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（HNSCC）表达高水平的表皮生长因子受体（EGFR）。西妥昔单抗是一种EGFR抗体，可阻断靶细胞中配体诱导的EGFR活化，已被FDA批准与常规疗法联合用于治疗HNSCC。然而，EGFR下游信号传导途径中关键分子的频繁致癌突变和EGFR以外的受体酪氨酸激酶对EGFR下游信号传导途径的交叉激活使得许多这些肿瘤对西妥昔单抗耐药。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。该项目的目的是开发一种创新的治疗策略，基于我们初步研究的几个新的观察结果，以改善对西妥昔单抗的反应，特别是在EGFR阳性但西妥昔单抗耐药的肿瘤患者中，对正常组织的毒性作用最小。我们发现，西妥昔单抗加靶向线粒体酶丙酮酸脱氢酶激酶1（PDK 1）的组合在西妥昔单抗敏感和西妥昔单抗耐药的HNSCC细胞中引起大量凋亡。PDK 1由于其在调节癌症代谢中的独特作用而成为癌症治疗的有希望的靶点，癌症代谢的特征在于所谓的有氧糖酵解朝向乳酸盐产生（即，瓦尔堡效应）。PDK 1的抑制迫使癌症代谢从有氧糖酵解转变为氧化磷酸化，这可能导致活性氧（ROS）的过度产生;反过来，ROS的过度产生可能导致细胞凋亡。然而，我们发现在HNSCC细胞中PDK 1敲低后不容易诱导凋亡，除非敲低与西妥昔单抗组合。我们的初步研究表明，西妥昔单抗具有以前未被重视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，并且这种活性可以用于帮助几种FDA批准的药剂在西妥昔单抗敏感性和西妥昔单抗耐药性癌细胞中诱导氧化应激和凋亡。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，并测试和进一步优化新的治疗策略，在HNSCC模型中使用现有和新开发的治疗药物。如果该项目的发现支持我们的假设，该研究可能为治疗HNSCC患者提供新的机会，这些患者的肿瘤表达高水平的EGFR，但由于遗传畸变而对西妥昔单抗耐药。这种新的治疗策略是高度创新的，因为与目前的策略不同，目前的策略只关注最大化西妥昔单抗抑制EGFR下游信号通路的效果，这种新的治疗方法利用了新发现的完全不同的西妥昔单抗活性。我们的新治疗策略可能会显着改善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.