Developing A Novel Combinatorial Therapy for Lethal Neuroendocrine Prostate Cancer

开发一种治疗致命性神经内分泌前列腺癌的新型组合疗法

• 批准号: 10518805
• 负责人: MING CHEN
• 金额: $ 38.54万
• 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/10518805
• 关键词: Architecture; BCL2 gene; Biological Assay; Biological Markers; Biological Models; British Columbia; Castration; Cell Death; Cell Line; Cells; Cellular Assay; Cessation of life; Characteristics; Clinic; Clinical; Clinical Trials; Collaborations; Data; Development; Drug Combinations; Event; Future; Genetically Engineered Mouse; Heterogeneity; Human; Immunodeficient Mouse; In Vitro; Iron; Lipid Peroxidation; Malignant Neoplasms; Malignant neoplasm of prostate; Metastatic Prostate Cancer; Molecular; Molecular Genetics; 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; Specimen; Testing; Therapeutic; Tissues; Translations; Treatment Efficacy; Universities; Validation; Visceral metastasis; Work; Xenograft Model; Xenograft procedure; base; combinatorial; cytotoxicity; design; hormone therapy; implantation; in vivo; in vivo evaluation; inhibitor; insight; interdisciplinary approach; loss of function; lung small cell carcinoma; neuroendocrine differentiation; novel; novel drug combination; 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.

项目概要/摘要 神经内分泌前列腺癌 (NEPC) 是一种高度侵袭性的前列腺癌亚型，可发生在 新发，但更常见于晚期前列腺腺癌 (PADC) 的激素治疗后发生。它 占前列腺癌相关死亡的 25%。目前 NEPC 的治疗方案只有 姑息治疗，大多数患者在几个月内死亡。因此，迫切需要开发尚未满足的需求 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 普遍存在并驱动前列腺癌去势抵抗、转移、谱系可塑性和致死率，这 表明 RB1 丢失是 NEPC 发展中的关键事件，可用于识别和定位 NEPC 的治疗脆弱性。在我们最近对潜在分子和遗传事件的研究中 铁死亡是一种由铁依赖性脂质过氧化驱动的受调节细胞死亡形式，我们发现 RB1 破坏使前列腺癌细胞对铁死亡显着敏感，至少部分是通过 RB/E2F/ACSL4 轴，铁死亡诱导剂优先杀死 RB1 缺失的 NEPC 细胞，而不是 RB1 完整的 PADC 细胞， 暗示铁死亡诱导剂在治疗 NEPC 中的治疗潜力。鉴于 NEPC 是 众所周知，这种疾病很难治疗，而且单一疗法通常只能使一小部分患者受益，例如 其他低分化神经内分泌肿瘤，如小细胞肺癌，我们建议 开发一种基于靶向铁死亡的有效 NEPC 组合疗法。我们激动人心的未发表 初步数据表明，铁死亡诱导剂与 BCL2 抑制剂的组合可强烈 在体外和细胞系衍生的异种移植 (CDX) 模型中诱导 NEPC 细胞协同细胞毒性 国家电力委员会。基于这些令人信服的初步发现，我们假设铁死亡诱导剂和 BCL2 抑制剂协同促进 NEPC 细胞的细胞死亡途径，并共同靶向铁死亡和 BCL2 代表了治疗致命性 NEPC 的一种有前景的组合方法。通过多学科方法 结合独特的前列腺癌模型系统、体内临床前研究以及成熟的分子和 细胞测定中，我们的目标是确定共同靶向铁死亡和 BCL2 是否代表一种有前途的方法 治疗致命性 NEPC 的组合方法。在目标 1 中，我们将确定铁死亡的治疗效果 在患者来源的 NEPC 异种移植模型中诱导结合 BCL2 抑制。在目标 2 中，我们将确定 诱导铁死亡联合抑制BCL2对基因工程小鼠的治疗效果 NEPC 模型。在目标3中，我们将阐明其抗肿瘤活性的分子机制。 NEPC 中铁死亡诱导与 BCL2 抑制相结合。