University of Pittsburgh Cancer Institute (UPCI)

Targeting Resistance Mechanisms

Targeted therapiesHNCP members have a long history of studying signal transduction in HNC. Targeted therapies are commonly used to block specific growth pathways that are overexpressed in cancer cells; for example, the drug cetuximab inhibits the epidermal growth factor receptor (EGFR), currently the only established molecular target in HNC. However, many cancers develop resistance mechanisms that enable cells to survive and replicate despite treatment with targeted therapies. Developing combination therapies that co-target multiple pathways, and identifying predictive biomarkers of response and resistance, are important areas of research within the HNCP.

Selected Publications

  • Cisplatin-radiotherapy is a preferred standard for locally advanced, head and neck squamous cell carcinoma (HNSCC). However, the cisplatin-attributable survival benefit is small and toxicity substantial. A biomarker of cisplatin resistance could guide treatment selection and spare morbidity. In a phase II trial, it was found that expression of the ERCC1-XPF nuclease, a critical DNA repair enzyme, in primary tumors is prognostic in patients undergoing definitive cisplatin-radiotherapy for HNSCC, irrespective of HPV status. (Bauman et. al., Br J Cancer. 2013 Oct 15;109(8):2096-105.)
  • Cetuximab treatment prolongs survival in only 10-20% of HNC patients. An immunological mechanism of action such as natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) has been suggested. The effects of activating toll-like receptor (TLR)-8 to enhance activity of cetuximab-stimulated, FcγR-bearing cells were investigated. Results demonstrated that TLR8 stimulation enhances cetuximab-mediated NK cell lysis of HNC cells and dendritic cell (DC) cross-priming of EGFR-specific CD8(+) T cells. (Stephenson et. al., Cancer Immunol Immunother. 2013 Aug;62(8):1347-57.)
  • Strategies to inhibit the EGF receptor (EGFR) using the tyrosine kinase inhibitor erlotinib have been associated with limited clinical efficacy in head and neck squamous cell carcinoma (HNSCC). HNSCC cells expressing dominant-active c-Src (DA-Src) were generated to determine the contribution of c-Src activation to erlotinib response. Results indicate that ligand-independent activation of c-Met contributes specifically to erlotinib resistance, not cetuximab resistance, in HNSCC with activated c-Src, where c-Met activation is more dependent on c-Src than on EGFR, providing an alternate survival pathway. Addition of a c-Met or c-Src inhibitor to erlotinib may increase efficacy of EGFR inhibition in patients with activated c-Src. (Stabile et. al., Clin Cancer Res. 2013 Jan 15;19(2):380-92.)

Members


Anderson, Carolyn, PhD
Radiology
Heron, Dwight, MD, FACRO
Radiation Oncology
Branstetter, Barton, MD
Radiology
Kim, Seungwon, MD, MS, FACS
Otolaryngology
Clump, David, MD, PhD
Radiation Oncology
Ohr, James, DO
Medicine
Duvvuri, Umamaheswar, MD, PhD, FACS
Otolaryngology
Saunders, William, PhD
Biological Sciences
Ferris, Robert L., MD, PhD, FACS
Otolaryngology
Seethala, Raja, MD, FASCP
Pathology
Gooding, William, MS
Biostatistics
Sorkin, Alexander, PhD
Cell Biology
Whiteside, Theresa, PhD
Pathology