Synergistic combinatorial DNA damage response/repair inhibition and Sacituzumab Govitecan in triple-negative breast cancer

项目摘要 该项目的长期目标是寻找新的、更有效、毒性更小的治疗方法。 对于三阴性乳腺癌(TNBC)，是最具侵袭性和预后最差的乳腺癌亚型。我们的 该团队最近领导了第一个治疗转移性TNBC的抗体-药物结合物(ADC)的临床开发 (MTNBC)，Sacituzumab Govitecan(SG，又名Trodelvy)，实现了显著改善的客观反应 比率(ORR)、无进展生存期(PFS)和总生存期(OS)，并导致FDA加速 2020年批准。SG含有拓扑异构酶1(TOP1)抑制剂SN-38(其活性代谢物 伊立替康)与针对trop-2的人源化单抗偶联，trop-2是一种在~gt；90%中表达的肿瘤抗原。 MTNBC的。虽然它代表了一种改变范式的疗法，但只有大约30%的mTNBC患者 体验对SG的治疗反应，强调需要确定与SG的组合疗法 将独一无二地补充和提高其功效。我们的初步数据导致假设PARP 在mTNBC中，抑制(PARPI)与SG具有协同作用。因此，我们正在进行一项受资助的调查员- SG1b/2期临床试验(NCT04039230)启动，值得注意的是，SG和PARPI(他拉唑巴利)治疗mTNBC 通过顺序给药计划，将毒性降至最低，并改善治疗窗口。在这里，我们的团队 临床、翻译和基础科学研究人员寻求推动SG的合理治疗使用 和SG/PARPI，并发现合并SG的新的组合疗法。我们的目标是：i)建立 治疗前疗效与DNA损伤及药效学标志物的关系 通过临床试验和其他患者的分析，比较SG/他唑帕利与单独使用SG对mTNBC的修复作用 样本；ii)通过CRISPR确定对SG单一疗法和SG/PARPI的耐药机制 筛选和分析进展后患者样本，并测试选择要克服的可用药靶点 以及iii)优化药物调度和体内疗效，以克服SG/PARPI的新组合 抵抗。总的来说，这些研究将使下一代以机制为基础的 研究基于SG的联合治疗mTNBC患者的治疗试验。

Project Summary The long-term objective of this project is to identify new, more effective, and less toxic therapeutic approaches for triple-negative breast cancer (TNBC), the most aggressive and poor-prognosis breast cancer subtype. Our team recently led the clinical development of the first antibody-drug conjugate (ADC) for metastatic TNBC (mTNBC), Sacituzumab Govitecan (SG, aka Trodelvy), achieving dramatically improved objective response rates (ORRs), progression-free survival (PFS), and overall survival (OS), and resulting in accelerated FDA approval in 2020. SG comprises the topoisomerase 1 (TOP1) inhibitor SN-38 (the active metabolite of irinotecan) coupled to a humanized monoclonal antibody targeting Trop-2, a tumor antigen expressed in >90% of mTNBC. While it represents a paradigm-changing therapy, only approximately 30% of mTNBC patients experience a therapeutic response to SG, highlighting the need to identify combination therapies with SG that will uniquely complement and enhance its efficacy. Our preliminary data lead to the hypothesis that PARP inhibition (PARPi) is synergistic with SG in mTNBC. Accordingly, we are carrying out a funded investigator- initiated phase 1b/2 clinical trial (NCT04039230) of SG and PARPi (talazoparib) for mTNBC, notably delivered via a sequential dosing schedule to minimize toxicity and improve the therapeutic window. Here, our team of clinical, translational, and basic science investigators seeks to move forward the rational therapeutic use of SG and SG/PARPi, and to discover new combinatorial therapies incorporating SG. Our aims are: i) to establish the association of therapeutic response with pre-treatment and pharmacodynamic markers of DNA damage and repair with SG/talazoparib versus SG alone for mTNBC through analysis of clinical trial and other patient samples; ii) to determine mechanisms of resistance to SG monotherapy and SG/PARPi through CRISPR screens and analysis of post-progression patient samples, and to test select druggable targets to overcome them; and iii) to optimize drug scheduling and in vivo efficacy for novel combinations to overcome SG/PARPi resistance. Collectively, these studies will enable and inform the next generation of mechanism-based therapeutic trials investigating SG-based combinatorial therapy for patients with mTNBC.