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确定新的、更有效的、毒性更小的治疗方法 三阴性乳腺癌（TNBC），最具侵略性和预后不良的乳腺癌亚型。我们 一个团队最近领导了第一个用于转移性TNBC的抗体-药物偶联物（ADC）的临床开发 （mTNBC），Sacituzumab Govitecan（SG，又名Trodelvy），实现了显著改善的客观缓解 降低了总生存期（OS）、无进展生存期（PFS）和总生存期（OS），并导致FDA 2020年批准。SG包含拓扑异构酶1（TOP 1）抑制剂SN-38（拓扑异构酶1的活性代谢物）。 伊立替康）偶联至靶向Trop-2的人源化单克隆抗体，Trop-2是一种在> 90% 关于mTNBC虽然它代表了一种范式改变疗法，但只有大约30%的mTNBC患者 对SG有治疗反应，强调需要确定与SG联合治疗， 将独特地补充和增强其功效。我们的初步数据导致的假设，PARP 在mTNBC中，抑制（PARPi）与SG是协同的。因此，我们将派出一名有资金支持的调查员- 启动了SG和PARPi（talazoparib）用于mTNBC的1b/2期临床试验（NCT 04039230），特别是 通过顺序给药方案，以最大限度地减少毒性并改善治疗窗。在这里，我们的团队 临床、转化和基础科学研究者寻求推进SG的合理治疗应用 和SG/PARPi，并发现结合SG的新的组合疗法。我们的目标是：i）建立 治疗反应与治疗前和DNA损伤的药效学标志物的相关性， 通过临床试验和其他患者分析，SG/talazoparib与单独SG治疗mTNBC的修复 ii）通过CRISPR确定对SG单一疗法和SG/PARPi的抗性机制 筛选和分析进展后患者样本，并测试选择的可药物靶点，以克服 iii）优化药物调度和克服SG/PARPi的新型组合的体内功效 阻力总的来说，这些研究将为下一代基于机制的 研究用于mTNBC患者的基于SG的组合疗法的治疗性试验。

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.