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Targeting replication stress and homologous recombination repair mechanisms in HPV-positive and negative head and neck cancer

针对 HPV 阳性和阴性头颈癌的复制应激和同源重组修复机制

基本信息

批准号：
10297645
负责人：
MITCHELL J. FREDERICK
金额：
$ 39.83万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10297645
关键词：
Anatomy Area Automobile Driving Biology Bone Marrow Cancer Patient Cell Cycle Cell Line Cell Survival Cells Cessation of life Cisplatin Clinical Clinical Trials Complex DNA Repair DNA analysis Data Defect Disease Down-Regulation Drug Combinations Drug Targeting Epidemic Etiology Gene Expression Generations Genes Genomics HPV E7 HPV-High Risk Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Hematopoietic Heterogeneity Human Human Papillomavirus Human papilloma virus infection Immunocompetent Incidence Individual Inferior Laboratories Lead Link Location Low risk HPV Malignant Neoplasms Mediator of activation protein Mitotic Molecular Morbidity - disease rate Mus NOTCH1 gene Natural History Normal Cell Oncogenes Operative Surgical Procedures Outcome Patients Pattern Pharmaceutical Preparations Phosphotransferases Pre-Clinical Model Primary Neoplasm Prognosis Proteins Publishing Radiation Refractory Resistance Risk Risk Factors Salivary Glands Sampling Smoker Smoking Survival Rate TP53 gene Testing Tobacco use Toxic effect Tumor Suppressor Proteins Virus Diseases Virus Replication Work Xenograft Model cancer subtypes chemoradiation chemotherapy disorder risk drug sensitivity gene repair high risk homologous recombination human model human papilloma virus oncogene improved inhibitor/antagonist malignant mouth neoplasm malignant oropharynx neoplasm mouse model new therapeutic target overexpression overtreatment patient derived xenograft model precision oncology protein function recombinational repair replication stress response side effect standard of care stem cells targeted agent tumor tumor growth tumor-immune system interactions

项目摘要

Abstract Head and Neck squamous cell carcinoma (HNSCC) is the seventh most common cancer world-wide and afflicts more than 50,000 individuals in the U.S. each year. Because of its anatomic location and poor survival rate HNSCC is a devastating disease. Treatment can lead to profound functional defects and disfigurement. In the U.S., HNSCC incidence is increasing in large part due to the human papillomavirus (HPV). Although HPV- driven HNSCC generally has a better outcome than its HPV-negative counterpart, smokers with HPV-driven HNSCC demonstrate inferior oncologic outcomes and are clinically defined as intermediate risk disease. The significant complexity of HNSCC biology results in a complex clinical scenario, in which some patients are overtreated while others are undertreated, leading to unnecessary long-term side effects and suboptimal clinical response. In the laboratory, we discovered that HPV+ HNSCCs have unusually high expression of genes involved in DNA damage and repair (DDR) and are highly sensitive to drugs targeting RAD51, a DDR protein functioning in homologous recombination repair (HRR) that also protects cells from replication stress (RS). We hypothesize that the HPV-driven biology of this genomic subset of HNSCC renders them more sensitive to drugs targeting RS and HRR. We further hypothesize that HPV-neg HNSCC that share the same pattern of overexpressed DDR genes may also be susceptible to drugs targeting RS/HRR. In this translational proposal, we plan to: 1) Determine the efficacy and feasibility of replacing cisplatin with a RAD51 inhibitor to sensitize tumors to radiation using preclinical models of HPV+ HNSCC; 2) Elucidate the molecular mechanisms governing sensitivity of HPV+HNSCC to RAD51 inhibition; 3) Determine if drug combinations targeting RS or HRR are efficacious in preclinical models of HNSCC. Progress in this area could lead directly to human clinical trials that may improve tumor control with less toxicity.

摘要