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

摘要 前列腺癌是癌症死亡的第二大原因， 在美国男性中，是雄激素剥夺疗法（ADT）的短期疗效，ADT是治疗 晚期和症状性疾病。DNA损伤修复（DDR）基因的改变越来越多， 主要是BRCA 2，与ADT耐药和预后不良有关。我们之前已经证明， BRCA 2的有害改变足以在去势敏感性前列腺癌中诱导ADT抗性 (PC)细胞我们目前的提案将研究BRCA 2缺失/突变的分子机制- 诱导ADT耐药并进展为致死性前列腺癌。 使用PROREPAIR B组的107个DDR相关基因，我们进行了新的观察 约82%的mCRPC患者存在一个或多个DDR基因的改变。在此，我们的目标是 全面研究DDR改变（BRCA 2除外）在mCRPC发生中的作用 和对治疗的抵抗为此，我们将使用CRISPR筛选来前瞻性地研究如何获得 或DDR基因的功能丧失改变诱导去势抗性。 我们已经观察到高水平的前列腺特异性膜抗原（PSMA）的表达， BRCA 2和其他DDR基因的缺失（例如，ATM）。我们的第二个目标是研究PSMA的影响- [177 Lu]-PSMA-617和PARP抑制剂组合在BRCA 2/DDR缺陷型PC中的靶向放疗。 前列腺癌主要对免疫疗法有抗性。由于BRCA 2缺陷细胞也表现出更高的 由于基因组不稳定性增加，PSMA表达和可能具有免疫原性，我们将探讨 靶向PSMA的CAR T细胞对BRCA 2缺陷型前列腺癌的作用。最后，作为两种PARP抑制剂 （olaparib和rucaparib）已被批准用于治疗DDR缺陷型前列腺癌患者，我们将 研究PARP抑制剂是否与CAR T细胞疗法协同作用。 拟议项目将首次表明BRCA 2/复员方案改建在 前列腺癌生物学，并可能为考虑DDR改变作为主要驱动因素奠定基础 从惰性、局限性前列腺癌向致死性mCRPC的转化。我们相信这项工作将导致 到临床试验，将建立新的和有效的治疗这种致命疾病。

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.