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

• 批准号: 8354347
• 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
• 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/8354347
• 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 progression

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. PUBLIC HEALTH RELEVANCE: OSCC is a major public health issue in the US, accounting for approximately 36,000 annual cases and 8000 deaths as well as severe treatment-related disabilities in many survivors. The applicant's preliminary data support that MLSP cells contribute to aggressive clinical behavior and drug resistance in these tumors. This proposal pursues the mechanisms underlying these MLSP-mediated effects in order to improve outcomes for OSCC patients.

描述（由申请人提供）：申请人是一名头颈部肿瘤外科医生，总体目标是成为一名独立的科学家，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、预后不良的疾病形式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各个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中表皮生长因子受体（EGFR）依赖性的理解基础上，这导致了临床上用于这种恶性肿瘤的主要靶向药物，抗EGFR抗体西妥昔单抗。候选人寻求联合治疗以提高EGFR靶向的部分疗效是由上皮间质转化（EMT）是OSCC进展和西妥昔单抗耐药的关键方面的证据指导的。初步研究表明，EMT通过产生具有间充质样基因表达的癌细胞亚群，在OSCC内产生细胞异质性。在此指定为间充质样亚群（MLSP），这些细胞被预测促进肿瘤进展并表达对西妥昔单抗抗性具有潜在影响的分泌因子的独特谱。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与基质成纤维细胞的串扰介导的间接效应驱动OSCC进展和西妥昔单抗抗性。为了验证这一假设，拟议的研究描述了MLSP细胞对OSCC生长和进展的贡献，并确定了肿瘤细胞自主性和成纤维细胞依赖性机制，它们通过这些机制驱动EGFR抑制剂耐药。在此过程中，本申请通过解决MLSP对肿瘤微环境的全面影响，寻求与西妥昔单抗联合治疗的基础。 公共卫生相关性：口腔鳞状细胞癌在美国是一个主要的公共卫生问题，每年约有36，000例病例和8000例死亡，以及许多幸存者的严重治疗相关残疾。申请人的初步数据支持MLSP细胞有助于这些肿瘤的侵袭性临床行为和耐药性。该提案追求这些MLSP介导的作用的机制，以改善OSCC患者的预后。