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

基本信息

批准号：
10390503
负责人：
Aditya Bardia
金额：
$ 55.98万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
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/10390503
关键词：
1-Phosphatidylinositol 3-Kinase Address 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 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 base 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

项目摘要

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.

项目概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)，这是最具侵袭性和预后最差的乳腺癌亚型。我们的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），显着改善了客观反应率（ORR）、无进展生存期（PFS）和总生存期（OS），并导致 FDA 加速于 2020 年获得批准。SG 包含拓扑异构酶 1 (TOP1) 抑制剂 SN-38（拓扑异构酶 1 (TOP1) 的活性代谢物伊立替康）与靶向 Trop-2 的人源化单克隆抗体偶联，Trop-2 是一种肿瘤抗原，表达量 >90% mTNBC。虽然它代表了一种改变范式的疗法，但只有大约 30% 的 mTNBC 患者经历对 SG 的治疗反应，强调需要确定 SG 的联合疗法，将独特地补充和增强其功效。我们的初步数据得出这样的假设：PARP 抑制 (PARPi) 与 mTNBC 中的 SG 具有协同作用。因此，我们正在开展一项资助的调查—— 启动 SG 和 PARPi (talazoparib) 治疗 mTNBC 的 1b/2 期临床试验 (NCT04039230)，特别是已交付通过顺序给药方案来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人员致力于推动 SG 的合理治疗应用和 SG/PARPi，并发现包含 SG 的新组合疗法。我们的目标是： i) 建立治疗反应与治疗前和 DNA 损伤的药效学标记物的关系通过临床试验和其他患者的分析，SG/talazoparib 修复与单独 SG 治疗 mTNBC 样品； 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，并测试选定的可药物靶标以克服他们; iii) 优化新组合的药物调度和体内功效，以克服 SG/PARPi 反抗。总的来说，这些研究将为下一代基于机制的研究提供支持和信息研究基于 SG 的组合疗法对 mTNBC 患者的治疗试验。