Research Project 1

研究项目1

• 批准号: 10732990
• 负责人: Cynthia X Ma
• 金额: $ 23.09万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10732990
• 关键词: Address; Aftercare; Antibody-drug conjugates; Apoptosis; Area; Biological Assay; Biological Markers; Biopsy; Cell Death; Clinic; Clinical; Clinical Trials; Colorectal Cancer; DNA; DNA Damage; DNA Markers; Data; Development; Drug Design; ERBB2 gene; Future; Immunohistochemistry; In Vitro; Investigation; Malignant Neoplasms; Malignant neoplasm of lung; Mass Spectrum Analysis; Modeling; Mutation; Non-Small-Cell Lung Carcinoma; Organoids; Pancreatic Adenocarcinoma; Pathway interactions; Patient Selection; Patient-derived xenograft models of breast cancer; Pharmaceutical Preparations; Poly(ADP-ribose) Polymerase Inhibitor; Proteins; Proteome; Proteomics; Research Project Grants; Sampling; Small Nuclear RNA; Spatial Distribution; Surface; Testing; Topoisomerase-I Inhibitor; Trastuzumab; Tumor-Derived; Type I DNA Topoisomerases; Universities; Validation; Washington; antitumor effect; cancer cell; cancer type; cell killing; chemotherapy; cytotoxic; design; drug testing; exome sequencing; gastroesophageal cancer; homologous recombination; improved; in vitro Model; in vivo; inhibitor; malignant breast neoplasm; malignant stomach neoplasm; multiple reaction monitoring; next generation; patient derived xenograft model; patient subsets; phosphoproteomics; predicting response; proteogenomics; repaired; response; response biomarker; synergism; transcriptome; transcriptome sequencing; transcriptomics; treatment effect; treatment response; tumor; tumor heterogeneity; uptake

RESEARCH PROJECT 1 - SUMMARY Antibody-drug conjugates (ADCs) are a rapidly growing class of chemotherapy drugs designed to deliver cancer cell specific cytotoxic payloads. Trastuzumab-deruxtecan (DS-8201a) is a pioneer next generation ADC comprised of trastuzumab attached to a topoisomerase I (TOP1) inhibitor payload via a unique cleavable linker. DS-8201a is under active investigation for the treatment of multiple cancer types, and has received FDA approval for several indications, including advanced HER2-positive (IHC 3+ or ISH+) and more recently the HER2-low (IHC 1+, 2+/ISH-) breast cancer (BC). However, a subset of patients with HER2 IHC 0 BC also responded to DS-8201a in clinical trials. The immunohistochemistry (IHC) assay routinely used in the clinic is inadequate in distinguishing the lower ranges of HER2 expression. Development of a more quantitative HER2 assay is an unmet need. Using multiple-reaction monitoring mass spectrometry (MRM-MS) proteomic approach, our collaborator Dr. Amanda Paulovich has developed a CLIA assay which is capable of detecting a large range of HER2 expression in BCs that are HER2-low or HER2 0 by conventional IHC. In this proposal, we will examine the utility of this assay in predicting DS-8201a efficacy in “HER2 low” BC, defined by HER2 IHC 0-2+/ISH-. We hypothesize that HER2 expression quantified by the MRM-MS could predict DS-8201a activity. Another area of unmet clinical need that this project addresses is to develop mechanism-based strategies to improve the efficacy of DS-8201a for HER2 low tumors since they often derive less benefit from DS-8201a monotherapy. Based on our preliminary data, we hypothesize that inhibitors against components of the DNA damage response and repair pathway (DDRi) could enhance the anti-tumor effect of DS-8201a. In Aim 1, we will examine whether the HER2 expression by MRM-MS and DDR pathway alterations predict response to single agent DS-8201a using 100 HER2 low BC PDX derived organoid models. Drug response in organoids will be validated in selected PDX models in vitro. In Aim 2, we will determine whether DDRi, including the PARPi (olaparib), ATRi (AZD6738), ATMi (AZ1930), BERi (TRC-102), and DNA-PKi (M3814), enhances the anti-tumor effect of DS-8201a in HER2 low BC in vitro and in vivo. We will investigate treatment effects of DDRi and DS-8201a, alone or in combination, on HER2 level, markers of DNA damage, apoptosis, and on the transcriptome and proteome/phosphoproteome. We will also perform spatial transcriptomics and snRNA sequencing of selected PDX models to analyze intra- tumor heterogeneity in treatment response. In Aim 3, we will examine whether DDRi enhances the anti-tumor activity of DS-8201a in HER2 low colorectal cancer, lung cancer, and pancreatic adenocarcinoma. By assessing the utility of a quantitative HER2 assay and proteogenomic analyses of DDR pathway, we aim to improve the selection of patients likely to respond to DS-8201a in future trials. Results from the PDX and organoid testing of DDRi in combination with DS-8201a will likely lead to the design of biomarker directed clinical trials.

研究项目1 -摘要 抗体-药物缀合物（ADC）是一类快速增长的化疗药物，其设计用于递送癌症， 细胞特异性细胞毒性有效载荷。曲妥珠单抗-德鲁克替康（DS-8201 a）是下一代ADC的先驱 包含通过独特的可切割接头连接至拓扑异构酶I（TOP 1）抑制剂有效负载的曲妥珠单抗。 DS-8201 a正在积极研究用于治疗多种癌症类型，并已获得FDA批准 用于几种适应症，包括晚期HER 2阳性（IHC 3+或ISH+）和最近的HER 2低 (IHC 1+，2+/ISH-）乳腺癌（BC）。然而，HER 2 IHC 0 BC的患者亚组也对 DS-8201 a临床试验。临床上常规使用的免疫组织化学（IHC）测定不足以 区分HER 2表达的较低范围。开发更定量的HER 2检测是一个重要的挑战。 未满足的需求使用多反应监测质谱（MRM-MS）蛋白质组学方法，我们 合作者阿曼达Paulovich博士开发了一种CLIA测定法，该测定法能够检测大范围的 通过常规IHC测定的低HER 2或0 HER 2的BC中的HER 2表达。在本建议中，我们将研究 该试验在预测DS-8201 a在“低HER 2”BC（定义为HER 2 IHC 0-2+/ISH-）中的疗效方面的效用。我们 假设通过MRM-MS定量的HER 2表达可预测DS-8201 a活性。的另一个领域 该项目解决的未满足的临床需求是开发基于机制的策略以提高疗效 DS-8201 a治疗HER 2低水平肿瘤的有效性，因为它们通常从DS-8201 a单药治疗中获益较少。基于 根据我们的初步数据，我们假设抑制剂对DNA损伤反应和修复的成分， DDRi通路（DDRi）可增强DS-8201 a的抗肿瘤作用。在目标1中，我们将检查HER 2是否 MRM-MS表达和DDR通路改变预测了使用100 HER 2低BC PDX衍生的类器官模型。将在选定的PDX中验证类器官中的药物反应 体外模型。在目标2中，我们将确定DDRi，包括PARPi（奥拉帕尼）、ATRi（AZD 6738）， ATMi（AZ 1930）、BERi（TRC-102）和DNA-PKi（M3814）可增强DS-8201 a在HER 2中的抗肿瘤作用 低BC在体外和体内。我们将研究DDRi和DS-8201 a单独或联合使用的治疗效果， HER 2水平、DNA损伤标志物、细胞凋亡以及转录组和蛋白质组/磷酸化蛋白质组。 我们还将对选定的PDX模型进行空间转录组学和snRNA测序，以分析细胞内的 治疗反应的肿瘤异质性。在目标3中，我们将检查DDRi是否增强抗肿瘤作用。 DS-8201 a在HER 2低水平结直肠癌、肺癌和胰腺癌中的活性。通过评估 利用定量HER 2测定和DDR途径的蛋白基因组学分析，我们旨在改善 在未来试验中选择可能对DS-8201 a有应答的患者。PDX和类器官检测的结果 DDRi与DS-8201 a联合使用可能会导致生物标志物导向临床试验的设计。