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

描述(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，可以阻断配体诱导的靶细胞中EGFR的激活，FDA批准将其与传统疗法结合用于治疗HNSCC。然而，EGFR下游信号通路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，使得许多肿瘤对西妥昔单抗产生耐药。进一步研究西妥昔单抗对HNSCC和其他癌症的疗效是非常有必要的。该项目的目标是基于我们初步研究中的几个新观察结果，开发一种创新的治疗策略，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--同时对正常组织的毒性影响最小。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。由于PDK1在调节肿瘤代谢方面的独特作用，它被认为是一个很有希望的癌症治疗靶点，其特点是所谓的有氧糖酵解转化为乳酸的产生(即Warburg效应)。抑制PDK1可强制将肿瘤代谢从有氧糖酵解转换为氧化磷酸化，从而导致活性氧物种(ROS)的过量产生，进而导致细胞凋亡。然而，我们发现，除非将PDK1基因敲除与西妥昔单抗联合使用，否则HNSCC细胞在PDK1基因敲除后不容易诱导细胞凋亡。我们的初步研究表明，西妥昔单抗具有先前未被认识的氧化还原调节活性。我们推测，西妥昔单抗这种新的活性可以降低癌细胞的抗氧化防御，而不依赖于西妥昔单抗介导的对EGFR激酶的抑制，并且这种活性可以被利用来帮助几种FDA批准的药物在西妥昔单抗敏感和耐药的癌细胞中诱导氧化应激和凋亡。我们的研究战略包括4个具体目标，旨在阐明我们初步研究的新发现背后的机制，并在HNSCC模型中使用现有的和新开发的治疗药物来测试和进一步优化新的治疗策略。如果拟议项目的研究结果支持我们的假设，这项研究可能会为治疗HNSCC患者提供新的机会，这些患者的肿瘤表达高水平的EGFR，但由于基因突变而对西妥昔单抗耐药。这一新的治疗策略具有很高的创新性，因为与目前的策略不同，目前的策略只专注于最大限度地发挥西妥昔单抗抑制EGFR下游信号通路的作用，这种新疗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著改善HNSCC和其他EGFR过表达实体瘤患者的治疗结果。

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.