HER2-mediated delivery of cytotoxic agents in solid tumors

实体瘤中 HER2 介导的细胞毒药物递送

基本信息

批准号：
10608129
负责人：
Sarat Chandarlapaty
金额：
$ 57.6万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10608129
关键词：
Antibody-drug conjugates Automobile Driving Basic Science Binding Biological Biopsy Breast Cancer Patient Cell Death Induction Cell Line Cell model Cell surface Characteristics Clinical Clinical Trials Colon Carcinoma Colorectal Complex Coupled Cytotoxic agent DNA Sequence Alteration Data Data Correlations Dependence Development Dimerization Disease Progression ERBB2 gene ERBB3 gene Endocytosis Endometrial Carcinoma Enrollment Epidermal Growth Factor Receptor Evolution Fc Receptor Fluorescence Resonance Energy Transfer Fluorescent in Situ Hybridization Gene Amplification Genomics Head and Neck Cancer Heterodimerization Histology Homodimerization Hyperactivity Image Immunohistochemistry In Vitro Institution Leadership Lung Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Malignant neoplasm of urinary bladder Mass Spectrum Analysis Mediating Membrane Modeling Molecular Mutation Oncogenes Oncogenic Organoids PET/CT scan Patient Monitoring Patients Pharmaceutical Preparations Phosphorylation Phosphotransferases Positioning Attribute Pre-Clinical Model Proteins Proteomics Rare Diseases Receptor Protein-Tyrosine Kinases Resistance Role Salivary duct structure Sampling Schedule Slice Solid Neoplasm Techniques Testing Therapeutic Time Tissues Toxic effect Translating Trastuzumab Treatment Protocols Tumor Biology Ubiquitination Variant Xenograft procedure biliary tract cancer cell cancer imaging cell free DNA clinical predictors cohort combinatorial cytotoxic data integration digital dosage efficacious treatment exome sequencing gastroesophageal cancer genome sequencing in vivo inhibitor insight kinase inhibitor malignant breast neoplasm malignant stomach neoplasm mutant novel therapeutic intervention novel therapeutics overexpression participant enrollment patient derived xenograft model patient population patient stratification potential biomarker predicting response proteomic signature receptor receptor binding receptor expression response response biomarker standard of care success targeted exome sequencing targeted treatment trafficking transcriptomics treatment response tumor tumor heterogeneity tumorigenesis

项目摘要

PROJECT SUMMARY ERBB2/HER2 is a receptor tyrosine kinase (RTK) that is amplified/overexpressed in 15-20% of breast and gastroesophageal cancers, for which anti-HER2 therapy is now standard of care. HER2 can be hyperactivated by overexpression and by mutations driving oncogenesis through receptor phosphorylation, internalization, and increased turnover. Hyperactivating HER2 mutations, possessed by thousands of patients with non-breast/non- gastric solid tumors, do not respond to classical anti-HER2 kinase therapy. Anti-HER2 antibody-drug conjugates (ADCs) offer a new treatment avenue for non-breast/non-gastric HER2-altered tumors. ADCs bind to HER2 on the cell surface, get internalized, and release their cytotoxic payloads in the endolysosomes to induce cell death. Two “basket” trials at our institution testing the antitumor activity of the anti-HER2 ADCs, trastuzumab emtansine (T-DM1), and trastuzumab deruxtecan (T-DXd) in n found clinical responses in lung, colorectal, salivary duct, biliary tract, ovarian, and endometrial cancers. Moreover, we showed that HER2 mutant lung tumors are responsive to T-DM1 regardless of HER2 protein levels. Here, we plan to use several cell line-based and patient-derived preclinical models (organoids, xenografts) bearing different HER2 protein levels, mutations, and activation/phosphorylation statuses to study how the variation in receptor expression/phosphorylation modulates endocytosis and anti-HER2 ADC activity. We show that irreversible pan-HER inhibitors, such as neratinib, enhance ubiquitination, internalization, and consequent degradation of HER2. Neratinib also increases HER2-ADC complex internalization in vitro, leading to complete tumor regression in patient-derived xenograft models (lung and colon cancer) bearing amplification or mutations of ERBB2. We plan to identify determinants of sensitivity to DM1 or DXd payloads by integrating genomic, transcriptomic, and proteomic data acquired from sensitive and resistant models. Finally, we will use these data to prioritize biomarkers of response to T-DM1 and T-DXd identified by genomic and proteomic analysis of the tumor samples, and imaging tumors bearing different HER2 alterations from the 124 patients enrolled in our basket trials. Tumor biopsies and cell-free DNA samples collected before and during treatment, and at disease progression will be analyzed by targeted exome sequencing, whole exome sequencing, and droplet digital PCR. These data will characterize changes in ERBB2 status during treatment and whether other genomic alterations modulate response to therapy during tumor evolution. FRET and other imaging-based techniques will quantify the level of HER2 dimerization with other RTKs. Tumor biopsies, analyzed by global and targeted mass spectrometry, will identify a specific proteomic signature of response to the ADCs. Clinical on-breast/non-gastric solid tumors, response to ADCs will also be correlated with HER2 levels by 89Zr-trastuzumab PET/CT. Our studies will provide fundamental insights into the mechanism of action of anti-HER2 ADCs and will open new therapeutic horizons for patients without effective, targeted therapy options.

项目摘要 ERBB2/HER2是一种受体酪氨酸激酶（RTK），在15-20％的乳房和过度表达乳房和过表达胃食管癌癌症现在是抗HER2治疗的标准。 HER2可以被过度活化通过过表达和突变通过受体磷酸化，内在化和营业额增加。过度激活HER2突变，数千名非胸/非 - 患者拥有胃实体瘤，不要对经典的抗HER2激酶治疗反应。抗HER2抗体 - 药物缀合物（ADC）为非胸/非胃HER2改变的肿瘤提供了新的治疗途径。 ADC绑在HER2上细胞表面，内部化并释放其细胞毒性有效载荷在内溶液体中诱导细胞死亡。我们机构的两个“篮子”试验测试了抗HER2 ADC的抗肿瘤活性， trastuzumab emtansine（t-dm1）和trastuzumab deruxtecan（t-dxd）在肺，结直肠，唾液管，胆道，卵巢和子宫内膜癌中发现了临床反应。此外，我们表明HER2突变肺肿瘤对T-DM1反应不管HER2蛋白水平。在这里，我们计划使用几种基于细胞系和患者衍生的临床前模型（器官，异种移植物具有不同的HER2蛋白水平，突变和激活/磷酸化状态受体表达/磷酸化的变化如何调节内吞作用和抗HER2 ADC活性。我们表明，不可逆转的泛抑制剂，例如Neratinib，增强泛素化，内在化和随之而来的HER2退化。 Neratinib还增加了体外HER2-ADC复合体内化的内在化，领先在患者衍生的纳学模型（肺癌和结肠癌）中完成肿瘤回归或ERBB2的突变。我们计划通过集成来确定对DM1或DXD有效载荷敏感的决定者从敏感和抗性模型中获得的基因组，转录组和蛋白质组学数据。最后，我们将使用这些数据以优先考虑通过基因组和蛋白质组学识别的对T-DM1和T-DXD的响应的生物标志物分析肿瘤样品和成像肿瘤，这些肿瘤与124例患者有不同的HER2改变参加了我们的篮子试验。治疗前后收集的肿瘤活检和无细胞的DNA样品在疾病中，将通过针对性的外显子组测序，整个外显子组测序和液滴数字PCR。这些数据将表征治疗过程中ERBB2状态的变化，以及其他是否基因组改变调节肿瘤进化过程中对治疗的反应。 FRET和其他基于成像的技术将用其他RTK量化HER2二聚化水平。肿瘤活检，由全球和靶向质谱法将确定对ADC响应的特定蛋白质组学特征。临床胸部/非胃实体瘤，对ADC的响应也将与HER2级别相关 89ZR-TRASTUZUMAB PET/CT。我们的研究将提供对抗HER2 ADC的作用机理的基本见解，并将打开新的治疗视野适用于没有有效的，有针对性治疗的患者。