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.

Public Health Relevance

Patients with head and neck squamous cell carcinoma (HNSCC) respond to the FDA-approved drug cetuximab, but the response rate is low because of various resistance mechanisms in the cancer cells. We will attempt to improve the response of HNSCC to cetuximab by combining cetuximab with drugs that induce oxidative stress in cancer cells, a novel therapeutic strategy designed on the basis of several novel findings from our preliminary studies. Successful completion of this project could substantially improve survival of patients with both cetuximab-sensitive and cetuximab-resistant HNSCC.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA179015-05
Application #
9442720
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Arya, Suresh
Project Start
2014-04-01
Project End
2019-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Hospitals
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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