Targeting mesenchymal-like cells in oral cancer to overcome cetuximab resistance

靶向口腔癌中的间充质样细胞以克服西妥昔单抗耐药性

基本信息

批准号：
8729870
负责人：
Devraj Basu
金额：
$ 13.38万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8729870
关键词：
Ablation Accounting Address Antibodies Area Automobile Driving Behavior Biometry Bypass Carcinoma Cell Line Cells Cessation of life Cetuximab Clinical Combined Modality Therapy Communities Data Dependence Detection Diagnostic Neoplasm Staging Disease Drug resistance E-Cadherin Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Epigenetic Process Epithelial Feedback Fibroblasts Gene Expression Goals Green Fluorescent Proteins Growth Head and neck structure Heterogeneity Human IL8 gene In Vitro Individual Interleukin-6 International Laboratories Learning Life Malignant Epithelial Cell Malignant Neoplasms Mediating Mentorship Mesenchymal Modeling Molecular Neoplasm Metastasis Outcome Pathway interactions Patients Pattern Pharmacology Phenotype Play Production Public Health Receptor Inhibition Research Resistance Role Scientist Selection for Treatments Signal Pathway Signal Transduction Specificity Surgical Oncologist Survivors System Testing Thymidine Kinase Tissue Engineering Tissue Microarray Training Transforming Growth Factors Tumor stage Tumor-Derived Viral Work Xenograft Model Xenograft procedure aggressive therapy anticancer research base cancer therapy career cellular imaging chemotherapy clinical efficacy connective tissue growth factor disability epithelial to mesenchymal transition human tissue imaging modality improved in vitro Model in vivo Model innovation malignant mouth neoplasm meetings mouth squamous cell carcinoma neoplastic cell novel outcome forecast promoter response responsible research conduct self-renewal stem cell biology suicide gene trait tumor tumor growth tumor microenvironment tumor progression

项目摘要

DESCRIPTION (provided by applicant): The applicant is a head and neck oncologic surgeon with overall goals of becoming an independent scientist and contributing to innovation in oral cancer treatment. This proposal serves the applicant's long term objective of improving outcomes for oral squamous cell carcinoma (OSCC) by advancing targeted therapy for aggressive, poor prognosis forms of the disease. To achieve this goal, the candidate will pursue direct laboratory-based training with close support from a team with complementary expertise in mentorship of early career clinician-scientists and his specific research areas. The plan also includes didactic and tutorial learning across diverse fields of relevance to the research plan and overall goals. These areas include pharmacology, stem cell biology, tumor microenvironment, cell signaling, epigenetics, biostatistics, and the responsible conduct of research. In addition he will actively participate in the broader cancer research community through attendance at seminars and presentation at international meetings. The proposed research plan builds upon current understanding of the epidermal growth factor receptor (EGFR) dependence in OSCC, which has led to the main targeted agent in clinical use for this malignancy, the anti-EGFR antibody cetuximab. The candidate's pursuit of combination therapies to improve the partial efficacy of EGFR targeting is guided by evidence that epithelial to mesenchymal transition (EMT) underlies key aspects of OSCC progression and cetuximab resistance. Preliminary work shows that EMT produces cellular heterogeneity within OSCCs by creating a subset of carcinoma cells with mesenchymal-like gene expression. Designated here as a mesenchymal-like subpopulation (MLSP), these cells are predicted to enhance tumor progression and express a distinct profile of secreted factors with potential impact on cetuximab resistance. The overall hypothesis is that MLSP-derived factors drive OSCC progression and cetuximab resistance through direct, tumor cell- autonomous effects and indirect effects mediated by crosstalk with stromal fibroblasts. To test this hypothesis, the proposed studies delineate the contribution of MLSP cells to OSCC growth and progression and determine both tumor cell-autonomous and fibroblast-dependent mechanisms by which they drive EGFR inhibitor resistance. In doing so, this application pursues a basis for combination therapies with cetuximab by addressing the full impact of the MLSP on the tumor microenvironment.

描述（由申请人提供）：申请人是一名头颈肿瘤外科医生，其总体目标是成为一名独立科学家并为口腔癌治疗的创新做出贡献。该提案服务于申请人的长期目标，即通过推进针对侵袭性、预后不良的疾病的靶向治疗来改善口腔鳞状细胞癌（OSCC）的结果。为了实现这一目标，候选人将在一个团队的密切支持下进行直接的实验室培训，该团队在早期职业临床医生科学家及其特定研究领域的指导方面具有互补的专业知识。该计划还包括与研究计划相关的不同领域的教学和辅导学习总体目标。这些领域包括药理学、干细胞生物学、肿瘤微环境、细胞信号传导、表观遗传学、生物统计学和负责任的研究行为。此外他将通过参加研讨会和在国际会议上发表演讲，积极参与更广泛的癌症研究界。拟议的研究计划建立在目前对 OSCC 表皮生长因子受体 (EGFR) 依赖性的了解之上，这导致了临床上用于治疗这种恶性肿瘤的主要靶向药物——抗 EGFR 抗体西妥昔单抗。上皮间质转化 (EMT) 是 OSCC 进展和西妥昔单抗耐药性关键方面的基础，这一证据指导候选人寻求联合疗法以提高 EGFR 靶向的部分疗效。初步研究表明，EMT 通过产生具有间质样基因表达的癌细胞子集，在 OSCC 内产生细胞异质性。这些细胞在此被称为间充质样亚群 (MLSP)，预计会增强肿瘤进展并表达独特的分泌因子，对西妥昔单抗耐药性具有潜在影响。总体假设是，MLSP 衍生因子通过直接的肿瘤细胞自主效应和由基质成纤维细胞串扰介导的间接效应驱动 OSCC 进展和西妥昔单抗耐药。为了检验这一假设，拟议的研究描述了 MLSP 细胞对 OSCC 生长和进展的贡献，并确定了它们驱动 EGFR 抑制剂耐药性的肿瘤细胞自主和成纤维细胞依赖性机制。在此过程中，该申请通过解决 MLSP 对肿瘤微环境的全面影响，为西妥昔单抗联合治疗奠定了基础。