcinoma; neuroendocrine differentiation; novel; novel therapeutics; palliative; patient derived xenograft model; pre-clinical; preclinical study; prostate cancer cell; prostate cancer model; screening; targeted treatment; tumor

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.

项目摘要/摘要 神经内分泌前列腺癌（NEPC）是前列腺癌的高度侵略性亚型 Novo，但更常见的是在激素治疗晚期前列腺腺癌（PADC）之后发展。它 与前列腺癌有关的死亡人数最多高达25％。 NEPC的当前治疗选择仅是 姑息治疗，大多数患者在几个月内死亡。因此，有迫切需要开发的需求 NEPC患者的有效靶向疗法。 在与NEPC相关的分子事件中，视网膜母细胞瘤（RB）蛋白的损失几乎发生 普遍驱动前列腺癌去势抗性，转移，谱系可塑性和杀伤力，这是 表明RB1损失是NEPC开发中的关键事件，可能被利用以识别和目标 NEPC的治疗漏洞。在我们最近对分子和遗传事件基础事件的研究中 铁毒性是由铁依赖性脂质过氧化驱动的一种调节细胞死亡形式，我们发现RB1 破坏至少部分地通过RB/E2F/ACSL4敏感到前列腺癌细胞对铁毒细胞的敏感性。 轴，那该诱导剂优先杀死RB1-NULL NEPC细胞，而不是RB1 Intact PADC细胞， 暗示促氧化肌吞噬作用在NEPC治疗中的治疗潜力。鉴于NEPC是 众所周知，很难治疗和单一疗法通常只受益于一小部分患者，就像 其他分化较差的神经内分泌肿瘤，例如肺的小细胞癌，我们建议 基于靶向铁毒性，开发有效的NEPC组合疗法。我们令人兴奋的未发表 初步数据表明，诱导铁蛋白毒剂与BCL2抑制剂的组合强烈 在体外和细胞系衍生的异种移植（CDX）模型中诱导NEPC细胞的协同细胞毒性 NEPC。基于这些引人入胜的初步发现，我们假设铁铁蛋白诱导剂和BCL2 抑制剂协同促进NEPC细胞中的细胞死亡途径，并促进铁铁毒性和BCL2 代表了治疗致命NEPC的有希望的组合方法。通过多学科的方法 结合独特的前列腺癌模型系统，体内临床前研究以及公认的分子和 蜂窝测定，我们旨在确定共同靶向的铁毒和Bcl2是否代表了有希望的 联合方法治疗致命NEPC。在AIM 1中，我们将确定铁凋亡的治疗功效 NEPC的患者衍生异种移植模型中的诱导结合BCL2抑制。在AIM 2中，我们将确定 铁凋亡诱导的治疗功效与BCL2抑制在基因工程小鼠中的抑制作用 NEPC的模型。在AIM 3中，我们将阐明抗肿瘤活性的分子机制 铁凋亡诱导与NEPC中BCL2抑制结合。