Novel targeted therapies for BRCA-associated cancer

描述(申请人提供)：BRCA1或BRCA2(BRCA)突变的携带者不成比例地承受着乳腺癌(BC)和卵巢癌(OC)的负担，但他们的肿瘤具有独特的生物学特征，可以加以利用。肿瘤细胞中BRCA缺陷与DNA同源重组修复(HRR)受损有关。我们提出了BRCA相关癌症治疗方法的范式转变，并假设攻击肿瘤的弱点(DNA修复能力减弱)比瞄准肿瘤的优势(快速细胞增殖)更有效。这种方法有两个优点：1)它专门针对失去BRCA功能的肿瘤细胞，这几乎是BRCA相关癌症发展的必经之路，同时保留了完整的BRCA副本的正常细胞；2)这些抑制剂显示出高的治疗指数。聚(ADP-核糖)聚合酶(PARP)是一种在碱基切除修复中起作用的治疗靶点，是HRR的补充。在BRCA缺乏的情况下，卡铂是一种可能与PARP抑制剂具有显著协同效应的药物。我们将进行一项随机II期临床试验，以确定一种新的口服PARP抑制剂(ABT-888)作为单一药物与其作为卡铂增强剂在IV期BRCA相关乳腺癌患者的II期随机试验中的作用。相关研究将包括反应和耐药性的生物标记物。对可能通过恢复HRR功能而导致治疗耐药的BRCA逆转突变的前瞻性观察是进行新探索的关键机会--更好地了解机制将提出克服或规避治疗耐药的潜在补救措施。我们的临床基础设施由一个已建立的多机构临床试验联盟和一个临床癌症遗传学网络支撑，该网络拥有一大批患有遗传性BC和OC的女性。全国其他多个N01财团及其附属公司已同意就这项研究进行合作，支持及时完成这项CTEP批准的试验的可行性。未来的研究可能包括将所学到的经验应用于BRCA样乳腺癌和卵巢癌的治疗，以及迁移到更有限的分期和新辅助治疗环境中。关键是，通过利用在许多肿瘤中发现的弱点-DNA修复缺陷-这项创新研究提出了一种与癌症相关的治疗策略，可能会为患有BRCA相关BC的女性提供更有效的治疗方法，同时副作用更少。这些研究预计将导致逐步创新的项目，以进一步提高治疗和干预试验的有效性，这些干预措施旨在智能地绕过障碍。 公共卫生相关性：我们临床转化事业的主要目标是操纵DNA修复途径，以确定导致利用肿瘤中BRCA相关和3BRCA样2 HRR缺陷的新疗法的靶点。在这项建议中，我们将测试聚(ADP-核糖)聚合酶抑制剂和顺铂的组合，每个药物都有望在BRCA相关BC的女性中具有潜在的活性，并通过我们的相关科学，我们将探索影响和耐药机制的生物标记物。

DESCRIPTION (provided by applicant): Carriers of a BRCA1 or BRCA2 (BRCA) mutation are disproportionately burdened by breast cancer (BC) and ovarian cancer (OC), yet their tumors have a unique biological profile that can be exploited. BRCA deficiency in tumor cells is associated with impaired homologous recombination repair (HRR) of DNA. We propose a paradigm shift in the therapeutic approach to BRCA-associated cancer and hypothesize that assaulting a tumor's weak point (diminished DNA repair capacity) is more efficient than targeting a tumor's forte (rapid cell proliferation). There are two advantages to this approach: 1) it specifically targets tumor cells that have lost BRCA function, an almost obligatory step in the development of BRCA-associated cancer, while sparing normal cells with an intact copy of BRCA, and 2) these inhibitors manifest a high therapeutic index. Poly(ADP-ribose) polymerase (PARP) is a therapeutic target that functions in base excision repair and is complementary to HRR. Carboplatin is an agent that may have significant synergistic effect with PARP inhibitors in the BRCA-deficient setting. We will conduct a randomized phase II clinical trial that will determine the effect of a new oral PARP inhibitor (ABT-888), validated in our pre-clinical work, as a single agent versus its use as a potentiator of carboplatin in a phase II randomized trial in patients with stage IV BRCA- associated breast cancer. Correlative studies will include biomarkers of response and resistance. Prospective observation of possible BRCA reversion mutations that may confer resistance to therapy by restoring HRR function is a critical opportunity for novel exploration- better understanding of mechanisms will suggest potential remedies to overcome or circumvent therapy resistance. Our clinical infrastructure is anchored by an established multi-institutional clinical trial consortium and a clinical cancer genetics network with a large cohort of women with hereditary BC and OC. Multiple additional N01 consortia and their affiliates across the country have agreed to collaborate on this study, supporting the feasibility of timely completion of this CTEP-approved trial. Future studies may include applying the lessons learned to treatment of BRCA-like breast cancers and ovarian cancer, as well as migration to more limited stage and neoadjuvant settings. Critically, by exploiting a frailty found in many tumors-DNA repair deficiencies-this innovative study proposes a cancer-relevant therapeutic strategy that may provide more effective treatments with fewer side effects for women with BRCA-associated BC. These studies are expected to lead to progressively innovative projects to further enhance efficacy of treatments and trials of interventions intelligently designed to work around barriers. PUBLIC HEALTH RELEVANCE: The major goal of our clinical translational enterprise is to manipulate DNA repair pathways to identify targets leading to new therapies that exploit BRCA-associated and 3BRCA-like2 HRR deficiencies in tumors. In this proposal we will test the combination of a poly(ADP-ribose) polymerase inhibitor and cisplatin combination, each an agent expected to have potential activity in women with BRCA-associated BC, and through our correlative science we will explore biomarkers of effect and mechanisms of resistance.