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-药物结合物(Adc)是一类快速增长的化疗药物，旨在转移癌症。 细胞特异性细胞毒性有效载荷。曲妥珠单抗-deruxtecan(DS-8201a)是新一代ADC的先驱 由曲妥珠单抗通过独特的可切割连接子连接到拓扑异构酶I(TOP1)抑制剂有效载荷上。 DS-8201a正在积极研究中，用于治疗多种癌症类型，并已获得FDA的批准 对于几个指征，包括晚期HER2阳性(IHC 3+或ISH+)和最近的HER2低 (IHC 1+，2+/ISH-)乳腺癌。然而，HER2 IHC 0 BC患者的一部分也对 DS-8201a正在进行临床试验。临床上常规使用的免疫组织化学(IHC)分析方法不适用于 区分HER2表达的下限范围。开发一种更定量的HER2检测是一种 未得到满足的需求。利用多反应监测质谱学(MRM-MS)蛋白质组学方法，我们的 合作者阿曼达·保罗维奇博士开发了一种CLIA检测方法，能够检测出大范围的 HER2在常规免疫组化检测为HER2-低或HER20的BC中的表达。在这份提案中，我们将研究 本试验用于预测DS-8201a在HER2 IHC 0-2+/ISH-定义的“HER2低”BC中的疗效。我们 假设MRM-MS定量的HER2表达可以预测DS-8201a的活性。另一个领域 这个项目解决的未得到满足的临床需求是开发基于机制的策略来提高疗效 DS-8201a用于HER2低度肿瘤，因为它们通常从DS-8201a单一疗法中获益较少。基于 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 通路(DDRI)可增强DS-8201a的抗肿瘤作用。在目标1中，我们将研究HER2 MRM-MS和DDR途径改变的表达预测使用100对单一药物DS-8201a的反应 HER2低BC PDX衍生类有机物模型。有机化合物中的药物反应将在选定的PDX中得到验证 体外模型。在目标2中，我们将确定DDRI，包括PARPI(Olaparib)，ATRI(AZD6738)， ATMI(AZ1930)、BERI(TRC-102)和DNA-PKI(M3814)增强DS-8201a在HER2中的抗肿瘤作用 低BC的体外和体内实验。我们将研究DDRI和DS-8201a单独或联合治疗的效果， 在HER2水平上，DNA损伤、细胞凋亡的标志物，以及转录组和蛋白质组/磷酸蛋白质组的标志物。 我们还将对选定的PDX模型进行空间转录和SnRNA测序，以分析内部 治疗反应中的肿瘤异质性。在目标3中，我们将检查DDRI是否增强了抗肿瘤作用 DS-8201a在HER2低位结直肠癌、肺癌和胰腺癌中的活性通过评估 HER2定量分析和DDR途径的蛋白质组学分析的有效性，我们的目标是改善 在未来的试验中选择可能对DS-8201a有反应的患者。PDX和有机化合物测试的结果 DDRI与DS-8201a的结合可能会导致生物标记物导向临床试验的设计。