ALK 重排淋巴瘤对 ALK 抑制剂的耐药机制-猫眼课题宝

ALK 重排淋巴瘤对 ALK 抑制剂的耐药机制

批准号：

9111860

负责人：

Roberto Chiarle

金额：

$40.49万

依托单位：

BOSTON CHILDREN'S HOSPITAL

依托单位国家：

美国

项目类别：

财政年份：

2015

资助国家：

美国

项目状态：

已结题

起止时间：

2015-07-16 至 2020-06-30

来源：

https://reporter.nih.gov/project-details/9111860

关键词：

Amino Acids Apoptosis Binding Biological Biology Bypass CRISPR/Cas technology Candidate Disease Gene Cataloging Catalogs Cell Line Cells Clinical Clinical Research Data Dependency Development Dose Drug resistance Epidermal Growth Factor Receptor Future Gene Amplification Gene Rearrangement Generations Genes Genetic Genetic Screening Genomics Goals Growth Hematologic Neoplasms Human IGF1R gene In Vitro Inflammatory Pseudotumor Ki-1 Large-Cell Lymphoma Knock-out Libraries Lymphocyte Biology Lymphoma Malignant Neoplasms Modality Molecular Mutate Mutation NPM1 gene Neuroblastoma Non-Small-Cell Lung Carcinoma Oncogenes Oncogenic Pathway interactions Patients Pharmaceutical Preparations Phase III Clinical Trials Phosphatidylinositols Phosphotransferases Point Mutation Protein Tyrosine Kinase Proteomics Proto-Oncogene Protein c-kit Receptor Protein-Tyrosine Kinases Relapse Resistance Resistance development Role Sampling Series Signal Pathway Signal Transduction Solid Neoplasm Staging T-Cell Activation T-Cell Lymphoma T-Lymphocyte Therapeutic Time Tumor Biology Tyrosine Kinase Domain Tyrosine Kinase Inhibitor Up-Regulation Withdrawal anaplastic lymphoma kinase base cancer therapy clinical efficacy exome sequencing genome editing genome-wide in vitro Model in vivo inhibitor/antagonist kinase inhibitor knock-down mouse model mutant neoplastic cell novel novel strategies nucleophosmin overexpression phosphoproteomics preclinical study public health relevance relapse patients resistance mechanism response screening transcriptome sequencing tumor tumor growth tumor progression

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英文摘要

DESCRIPTION (provided by applicant): The Anaplastic Lymphoma Kinase (ALK) is a potent driver oncogene for a relevant subset of cancers, including Anaplastic Large Cell Lymphoma (ALCL), Non Small Cell Lung Cancer (NSCLC), Inflammatory Myofibroblastic tumors (IMT) and neuroblastoma. The recent development and FDA approval of first and second-generation ALK tyrosine kinase inhibitors (TKI) has revolutionized the therapeutic opportunities to treat ALK-driven cancers. In NSCLC TKI inhibitor have dramatic clinical efficacy on such tumors, but the effect is lost after a window of time of 8-10 months because of the development of TKI resistance by the tumor cells. Several molecular mechanisms of resistance have been elucidated or proposed for TKI resistant NSCLC, including ALK mutation, amplifications, or by-pass signaling by other tyrosine kinases. The elucidation of the mechanisms of resistance can dictate additional lines of therapies in relapsing patients. In contrast to NSCLC, in ALCL the clinical studies with TKI are at a very early stage and mechanisms of resistance are almost completely unknown. In this project, we aim at generating a comprehensive characterization of the molecular mechanisms that generate resistance to ALK TKI in ALCL. By hypothesis-driven or screening approaches, we will elucidate most of the resistance mechanisms and we will evaluate in pre-clinical studies additional therapeutic strategies that could be specifically used for each mechanism. Specifically, we will generate a comprehensive catalog of ALK mutations that confer resistance to TKI and their sensitivity to different ALK inhibitors. We will validate ad propose therapies for patients that become resistant by ALK amplification or PI3K upregulation. Finally we will use proteomic and genetic screens to discover novel mechanisms of resistance. Thus, our results will provide an experimental guide for the therapeutic management of lymphoma patients that develop resistance to ALK TKI.

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