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

摘要 头颈部鳞状细胞癌(HNSCC)是世界上第七大最常见的癌症， 在美国，每年有超过5万人遭受这种疾病的折磨。因为它的解剖位置和低存活率 HNSCC是一种毁灭性的疾病。治疗可能会导致严重的功能缺陷和毁容。在……里面 在美国，HNSCC的发病率正在增加，这在很大程度上是由于人类乳头瘤病毒(HPV)。尽管人乳头瘤病毒- 与HPV阴性的吸烟者相比，HPV驱动的HNSCC通常有更好的结果 HNSCC表现出较差的肿瘤学结果，临床上被定义为中等风险疾病。这个 HNSCC生物学的显著复杂性导致了复杂的临床场景，其中一些患者 过度治疗，而其他人治疗不足，导致不必要的长期副作用和次优 临床反应。 在实验室中，我们发现HPV+HNSCCs有异常高表达的基因参与 DNA损伤和修复(DDR)，并对针对RAD51的药物高度敏感，RAD51是一种具有DDR功能的蛋白质 在同源重组修复(HRR)中，也保护细胞免受复制应激(RS)。我们 假设HNSCC的这个基因组子集的HPV驱动的生物学使它们对 针对RS和HRR的药物。我们进一步假设HPV阴性的HNSCC具有相同的模式 过表达的DDR基因也可能对针对RS/HRR的药物敏感。在这份翻译提案中， 我们计划：1)确定用RAD51抑制剂替代顺铂增敏的有效性和可行性 利用HPV+HNSCC的临床前模型研究肿瘤的放射治疗2)阐明其分子机制 控制HPV+HNSCC对RAD51抑制的敏感性；3)确定针对RS或RAD51的药物组合 HRR在HNSCC的临床前模型中是有效的。这一领域的进展可能直接导致人类临床 可能以较低的毒性改善肿瘤控制的试验。

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.