A novel targeted therapy for HNSCC based on a novel activity of cetuximab

描述（由申请人提供）：超过90%的头颈部鳞状细胞癌（HNSCCs）表达高水平的表皮生长因子受体（EGFR）。西妥昔单抗（Cetuximab）是一种阻断靶细胞中配体诱导的EGFR激活的EGFR抗体，已被FDA批准与传统疗法联合用于治疗HNSCC。然而，EGFR下游信号通路中关键分子的频繁致癌突变以及EGFR以外的受体酪氨酸激酶对EGFR下游信号通路的交叉激活，使得许多此类肿瘤对西图昔单抗具有耐药性。进一步研究以提高西妥昔单抗在HNSCC和其他癌症中的疗效是非常必要的。该项目的目标是开发一种创新的治疗策略，基于我们初步研究的几个新观察结果，以提高对西妥昔单抗的反应，特别是对egfr阳性但西妥昔单抗耐药的肿瘤患者，同时对正常组织的毒性作用最小。我们发现西妥昔单抗联合靶向线粒体酶丙酮酸脱氢酶激酶1 （PDK1）可导致西妥昔单抗敏感和耐药的HNSCC细胞大量凋亡。PDK1正成为癌症治疗的一个有希望的靶点，因为它在调节癌症代谢中的独特作用，其特点是所谓的有氧糖酵解产生乳酸（即Warburg效应）。抑制PDK1强行将癌症代谢从有氧糖酵解转换为氧化磷酸化，这可能导致活性氧（ROS）的过量产生；反过来，ROS的过量产生会导致细胞凋亡。然而，我们发现在HNSCC细胞中，除非与西妥昔单抗联合敲除PDK1，否则不容易诱导细胞凋亡。我们的初步研究表明西妥昔单抗具有以前未被认识到的氧化还原调节活性。我们假设西妥昔单抗的这种新活性可以独立于西妥昔单抗介导的EGFR激酶抑制而降低癌细胞的抗氧化防御能力，并且这种活性可以用于帮助几种FDA批准的药物诱导西妥昔单抗敏感和西妥昔单抗耐药癌细胞的氧化应激和凋亡。我们的研究策略包括4个具体目标，旨在阐明我们初步研究中新发现的机制，并使用现有和新开发的治疗药物在HNSCC模型中测试和进一步优化新的治疗策略。如果该项目的研究结果支持我们的假设，该研究可能为治疗因基因异常而对西妥昔单抗有抗性的高水平EGFR的HNSCC患者提供新的机会。这种新的治疗策略是高度创新的，因为不像目前的策略，只关注最大化西妥昔单抗对抑制EGFR下游信号通路的作用，这种新疗法利用了西妥昔单抗新发现的完全不同的活性。我们的新治疗策略可能会显著改善HNSCC患者以及其他egfr过表达实体瘤的治疗结果。

DESCRIPTION (provided by applicant): Over 90% of head and neck squamous cell carcinomas (HNSCCs) express high levels of epidermal growth factor receptor (EGFR). Cetuximab, an EGFR antibody that blocks ligand-induced EGFR activation in targeted cells, is approved by the FDA for use in combination with conventional therapy for treatment of HNSCC. However, frequent oncogenic mutations of key molecules in EGFR downstream signaling pathways and cross-activation of EGFR downstream signaling pathways by receptor tyrosine kinases other than EGFR render many of these tumors resistant to cetuximab. Further investigation to improve the efficacy of cetuximab in HNSCC and other cancers is strongly warranted. The objective of this project is to develop an innovative therapeutic strategy, based on several novel observations from our preliminary studies, to improve response to cetuximab-particularly in patients with EGFR-positive but cetuximab-resistant tumors-with minimal toxic effects on normal tissues. We found that the combination of cetuximab plus targeting of the mitochondrial enzyme pyruvate dehydrogenase kinase 1 (PDK1) caused substantial apoptosis in both cetuximab-sensitive and cetuximab-resistant HNSCC cells. PDK1 is emerging as a promising target for cancer therapy because of its unique role in regulating cancer metabolism, which is characterized by so-called aerobic glycolysis towards lactate production (i.e., the Warburg effect). Inhibition of PDK1 forcibly switches cancer metabolism from aerobic glycolysis to oxidative phosphorylation, which can cause overproduction of reactive oxygen species (ROS); in turn, overproduction of ROS can cause apoptosis. However, we found that apoptosis was not readily induced after knockdown of PDK1 in HNSCC cells unless the knockdown was combined with cetuximab. Our preliminary studies suggest that cetuximab has a previously unappreciated redox regulatory activity. We hypothesize that this novel activity of cetuximab can diminish cancer cells' antioxidant defense independently of cetuximab-mediated inhibition of EGFR kinase and that this activity can be exploited to help several FDA- approved agents induce oxidative stress and apoptosis in both cetuximab-sensitive and cetuximab-resistant cancer cells. Our research strategy includes 4 specific aims designed to elucidate the mechanisms underlying the novel findings from our preliminary studies and test and further optimize a new therapeutic strategy, using existing and newly developed therapeutic agents in HNSCC models. If findings from the proposed project support our hypothesis, the research may offer new opportunities for treating patients with HNSCC whose tumors express high levels of EGFR but are resistant to cetuximab because of genetic aberrations. This new therapeutic strategy is highly innovative because unlike the current strategies, which focus only on maximizing cetuximab's effects on inhibiting EGFR downstream signaling pathways, this new therapy takes advantage of a newly identified and entirely different activity of cetuximab. Our novel therapeutic strategy may significantly improve the treatment outcomes of patients with HNSCC as well as other EGFR-overexpressing solid tumors.