Although chemoradiation for patients with locally advanced head and neck cancer improves survival compared to radiation alone, combination treatment is associated with an increased rate of serious and life threatening mucositis and dysphagia. EGFR plays a key role in head and neck cancer, in that its over-expression is associated with more aggressive behavior, and its blockade increases the survival of patients treated with radiation without increasing (non-skin) toxicity. In addition, we have carried out preclinical studies indicating that a decrease in activation of key signal transduction molecules after cetuximab administration may predict the response to the combination of cetuximab and radiation. The goal of this application is to determine the pharmacodynamic profile of response in patients receiving cetuximab and radiation so that we can determine who benefits from this extremely expensive and moderately toxic therapy. We wish to identify in patients the established preclinical and novel downstream markers of EGFR activity that are associated with EGFR inhibition and eventual response. We also propose preclinical studies to optimize the use of cetuximab in combination with chemotherapy that will be incorporated into future clinical trials. These goals will be achieved through 3 specific aims:
Specific Aim 1 is to improve the outcome of patients with locally advanced head and neck squamous cell carcinoma who would not be anticipated to benefit from adding chemotherapy to radiation, and who would typically receive radiation alone, by using cetuximab-radiation.
Specific Aim 2 is to discover potential new biomarkers (Aim 2A) and to validate in preclinical models the potential of new and established markers (Aim 2B) of EGFR activity to predict response to cetuximab (with radiation).
Specific Aim 3 is to carry out preclinical studies to determine the optimum schedule for combining EGFR inhibition with chemoradiotherapy, with the goal of designing a future clinical trial for patients who are candidates for chemotherapy.
Our long term goal is to improve local control in patients with locally advanced head and neck cancer by combining cetuximab with the best current therapy. In this proposal, we will: (1) Test the combination of cetuximab and radiation therapy in patients who are over the age of 70 with locally advanced head and neck cancer who do not benefit from concurrent chemoradiation. (2) Discover novel biomarkers, using proteomics techniques, which predict response to cetuximab. These biomarkers will be validated in specimens obtained from our clinical trial. (3) Optimize, in preclinical studies, the schedule for adding cetuximab to the standard regimen of concurrent chemoradiation in preparation for a future clinical trial.
|Elaimy, Ameer L; Ahsan, Aarif; Marsh, Katherine et al. (2016) ATM is the primary kinase responsible for phosphorylation of Hsp90? after ionizing radiation. Oncotarget 7:82450-82457|
|Ray, Paramita; Tan, Yee Sun; Somnay, Vishal et al. (2016) Differential protein stability of EGFR mutants determines responsiveness to tyrosine kinase inhibitors. Oncotarget 7:68597-68613|
|Ray, Dipankar; Cuneo, Kyle C; Rehemtulla, Alnawaz et al. (2015) Inducing Oncoprotein Degradation to Improve Targeted Cancer Therapy. Neoplasia 17:697-703|
|Raghunathan, Krishnan; Ahsan, Aarif; Ray, Dipankar et al. (2015) Membrane Transition Temperature Determines Cisplatin Response. PLoS One 10:e0140925|
|Ahsan, Aarif; Ramanand, Susmita G; Bergin, Ingrid L et al. (2014) Efficacy of an EGFR-specific peptide against EGFR-dependent cancer cell lines and tumor xenografts. Neoplasia 16:105-14|
|Shukla, Shirish; Allam, Uday Sankar; Ahsan, Aarif et al. (2014) KRAS protein stability is regulated through SMURF2: UBCH5 complex-mediated ?-TrCP1 degradation. Neoplasia 16:115-28|
|Tsien, Christina I; Nyati, Mukesh K; Ahsan, Aarif et al. (2013) Effect of erlotinib on epidermal growth factor receptor and downstream signaling in oral cavity squamous cell carcinoma. Head Neck 35:1323-30|
|Ahsan, Aarif; Ray, Dipankar; Ramanand, Susmita G et al. (2013) Destabilization of the epidermal growth factor receptor (EGFR) by a peptide that inhibits EGFR binding to heat shock protein 90 and receptor dimerization. J Biol Chem 288:26879-86|
|Ahsan, Aarif; Ramanand, Susmita G; Whitehead, Christopher et al. (2012) Wild-type EGFR is stabilized by direct interaction with HSP90 in cancer cells and tumors. Neoplasia 14:670-7|
|Ray, Dipankar; Ahsan, Aarif; Helman, Abigail et al. (2011) Regulation of EGFR protein stability by the HECT-type ubiquitin ligase SMURF2. Neoplasia 13:570-8|
Showing the most recent 10 out of 11 publications