Mentored Career Development Award: Isothiocyanates to Improve Response to Proton Radiotherapy

点击翻译按钮获取中文摘要

Project Summary/Abstract This application is for a Mentored Career Development Award to Promote Diversity in the Dental, Oral and Craniofacial Research Workforce (K01). I am testing the hypothesis that combining a dietary antioxidant with proton radiation will improve outcome in patients with head and neck cancer (HNC). This award will provide me with the resources I need to achieve the following goals: (1) To become a leading expert in proton radiation as well as novel therapeutic strategies to improve outcome in patients with HNC. (2) To complete the research and career development activities proposed in this application. (3) To increase the visibility of, to mentor and to promote inclusion of researchers who are underrepresented or who are from a disadvantaged background in the field of HNC. To achieve these goals, I have assembled a multidisciplinary mentorship team with complementary expertise. These include: (1) Dr. Vinita Takiar (primary mentor, radiation oncology and HNC), (2) Dr. Susan Waltz (co-primary mentor, tumor growth, senior researcher, microenvironment and metastasis), (3) Dr. Trisha Wise-Draper (committee member, hematology oncology, immunology and HNC), (4) Dr. Susanne Wells (committee member, senior researcher, organoids, proton and photon radiation, and HNC). Resistance to therapeutic treatment in head and neck squamous cell carcinoma (HNSCC), a form of HNC, significantly contributes to increased morbidity and mortality. As salvage options remain limited, there is a critical need to develop novel therapeutic approaches to extend survival in patients with HNSCC. Previous research by the PI and others has demonstrated that the dietary antioxidant isothiocyanate compounds can sensitize cancer cells to radiation and cytokine. Isothiocyanates also protect normal cells from the effects of radiation. The long-term goal of this project is to improve patient outcomes by improving treatment response. The overall objective of this proposal is to test whether isothiocyanate, phenethyl isothiocyanate (PEITC), in combination with proton radiation, generates increased DNA damage and lethality in HNSCC cells. The central hypothesis is that the combination of proton radiation with PEITC is superior to the current standard of care combination, which is cisplatin with photon beam therapy (XRT). To examine the central hypothesis, we propose the following specific aims: 1) Examine how PEITC enhances proton radiation mediated cell death and 2) investigate the effects of PEITC in protecting normal head and neck cells from radiation. Developing alternative treatment strategies to improve radiation response is significant since failed response to radiation results in decreased patient survival. This research proposal is innovative in that it focuses on utilizing well- tolerated, dietary antioxidants as an alternative strategy to overcoming radiation resistance in HNSCC and employs the use of cutting edge proton radiation. This proposal will ultimately provide insight and mechanistic understanding into developing alternative treatment strategies to overcome radiation treatment resistance in HNSCC patients as well as potentially other cancer types.