Novel targeted therapies for BRCA-associated cancer

描述（由申请人提供）：BRCA1或BRCA2 （BRCA）突变的携带者患乳腺癌（BC）和卵巢癌（OC）的负担不成比例，但他们的肿瘤具有独特的生物学特征，可以利用。肿瘤细胞中BRCA缺乏与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）比靶向肿瘤的强项（细胞快速增殖）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步骤，同时保留具有完整BRCA拷贝的正常细胞；2)这些抑制剂表现出高治疗指数。聚（adp -核糖）聚合酶（PARP）是一种治疗靶点，在碱基切除修复中起作用，并与HRR互补。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作用的药物。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）的效果，该抑制剂在我们的临床前工作中得到验证，在IV期BRCA相关乳腺癌患者的II期随机试验中，作为单一药物与作为卡铂的增强剂使用。相关研究将包括反应和耐药的生物标志物。对可能通过恢复HRR功能而赋予治疗耐药性的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性的潜在补救措施。我们的临床基础设施是由一个已建立的多机构临床试验联盟和一个包含大量遗传性BC和OC女性的临床癌症遗传学网络所支撑的。全国多个N01财团及其附属机构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经验教训应用于brca样乳腺癌和卵巢癌的治疗，以及转移到更有限的阶段和新辅助设置。关键的是，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，可能为brca相关的乳腺癌女性提供更有效的治疗方法，副作用更少。这些研究预计将导致逐步创新的项目，以进一步提高治疗的有效性，并对智能设计的干预措施进行试验，以绕过障碍。

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.