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.

项目概要头颈癌 (HNC) 治疗中最常用的分子靶向药物之一是表皮生长因子受体 (EGFR) 靶向单克隆抗体西妥昔单抗 (CTX)。西妥昔单抗是一种一线 EXTREME 方案的核心组成部分并与放射治疗相结合，是唯一该药物对局部晚期和复发/转移性 HNC 均有效。尽管许多 HNC 患者在癌症治疗过程中接受 CTX 治疗，过去十年的研究表明许多最初有反应的患者最终会对 CTX 产生耐药性。为了确定 HNC 中 CTX 耐药性 (CTXR) 的驱动因素，我们的实验室利用了 HNC 人类肿瘤标本，患者来源的异种移植物（PDX）和一系列获得性和固有耐药的体外和体内模型系统。这项工作导致受体酪氨酸激酶 (RTK) AXL 被鉴定为 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）经过突变并绘制了它们对 CTX 的敏感性。体外和体内分析显示 1) CTXR 通过 c-Abl 激酶源自 AXL Y821 的信号传导，2) 临床前模型（PDX）表明，CTX 与伊马替尼（IMT）（一种 c-Abl 激酶抑制剂）的组合可导致 HNC 模型中肿瘤完全消退且无复发，以及 3) 此应用的初步数据表明 AXL 通过 Y821 将 c-Abl 隔离在细胞质中并阻止其移动到细胞核，这由IMT诱导，促进细胞凋亡。总的来说，我们假设 AXL 通过以下方式在 CTXR 中发挥关键作用：将 c-Abl 隔离在细胞质中，并且靶向 c-Abl 的治疗与 CTX 组合将导致 HNC 患者的深刻反应。我们计划开展这个跨学科项目，从基础到通过以下三个目标将生物学应用于试点临床试验： 1) 研究是否 a) 细胞质隔离 c-Abl 的 c-Abl 负责 AXL 介导的 CTXR，并且如果 b) 如果 AXL 和 c-Abl 关联是预测性生物标志物 CTX 反应的影响，2) 确定在 CTXR PDX 中同时靶向 EGFR 和 c-Abl 是否可以增强和重新对 CTX 敏感，以及 3) 在患有以下疾病的患者中进行 CTX 加伊马替尼的试点机会窗口研究复发性或转移性 HNC。最终，我们的目标是改善 HNC 患者的治疗结果。成功开展这些研究有可能显着改进和完善当前的 HER 通过了解 Axl 和 HNC 的分子机制，以家庭为中心的治疗方法 c-Abl 赋予 CTXR。此外，该项目通过将两种 FDA 批准的药物重新用于一个新的用途，具有很高的意义。新的癌症设置以改善结果。总的来说，这项工作将影响未来的临床治疗范式并确定最有可能从 HNC 中靶向 EGFR 和 c-Abl 获益的患者。