Head and neck malignancies are a serious problem with ~40,000 new head and neck squamous cell cancers (HNSCC) and 13,000 deaths each year in the US alone. Despite advances in therapy, HNSCC recurrences occur in up to 50% of patients with advanced stage disease. Hence, there is a need for targeted adjuvant therapy, similar to Herceptin(R) in breast cancer and Gleevec(R) in multiple myeloma. The mission of this program announcement is to conduct correlative laboratory studies using tumor specimens collected from a multi-institutional clinical trial to identify new biomarkers that can facilitate predictions of clinical outcomes of therapeutic interventions. The main goal of this proposal is to determine whether the degree of Akt/mTOR pathway biomarker activation in tumor-free surgical margins or adjacent mucosa can predict outcomes in a randomized phase 2 clinical trial assessing the efficacy of mTOR-targeted therapy with everolimus in patients with locally advanced HNSCC. Our long-term objectives are to improve survival and to decrease recurrences and second primaries in HNSCC patients by making it a chronic disease using the mTOR inhibitors as targeted adjuvant therapy. There are no validated markers that predict responsiveness to mTOR-targeted therapy and identifying patients that would benefit from therapy is essential to success of targeted agents. The studies proposed in this application will evaluate if the Akt/mTOR pathway components that are over expressed in over 90% of HNSCC and frequently activated in tumor-free surgical margins correlate with the efficacy of mTOR-targeted therapy. To achieve this goal, tumor tissues and tumor-free surgical margins or adjacent normal mucosa of up to 160 clinical trial patients will be analyzed to determine expression and genetic mutations of the Akt/mTOR pathway. Expression levels and genetic mutations will be correlated with the clinical trial patients'survival and recurrence rate. We will also determine whether changes in serum growth factor levels after everolimus therapy correlate with clinical outcomes and can be used as a surrogate marker of drug activity. These studies can potentially identify markers for selecting head and neck cancer patients who will benefit from mTOR-targeted therapy, which would decrease unnecessary toxicity and healthcare costs. Results from this study will be used for subsequent mTOR inhibitor therapy studies in head and neck cancer patients, including a possible phase 3 randomized clinical trial. If successful this therapy could also be used for treatment of squamous carcinomas of other upper aerodigestive tract malignancies such as lung and esophagus.
Preclinical studies as a result of our current grant have shown that everolimus has great potential in decreasing recurrence rates, inhibiting metastatic spread to the lymph nodes and improving survival of head and neck cancer patients. This study will evaluate prognostic and predictive biomarkers in a clinical trial of everolimus as therapy in locally advanced head and neck cancer patients. Therefore, this study will help to define the most optimal candidates for targeted therapy, decreasing unnecessary toxicities and medical costs.
|Ekshyyan, Oleksandr; Moore-Medlin, Tara N; Raley, Matthew C et al. (2013) Anti-lymphangiogenic properties of mTOR inhibitors in head and neck squamous cell carcinoma experimental models. BMC Cancer 13:320|
|Hu, Melissa; Ekshyyan, Oleksandr; Herman Ferdinandez, Lilantha et al. (2011) Efficacy and comparative effectiveness of sirolimus as an anticancer drug. Laryngoscope 121:978-82|
|Clark, Cheryl; Shah, Shivang; Herman-Ferdinandez, Lilantha et al. (2010) Teasing out the best molecular marker in the AKT/mTOR pathway in head and neck squamous cell cancer patients. Laryngoscope 120:1159-65|
|Ekshyyan, Oleksandr; Rong, Youhua; Rong, Xiaohua et al. (2009) Comparison of radiosensitizing effects of the mammalian target of rapamycin inhibitor CCI-779 to cisplatin in experimental models of head and neck squamous cell carcinoma. Mol Cancer Ther 8:2255-65|
|Nathan, Cherie-Ann O; Amirghahari, Nazanin; Rong, Xiaohua et al. (2007) Mammalian target of rapamycin inhibitors as possible adjuvant therapy for microscopic residual disease in head and neck squamous cell cancer. Cancer Res 67:2160-8|