GPCR Signaling in SCCHN: Integration with EGFR

描述(申请人提供)：表皮生长因子受体(EGFR)在头颈部鳞状细胞癌(SCCHN)中上调，肿瘤中EGFR的表达水平与生存率下降相关。EGFR单抗西妥昔单抗于2006年获得FDA批准用于治疗SCCHN，是45年来治疗这种癌症的第一种新药。然而，尽管在SCCHN肿瘤中普遍存在EGFR的表达，但作为单一药物治疗的西妥昔单抗的临床应答率有限，这突显了在野生型EGFR阻断的背景下阐明肿瘤持续生长机制的重要性。我们已经积累了大量的证据表明，GPCR通过EGFR依赖和非EGFR依赖的途径介导的信号转导有助于SCCHN的生长和存活。对西妥昔单抗没有反应的患者很可能死于头颈癌。我们目前不知道如何确定将从EGFR靶向中受益的SCCHN患者。我们的工作假设是，在EGFR阻断的背景下持续的GPCR信号有助于肿瘤的进展。这些研究的完成将阐明对EGFR靶向策略的抵抗机制，从而促进治疗方案的设计，以提高临床疗效。为了实现这一建议的目标，我们将：1)确定在SCCHN中被激活的EGFR上游或下游的GPCR刺激的通路，以确定治疗靶点；2)阐明在SCCHN中由GPCR诱导的不依赖于EGFR的通路；以及3)在临床前SCCHN模型中，确定EGFR靶向与关键的GPCR信号中间产物相结合的抗肿瘤作用。

DESCRIPTION (provided by applicant): The epidermal growth factor receptor (EGFR) is upregulated in squamous cell carcinomas of the head and neck (SCCHN) where EGFR expression levels in the tumor correlate with decreased survival. The EGFR monoclonal antibody, cetuximab, was FDA-approved in 2006 for the treatment of SCCHN and is the first new drug for this cancer in 45 years. However, despite the ubiquitous expression of EGFR in SCCHN tumors, the clinical response rate to cetuximab as single agent therapy is limited, underscoring the importance of elucidating the mechanisms of persistent tumor growth in the setting of wild-type EGFR blockade. We have accumulated extensive evidence that GPCR-mediated signaling through EGFR-dependent and EGFR-independent pathways contributes to SCCHN growth and survival. Patients who do not respond to cetuximab are likely to succumb to their head and neck cancer. We currently do not know how to identify SCCHN patients who will benefit from EGFR targeting. Our working hypothesis is that persistent GPCR signaling in the setting of EGFR blockade contributes to tumor progression. Completion of these studies will elucidate mechanisms of resistance to EGFR targeting strategies thus facilitating the design of therapeutic regimens to enhance clinical response. To accomplish the goals of this proposal, we will: 1) determine the GPCR-stimulated pathways in SCCHN that are activated upstream or downstream of EGFR with the goal of identifying therapeutic targets; 2) elucidate the EGFR-independent pathways induced by GPCR in SCCHN; and 3) determine the antitumor effects of EGFR targeting in combination with key GPCR signaling intermediates in preclinical SCCHN models.