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.

项目总结/文摘