PI3K Pathway Mutations in Head and Neck Cancer

描述（由申请人提供）：头颈部鳞状细胞癌（HNSCC）通常是致命的，缺乏指导治疗的预测性生物标志物。我们最近确定了74例HNSCC的突变谱，在近四分之一的这些癌症中检测到PI3K信号通路中的基因突变。这些结果随后在较大的HNSCC队列（包括HNSCC TCGA）中得到验证。由于PI3K通路是处于早期临床开发阶段的多种药物的显著靶向，这为定义预测性生物标志物和实施HNSCC的潜在有效治疗方法提供了直接机会。我们已经开发了新的HPV阳性和HPV阴性HNSCC模型，以确定这种癌症中的致癌“驱动”突变。此外，我们可以评估在小鼠中作为异位肿瘤移植物生长的人HNSCC肿瘤以及来自参加PI3K通路抑制剂的新II期试验的HNSCC患者的肿瘤中的PI3K通路突变和扩增。因此，该项目将阐明PI3K活化作为HNSCC进展中的生物标志物的作用，并促进HNSCC患者亚组的鉴定，其中PI3K靶向药物治疗代表有效的治疗策略。

DESCRIPTION (provided by applicant): Head and neck squamous cell carcinomas (HNSCC) are frequently lethal and predictive biomarkers to guide treatment are lacking. We recently determined the mutational profile of 74 HNSCC, and mutations of genes in the PI3K signaling pathway were detected in nearly one quarter of these cancers. These results were subsequently validated in larger HNSCC cohorts including the HNSCC TCGA. As the PI3K pathway is eminently targeted with multiple drugs that are in early phase clinical development, this provides an immediate opportunity to define predictive biomarkers and implement potentially effective therapeutic approaches for HNSCC. We have developed novel HPV-positive and HPV-negative HNSCC models to identify oncogenic "driver" mutations in this cancer. In addition, we can assess PI3K pathway mutation and amplification in human HNSCC tumors to be grown as heterotopic tumorgrafts in mice as well as tumors from HNSCC patients enrolled on a novel phase II trial of a PI3K pathway inhibitor. This project will therefore elucidate the role of PI3K activation as a biomarker in HNSCC progression, and facilitate the identification of a subset of HNSCC patients where treatment with a PI3K targeting agent represents an effective therapeutic strategy.