Cooperation of the TAM and Abl family kinases in therapeutic resistance in HNC

TAM 和 Abl 家族激酶在 HNC 治疗耐药中的合作

基本信息

批准号：
10444423
负责人：
Ravi Salgia
金额：
$ 50.46万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10444423
关键词：
ABL1 gene Ablation Antibodies Apoptosis Architecture Biological Markers Biological Models Biology CRISPR/Cas technology Cancer Model Cancer cell line Cell Line Cell Nucleus Cetuximab Clinic Clinical Clinical Treatment Clinical Trials Cyclophosphamide Cytosol Data Diagnosis Distant Metastasis Epidermal Growth Factor Receptor Exhibits FDA approved Family Future Genetic Goals Head and Neck Cancer Human Human Papillomavirus Imatinib Immunotherapy In Vitro Investigation Lead Life Malignant Neoplasms Maps Measures Mediating Metastatic/Recurrent Modeling Molecular Molecular Target Monoclonal Antibodies Mus Mutate Neoplasm Circulating Cells Nuclear Nuclear Export Operative Surgical Procedures Pathologic Pathway Analysis Pathway interactions Patients Persons Pharmaceutical Preparations Phosphotransferases Platinum Play Pre-Clinical Model Protein Tyrosine Kinase Proteomics Radiation Radiation therapy Recurrence Refractory Regimen Relapse Resistance Resistance development Role Sequence Deletion Series Signal Pathway Signal Transduction Specimen Therapeutic Therapeutic Studies Tissues Translating Treatment outcome Tyrosine Wisconsin Work Xenograft procedure Zebrafish aggressive therapy axl receptor tyrosine kinase base cancer therapy chemotherapy cohort head and neck cancer patient improved improved outcome in vivo in vivo Model kinase inhibitor mutant novel novel therapeutics overexpression patient derived xenograft model predictive marker prevent response safety and feasibility small molecule inhibitor targeted agent therapeutic evaluation therapeutic target therapy resistant tumor virtual

项目摘要

PROJECT SUMMARY One of the most deployed molecular targeting agents in the treatment of head and neck cancer (HNC) is the Epidermal Growth Factor Receptor (EGFR)-targeted monoclonal antibody cetuximab (CTX). Cetuximab is a central component of the first-line EXTREME regimen and in combination with radiation therapy and is the only drug that exhibits efficacy in both locally advanced and recurrent/metastatic HNC. Although many HNC patients see CTX over the course of their cancer therapy, research over the past decade has revealed that many patients that do respond initially will eventually become refractory to CTX. To identify drivers of CTX resistance (CTXR) in HNC, our lab utilized HNC human tumor specimens, patient-derived xenografts (PDXs) and a series of acquired and intrinsically resistant in vitro and in vivo model systems. This work led to the identification of the receptor tyrosine kinase (RTK) AXL as a central driver of CTXR. To define the molecular mechanisms of how AXL signaling leads to CTXR, three tyrosine residues of AXL (Y779, Y821, Y866) were mutated and mapped for their sensitivity to CTX. Both in vitro and in vivo analysis revealed that 1) CTXR emanates from signaling from Y821 of AXL via the c-Abl kinase, 2) pre-clinical modeling (PDX) indicated that the combination of CTX plus imatinib (IMT), a c-Abl kinase inhibitor, lead to complete tumor regression without recurrence in HNC models and 3) preliminary data for this application suggests that AXL, via Y821, sequesters c-Abl in the cytosol and prevents it from moving to the nucleus, which is induced by IMT, to promote apoptosis. Collectively, we hypothesize that AXL plays a critical role in CTXR by sequestering c-Abl in the cytosol and that therapeutic targeting c-Abl in combination with CTX will lead to profound responses in HNC patients. We plan to conduct this interdisciplinary project, spanning from basic biology to a pilot clinical trial through the three following aims: 1) To investigate if a) cytoplasmic sequestration of c-Abl is responsible for AXL mediated CTXR and if b) if AXL and c-Abl association is a predictive biomarker of CTX response, 2) determine if targeting EGFR and c-Abl simultaneously in CTXR PDXs can enhance and re- sensitize to CTX, and 3) To perform a pilot window-of-opportunity study of CTX plus imatinib in patients with recurrent or metastatic HNC. Ultimately, our goal is to improve treatment outcomes for HNC patients. Successful pursuit of these investigations has the potential to significantly improve and refine current HER family-centric therapeutic approaches in HNC by understanding the molecular mechanisms of how Axl and c-Abl impart CTXR. In addition, this project has high significance by repurposing two FDA approved drugs in a new cancer setting to improve outcomes. Collectively, this work will impact future clinical treatment paradigms and identify patients most likely to benefit from targeting EGFR and c-Abl in HNC.

项目摘要在治疗头颈癌（HNC）中，部署最多的分子靶向剂之一是表皮生长因子受体（EGFR）靶向的单克隆抗体西妥昔单抗（CTX）。西妥昔单抗是一线极端方案的核心组成部分，并结合放射疗法，是唯一的在局部晚期和复发/转移性HNC中表现出功效的药物。虽然许多HNC 在过去的十年中，患者在癌症治疗过程中看到CTX的研究表明最初，许多确实有反应的患者最终会对CTX难治性。为了鉴定HNC中CTX耐药性（CTXR）的驱动因素，我们的实验室使用了HNC人类肿瘤标本，患者衍生的异种移植物（PDXS）以及一系列获得的和本质上的体外和体内抗性系统。这项工作导致了受体酪氨酸激酶（RTK）Axl的鉴定为 ctxr。为了定义AXL信号如何导致CTXR的分子机制，三个酪氨酸残基 AXL（Y779，Y821，Y866）被突变并映射，以使其对CTX的敏感性。体外和体内分析表明，1）CTXR通过C-ABL激酶从AXL的Y821发出的信号传导，2）临床前临床前建模（PDX）表明CTX Plus Imatinib（IMT）的组合是C-ABL激酶抑制剂，导致在HNC模型中完全没有复发的肿瘤回归和3）此应用的初步数据表明AXL通过Y821在细胞质中隔离C-ABL，并防止其移动到核中，该细胞核移动到该细胞核中，该核由IMT诱导，以促进凋亡。总的来说，我们假设AXL在CTXR中起着至关重要的作用在细胞质中隔离C-ABL和与CTX结合使用的治疗靶向C-ABL将导致 HNC患者的深刻反应。我们计划进行这个跨学科项目，涵盖基本生物学通过以下三个目的进行试验临床试验：1）研究是否a）胞质隔离 C-ABL的负责AXL介导的CTXR，如果B）如果AXL和C-ABL关联是预测性生物标志物 CTX响应，2）确定在CTXR PDX中同时靶向EGFR和C-ABL可以增强和重新对CTX的敏感，3）对CTX和伊马替尼进行试验窗口窗口研究经常性或转移性HNC。最终，我们的目标是改善HNC患者的治疗结果。成功追求这些调查有可能显着改善和完善她通过了解AXL和AXL的分子机制，以家庭为中心的治疗方法 C-Abl授予CTXR。此外，通过重新利用两种FDA批准的药物，该项目具有很高的意义新的癌症设置以改善结果。总体而言，这项工作将影响未来的临床治疗范式并确定最有可能受益于HNC中EGFR和C-ABL的患者。