The survival rate for head and neck squamous cell carcinomas has not improved in more than four decades, and new approaches to treat these cancers are needed. These tumors present along the mucosal linings of the head and neck and are notably heterogeneous in regards to their prognosis and response to therapy. Unlike advances in other adult cancers, there are no predictive biomarkers to indicate the best treatment options for head and neck cancer patients. Mutations in the Notch gene family were recently found in approximately one quarter of all head and neck squamous cell carcinomas and these mutations were associated with poor outcomes for patients with oral cancers. The Notch genes encode for Notch receptors which regulate many processes during development, maintain cellular differentiation in adult tissues, and help control stem cells. Notch signaling ha a known role in drug resistance for several adult tumors and there is even some evidence that Notch signaling may play a role in acquired drug resistance for head and neck squamous cell carcinomas. In addition, the epidermal growth factor receptor (EGFR) and microtubules, two targets of oral cancer chemotherapy, are regulated by Notch signaling, thus implicating Notch as a potential regulator of oral cancer sensitivity to EGFR and microtubule targeting drugs. Interestingly, the Notch mutations identified in oral cancers were inactivating, suggesting that the Notch signaling pathway is impaired and therefore that the drug sensitivity of these patients may be very different. While it is now accepted that the Notch pathway is implicated in acquired drug resistance for some cancers, the impact of impaired Notch signaling on oral cancer cell drug sensitivity has not been studied. I evaluated the concentration response relationship of nine oral cancer cell lines to erlotinib and docetaxel, an EGFR inhibitor and microtubule targeting agent respectively, and discovered that certain oral squamous cell carcinoma (OSCC) cell lines share sensitivity or resistance to both drugs. In addition, these sensitive cell lines express low basal levels of Notch receptors and the Notch target gene HES1, suggesting that they may have impaired Notch signaling. Based on these data, we hypothesize that impaired Notch signaling comprises a molecular subtype of OSCC with enhanced sensitivity to EGFR inhibition and microtubule disruption. To test this hypothesis, I will perform the following specifc aims: (1) To elucidate the status of the Notch signaling pathway in drug sensitive and drug resistant OSCC cell lines, (2) To determine the effect of inhibiting the Notch signaling pathway on anticancer drug sensitivity in OSCC cell lines and (3) To determine the effect of overexpressing activated Notch-1 on anticancer drug sensitivity in OSCC cell lines. These innovative studies will have significant impact by demonstrating the potential for Notch signaling as the first biomarker predictive of oral cancer drug sensitivity. Successful completion of this project will facilitate exceptional training, meet my short-term goals and position me to meet my long-term goal to become an independent oral and maxillofacial surgeon clinician scientist.
Oral cancer is a deadly disease with limited treatment options which has seen little improvement in patient survival for decades. A gene family was recently identified that is commonly mutated in oral cancers and associates with poor outcomes for patients. Our studies will determine the relationship of this gene family with oral cancer drug sensitivity and in doing so, will demonstrate if chemotherapy could be personalized for patients with or without mutations in this gene family thereby improving treatment outcomes.
|Risinger, April L; Dybdal-Hargreaves, Nicholas F; Mooberry, Susan L (2015) Breast Cancer Cell Lines Exhibit Differential Sensitivities to Microtubule-targeting Drugs Independent of Doubling Time. Anticancer Res 35:5845-50|
|Dasari, Ramesh; De Carvalho, Annelise; Medellin, Derek C et al. (2015) Wittig derivatization of sesquiterpenoid polygodial leads to cytostatic agents with activity against drug resistant cancer cells and capable of pyrrolylation of primary amines. Eur J Med Chem 103:226-37|
|Dasari, Ramesh; De Carvalho, Annelise; Medellin, Derek C et al. (2015) Synthetic and Biological Studies of Sesquiterpene Polygodial: Activity of 9-Epipolygodial against Drug-Resistant Cancer Cells. ChemMedChem 10:2014-26|