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

基于西妥昔单抗新活性的 HNSCC 新型靶向治疗

基本信息

批准号：
8697574
负责人：
Zhen Fan
金额：
$ 33.2万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8697574
关键词：
Affect Antioxidants Apoptosis Binding Blocking Antibodies Cells Cetuximab Co-Immunoprecipitations Colorectal Cancer Dichloroacetic Acid Endocytosis Engineering Enzymes Epidermal Growth Factor Receptor FDA approved Gefitinib Genetic Glutamine Glutathione Head and Neck Squamous Cell Carcinoma Investigation Lead Ligands Malignant Epithelial Cell Malignant Neoplasms Mediating Mitochondria Modeling Mus Mutation Normal tissue morphology Oncogenic Outcome Oxidation-Reduction Oxidative Phosphorylation Oxidative Stress PDH kinase Pathway interactions Patients Pharmaceutical Preparations Production Reactive Oxygen Species Receptor Activation Receptor Protein-Tyrosine Kinases Recombinants Research Resistance Role Signal Pathway Signal Transduction Solid Neoplasm Testing Therapeutic Therapeutic Agents Toxic effect Treatment outcome Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factors Warburg Effect aerobic glycolysis angiogenesis antibody-dependent cell cytotoxicity base cancer cell cancer therapy conventional therapy design improved in vivo inhibitor/antagonist innovation kinase inhibitor mutant novel novel strategies novel therapeutics overexpression public health relevance resistance mechanism response small molecule tumor tumor metabolism tumor xenograft uptake

项目摘要

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.

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）。西妥昔单抗是一种阻断靶细胞中配体诱导的EGFR激活的EGFR抗体，FDA批准与常规疗法结合使用以治疗HNSCC。然而，EGFR下游信号通路中的关键分子的频繁致癌突变以及EGFR下游信号传导途径通过受体酪氨酸激酶除EGFR以外的其他许多肿瘤对Cetuximab抗性。强烈保证进一步的研究以提高西妥昔单抗在HNSCC和其他癌症中的功效。该项目的目的是根据我们的初步研究的几个新观察结果制定创新的治疗策略，以在EGFR阳性但可妥昔单抗耐药性肿瘤的患者中改善对西替昔单抗的反应，而对正常组织的毒性最少。我们发现西妥昔单抗加上线粒体丙酮酸脱氢酶激酶1（PDK1）的靶向靶向，在西妥昔单抗敏感性和抗tuxuximab的抗妥昔单抗HNSCC细胞中引起了大量凋亡。 PDK1成为癌症治疗的有希望的靶标，因为它在调节癌症代谢中的独特作用，其特征是所谓的有氧有氧糖酵解对乳酸产生的产生（即沃堡效应）。 PDK1抑制可强行将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）的过量产生；反过来，ROS的过量产生会导致凋亡。但是，我们发现，除非将敲除与西妥昔单抗结合，否则在HNSCC细胞中敲低PDK1后，细胞凋亡不会容易诱导。我们的初步研究表明，西妥昔单抗具有先前未接受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减少癌细胞的抗氧化剂防御，独立于西妥昔单抗介导的EGFR激酶抑制抑制EGFR激酶，并且可以利用这种活性来帮助几种FDA-批准的药物诱导两种氧化应激，并在两种蛋白酶敏感的蛋白酶敏感性和蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白质中诱导氧化应激。我们的研究策略包括4个特定目标，旨在阐明我们的初步研究和测试中新发现的机制，并使用HNSCC模型中现有和新开发的治疗剂进一步优化了新的治疗策略。如果拟议项目的发现支持我们的假设，则该研究可能为治疗HNSCC患者的新机会提供新的机会，其HNSCC的肿瘤表现出高水平的EGFR，但由于遗传畸变而对西妥昔单抗具有抵抗力。这种新的治疗策略具有很高的创新性，因为与当前的策略不同，该策略仅着重于最大化西妥昔单抗对抑制EGFR下游信号传导途径的影响，这种新的疗法利用了西妥昔单抗的新鉴定和完全不同的活性。我们的新型治疗策略可能会显着改善HNSCC患者以及其他过表达EGFR的实体瘤的治疗结果。