Functional Characterization and Development of Therapeutic Paradigms for DNA Damage Repair (DDR)-deficient Lethal Prostate Cancer

DNA 损伤修复 (DDR) 缺陷的致死性前列腺癌的功能表征和治疗范例的开发

• 批准号: 10675929
• 负责人: Goutam Chakraborty
• 金额: $ 72.95万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10675929
• 关键词: Address; Androgen Receptor; Antigen Targeting; BRCA2 Mutation; BRCA2 gene; Biometry; CAR T cell therapy; CRISPR screen; CRISPR-mediated transcriptional activation; Cancer Biology; Cancer Etiology; Cancer Patient; Caring; Castrate sensitive prostate cancer; Castration; Cells; Cellular biology; Cessation of life; Clinical; Clinical Oncology; Clinical Trials; Clinical Trials Design; Combined Modality Therapy; DNA Double Strand Break; DNA Repair; DNA Sequence Alteration; Data; Development; Discipline; Disease; Epidemiology; Exhibits; FOLH1 gene; Foundations; Gene Mutation; Genes; Genomic Instability; Goals; Heterozygote; Immunology; Immunotherapy; Indolent; Induced Mutation; Knock-out; Lesion; Link; Malignant neoplasm of prostate; Molecular; Mutation; Organoids; PARP inhibition; Pathology; Patients; Poly(ADP-ribose) Polymerase Inhibitor; Pre-Clinical Model; Process; Prognosis; Prostate Cancer therapy; Radiation therapy; Radiochemistry; Reporting; Research Personnel; Resistance; Role; Signal Pathway; Targeted Radiotherapy; Testing; Therapeutic; Time; Transcriptional Regulation; Treatment Failure; Up-Regulation; Work; androgen deprivation therapy; castration resistant prostate cancer; chimeric antigen receptor T cells; cohort; effective therapy; efficacy study; gain of function; gene repair; immunogenic; in vivo; insight; loss of function; men; mortality; novel; pharmacologic; pre-clinical; programs; prospective; prostate cancer cell; prostate cancer cell line; prostate cancer progression; rational design; receptor function; response; synergism; targeted treatment; therapeutic development; therapy resistant; treatment strategy; tumor

Abstract A leading contributor to the significant mortality burden of prostate cancer, the second cause of cancer death among U.S. men, is the short-lived efficacy of androgen deprivation therapy (ADT), the mainstay of care for advanced and symptomatic disease. Increasingly alterations in DNA damage repair (DDR) genes, predominantly BRCA2, have been linked to ADT resistance and poor prognosis. We previously showed that deleterious alteration of BRCA2 is sufficient to induce ADT resistance in castration-sensitive prostate cancer (PC) cells. Our current proposal will investigate the molecular mechanism underlying BRCA2 loss/mutation- induced ADT resistance and progression to lethal prostate cancer. Using a panel of 107 DDR-associated genes from the PROREPAIR B cohort, we made the novel observation that ~82% of patients with mCRPC harbor alterations of one or more DDR genes. Herein, we aim to comprehensively investigate the role of DDR alterations (other than BRCA2) in the development of mCRPC and resistance to therapy. To do so, we will use CRISPR screening to prospectively investigate how the gain or loss-of-function alterations of DDR genes induce castration resistance. We have observed high expression levels of prostate-specific membrane antigen (PSMA) in response to the loss of BRCA2 and other DDR genes (e.g., ATM). Our second aim will investigate the impact of PSMA- targeted radiotherapy with [177Lu]-PSMA-617 and PARP inhibitor combination in BRCA2/DDR-deficient PC. Prostate cancer is predominantly resistant to immunotherapy. Since BRCA2-deficient cells also exhibit higher PSMA expression and are possibly immunogenic due to increased genomic instability, we will explore the effect of PSMA-targeted CAR T cells on BRCA2-deficient prostate cancer. Finally, as two PARP inhibitors (olaparib and rucaparib) have been approved to treat patients with DDR-deficient prostate cancer, we will investigate whether PARP inhibitors synergize with CAR T-cell therapy. For the first time, the proposed project will demonstrate the crucial importance of BRCA2/DDR alterations in prostate cancer biology and possibly lay the foundation for consideration of DDR alteration as the master driver of the transformation from indolent, localized prostate cancer to lethal mCRPC. We believe this work will lead to clinical trials that will establish new and effective treatments for this deadly disease.

抽象的 造成前列腺癌死亡率重大负担的主要贡献者，这是癌症死亡的第二个原因 在美国男性中，是雄激素剥夺疗法（ADT）的短暂效力，这是护理的主要护理 晚期和有症状的疾病。 DNA损伤修复（DDR）基因的越来越改变， BRCA2主要与ADT耐药性和预后不良有关。我们以前表明 BRCA2的有害变化足以诱导castration敏感的前列腺癌中的ADT耐药性 （PC）细胞。我们目前的建议将研究BRCA2损失/突变 - 诱导的ADT耐药性和对致命前列腺癌的发展。 使用PROREPAIR B队列中的107个DDR相关基因，我们进行了新的观察 MCRPC患者中约有82％的DDR基因改变了改变。在此，我们的目标是 全面研究DDR改变（BRCA2以外）在MCRPC发展中的作用 和对治疗的抵抗力。为此，我们将使用CRISPR筛选前瞻性地研究 DDR基因的功能丧失改变会诱导cast割抗性。 我们已经观察到前列腺特异性膜抗原（PSMA）的高表达水平。 BRCA2和其他DDR基因的丧失（例如ATM）。我们的第二个目标将研究PSMA- 在BRCA2/DDR缺陷型PC中使用[177LU] -PSMA-617和PARP抑制剂组合的靶向放射疗法。 前列腺癌主要抵抗免疫疗法。由于BRCA2缺陷型细胞也表现出更高的 PSMA表达，由于基因组不稳定的增加而可能具有免疫原性，我们将探索 靶向PSMA的CAR T细胞对BRCA2缺陷前列腺癌的影响。最后，作为两个PARP抑制剂 （Olaparib和Rucaparib）已批准治疗患有DDR缺陷前列腺癌患者，我们将 研究PARP抑制剂是否与CAR T细胞疗法协同作用。 拟议的项目首次将证明BRCA2/DDR改变的重要性 前列腺癌生物学，并可能为DDR改变作为主要驱动程序奠定基础 从懒惰的局部前列腺癌转变为致命的MCRPC。我们相信这项工作将领导 临床试验将为这种致命疾病建立新的有效治疗方法。