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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.

项目概要 ERBB2/HER2 是一种受体酪氨酸激酶 (RTK)，在 15-20% 的乳腺和胃食管癌，抗 HER2 疗法现已成为标准治疗方法。 HER2 可能过度激活通过过度表达和突变通过受体磷酸化、内化和驱动肿瘤发生营业额增加。数以千计的非乳腺癌/非乳腺癌患者拥有过度激活的 HER2 突变胃实体瘤对经典的抗 HER2 激酶疗法没有反应。抗 HER2 抗体-药物偶联物（ADC）为非乳腺癌/非胃 HER2 改变的肿瘤提供了新的治疗途径。 ADC 与 HER2 结合细胞表面，被内化，并在内溶酶体中释放其细胞毒性有效负载以诱导细胞死亡。我们机构的两项“篮子”试验测试了抗 HER2 ADC 的抗肿瘤活性，曲妥珠单抗 emtansine (T-DM1) 和曲妥珠单抗 deruxtecan (T-DXd) found clinical responses in lung, colorectal, salivary duct, biliary tract, ovarian, and endometrial cancers. 此外，我们发现 HER2 突变型肺肿瘤对 T-DM1 有反应，无论 HER2 蛋白如何水平。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（类器官、异种移植物）具有不同的 HER2 蛋白水平、突变和激活/磷酸化状态以供研究受体表达/磷酸化的变化如何调节内吞作用和抗 HER2 ADC 活性。我们发现，不可逆的泛 HER 抑制剂（例如来那替尼）可增强泛素化、内化和 HER2 随之发生降解。 Neratinib 还在体外增加 HER2-ADC 复合物的内化，领先在患者来源的异种移植模型（肺癌和结肠癌）中完成带有扩增的肿瘤消退或 ERBB2 突变。我们计划通过集成来确定对 DM1 或 DXd 有效负载敏感度的决定因素从敏感和耐药模型中获取的基因组、转录组和蛋白质组数据。最后，我们将使用这些数据可优先考虑通过基因组和蛋白质组学鉴定的对 T-DM1 和 T-DXd 反应的生物标志物对 124 名患者的肿瘤样本进行分析，并对具有不同 HER2 改变的肿瘤进行成像参加我们的篮子试验。治疗前和治疗期间收集的肿瘤活检和游离 DNA 样本，并在疾病进展时通过靶向外显子组测序、全外显子组测序和液滴数字PCR。这些数据将表征治疗期间 ERBB2 状态的变化以及是否有其他变化基因组改变在肿瘤进化过程中调节对治疗的反应。 FRET 和其他基于成像的技术将量化 HER2 与其他 RTK 的二聚化水平。肿瘤活检，通过全球和靶向质谱分析将识别对 ADC 反应的特定蛋白质组学特征。临床乳腺癌/非胃实体瘤，对 ADC 的反应也与 HER2 水平相关 89Zr-曲妥珠单抗 PET/CT。我们的研究将提供对抗 HER2 ADC 作用机制的基本见解并将开辟新的治疗视野对于没有有效、有针对性的治疗选择的患者。