Notch signaling and anticancer drug sensitivity in oral squamous cell carcinoma

 描述（由申请人提供）：头颈部鳞状细胞癌的存活率在四十多年来没有提高，需要新的方法来治疗这些癌症。这些肿瘤沿着头颈部的粘膜衬里出现，并且在预后和治疗反应方面明显异质。与其他成人癌症的进展不同，没有预测性生物标志物来指示头颈癌患者的最佳治疗方案。最近在大约四分之一的头颈部鳞状细胞癌中发现了Notch基因家族的突变，这些突变与口腔癌患者的不良预后相关。Notch基因编码Notch受体，其调节发育过程中的许多过程，维持成体组织中的细胞分化，并帮助控制干细胞。Notch信号在几种成人肿瘤的耐药性中具有已知的作用，甚至有一些证据表明Notch信号可能在头颈部鳞状细胞癌的获得性耐药性中起作用。此外，表皮生长因子受体（EGFR）和微管，口腔癌化疗的两个目标，是由Notch信号调节，从而暗示Notch作为一个潜在的调节剂的口腔癌敏感性EGFR和微管靶向药物。有趣的是，在口腔癌中发现的Notch突变是失活的，这表明Notch信号通路受损，因此这些患者的药物敏感性可能非常不同。虽然现在公认Notch途径与某些癌症的获得性耐药性有关，但尚未研究Notch信号传导受损对口腔癌细胞药物敏感性的影响。我评估了9个口腔癌细胞系对厄洛替尼和多西他赛的浓度响应关系，厄洛替尼和多西他赛分别是EGFR抑制剂和微管靶向剂，并发现某些口腔鳞状细胞癌（OSCC）细胞系对两种药物具有敏感性或耐药性。此外，这些敏感细胞系表达低基础水平的Notch受体和Notch靶基因HES 1，表明它们可能具有受损的Notch信号传导。基于这些数据，我们假设受损的Notch信号传导包括对EGFR抑制和微管破坏敏感性增强的OSCC分子亚型。为了验证这一假设，我将进行以下具体目标：（1）阐明Notch信号通路在药物敏感和耐药OSCC细胞系中的状态，（2）确定抑制Notch信号通路对OSCC细胞系抗癌药物敏感性的影响，（3）确定过表达活化的Notch-1对OSCC细胞系抗癌药物敏感性的影响。这些创新的研究将通过证明Notch信号作为预测口腔癌药物敏感性的第一个生物标志物的潜力产生重大影响。这个项目的成功完成将促进特殊的培训，满足我的短期目标，并定位我，以满足我的长期目标，成为一个独立的口腔颌面外科医生临床科学家。

 DESCRIPTION (provided by applicant): The survival rate for head and neck squamous cell carcinomas has not improved in more than four decades, and new approaches to treat these cancers are needed. These tumors present along the mucosal linings of the head and neck and are notably heterogeneous in regards to their prognosis and response to therapy. Unlike advances in other adult cancers, there are no predictive biomarkers to indicate the best treatment options for head and neck cancer patients. Mutations in the Notch gene family were recently found in approximately one quarter of all head and neck squamous cell carcinomas and these mutations were associated with poor outcomes for patients with oral cancers. The Notch genes encode for Notch receptors which regulate many processes during development, maintain cellular differentiation in adult tissues, and help control stem cells. Notch signaling ha a known role in drug resistance for several adult tumors and there is even some evidence that Notch signaling may play a role in acquired drug resistance for head and neck squamous cell carcinomas. In addition, the epidermal growth factor receptor (EGFR) and microtubules, two targets of oral cancer chemotherapy, are regulated by Notch signaling, thus implicating Notch as a potential regulator of oral cancer sensitivity to EGFR and microtubule targeting drugs. Interestingly, the Notch mutations identified in oral cancers were inactivating, suggesting that the Notch signaling pathway is impaired and therefore that the drug sensitivity of these patients may be very different. While it is now accepted that the Notch pathway is implicated in acquired drug resistance for some cancers, the impact of impaired Notch signaling on oral cancer cell drug sensitivity has not been studied. I evaluated the concentration response relationship of nine oral cancer cell lines to erlotinib and docetaxel, an EGFR inhibitor and microtubule targeting agent respectively, and discovered that certain oral squamous cell carcinoma (OSCC) cell lines share sensitivity or resistance to both drugs. In addition, these sensitive cell lines express low basal levels of Notch receptors and the Notch target gene HES1, suggesting that they may have impaired Notch signaling. Based on these data, we hypothesize that impaired Notch signaling comprises a molecular subtype of OSCC with enhanced sensitivity to EGFR inhibition and microtubule disruption. To test this hypothesis, I will perform the following specifc aims: (1) To elucidate the status of the Notch signaling pathway in drug sensitive and drug resistant OSCC cell lines, (2) To determine the effect of inhibiting the Notch signaling pathway on anticancer drug sensitivity in OSCC cell lines and (3) To determine the effect of overexpressing activated Notch-1 on anticancer drug sensitivity in OSCC cell lines. These innovative studies will have significant impact by demonstrating the potential for Notch signaling as the first biomarker predictive of oral cancer drug sensitivity. Successful completion of this project will facilitate exceptional training, meet my short-term goals and position me to meet my long-term goal to become an independent oral and maxillofacial surgeon clinician scientist.