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

三阴性乳腺癌中协同组合 DNA 损伤反应/修复抑制和 Sacituzumab Govitecan

• 批准号: 10544525
• 负责人: Aditya Bardia
• 金额: $ 54.86万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10544525
• 关键词: Acceleration; Antibody-drug conjugates; Basic Science; Biological Markers; Biopsy; Breast Cancer Cell; Breast Cancer Patient; CRISPR screen; Cell model; Cells; Clinical; Clinical Sciences; Clinical Trials; Combined Modality Therapy; Complement; Complex; Coupled; DNA Damage; DNA Repair; Data; Disease; Dose; Drug Combinations; Drug Targeting; Exhibits; FDA approved; Funding; Immunohistochemistry; Lead; Link; Mediating; Modeling; Molecular Analysis; Morbidity - disease rate; Organoids; PARP inhibition; PIK3CG gene; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase Ib/II Clinical Trial; Preclinical Testing; Prediction of Response to Therapy; Prognosis; Progression-Free Survivals; Refractory; Research Personnel; Resistance; SN-38; Sampling; Schedule; Series; Testing; Therapeutic; Therapeutic Trials; Therapeutic Uses; Topoisomerase; Toxic effect; Translational Research; Treatment-related toxicity; Triplet Multiple Birth; Tumor Antigens; Validation; Work; cancer subtypes; chemotherapy; clinical biomarkers; clinical development; clinical trial analysis; clinically relevant; combinatorial; druggable target; exome sequencing; experience; homologous recombination; humanized monoclonal antibodies; improved; improved outcome; in vivo; in vivo evaluation; inhibitor; innovation; irinotecan; malignant breast neoplasm; mortality; new combination therapies; new therapeutic target; next generation; novel; novel therapeutic intervention; objective response rate; optimal treatments; patient derived xenograft model; patient subsets; pharmacodynamic biomarker; predicting response; repaired; resistance mechanism; response; success; synergism; transcriptome sequencing; translational goal; treatment response; triple-negative invasive breast carcinoma; tumor

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.

项目摘要 该项目的长期目标是确定新的，更有效且毒性更少的治疗方法 对于三阴性乳腺癌（TNBC），乳腺癌亚型是最具侵略性，最不良的乳腺癌。我们的 团队最近领导了转移性TNBC的第一抗抗体 - 药物结合物（ADC）的临床开发 （MTNBC），Sacituzumab Govitecan（SG，又名Trodelvy），实现了极大改善的客观响应 率（ORR），无进展生存期（PFS）和总生存率（OS），并导致FDA加速 批准在2020年。SG包括拓扑异构酶1（TOP1）抑制剂SN-38 伊立替康）与靶向trop-2的人源化单克隆抗体耦合，肿瘤抗原以> 90％的形式表达 mtnbc。虽然它代表了改变范式的疗法，但只有大约30％的MTNBC患者 经历对SG的治疗反应，强调了与SG识别组合疗法的需求 将独特地补充并增强其功效。我们的初步数据导致了一个假设 抑制（PARPI）与MTNBC中的SG协同作用。因此，我们正在进行一名资助的调查员 - SG和PARPI（TALAZOPARIB）的启动1B/2期临床试验（NCT04039230）用于MTNBC，特别是交付 通过连续的给药时间表，以最大程度地减少毒性并改善治疗窗口。在这里，我们的团队 临床，转化和基础科学研究者试图推动SG的合理治疗使用 和SG/PARPI，并发现合并SG的新组合疗法。我们的目标是：i）建立 治疗反应与DNA损伤的预处理和药效学标记的关联 通过分析临床试验和其他患者，使用SG/Talazoparib与SG仅与SG进行MTNBC的维修 样品； ii）确定通过CRISPR的SG单一疗法和SG/PARPI的抗性机制 筛选和分析后期后的患者样品，并测试选定的可毒靶以克服 他们; iii）以优化新型组合的药物调度和体内功效以克服SG/PARPI 反抗。总的来说，这些研究将使并告知下一代基于机制 针对MTNBC患者的基于SG的组合治疗的治疗试验。