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

项目摘要/摘要 此申请表是为促进牙科、口腔和牙科专业的多样性而设立的导师职业发展奖。 颅面研究人员(K01)。我正在验证这样一种假设，将一种饮食抗氧化剂与 质子辐射将改善头颈部癌症(HNC)患者的预后。该奖项将提供 我拥有实现以下目标所需的资源：(1)成为质子辐射方面的领先专家 以及改善HNC患者预后的新治疗策略。(二)完成研究工作 以及本申请表中提出的职业发展活动。(3)提高知名度，指导和帮助 促进将任职人数不足或来自弱势背景的研究人员纳入 HNC领域。为了实现这些目标，我组建了一个多学科的指导团队， 互补的专业知识。这些人包括：(1)Vinita Takiar博士(放射肿瘤学和HNC的主要导师)， (2)Susan Waltz博士(共同初级导师，肿瘤生长，高级研究员，微环境和转移)， (3)Trisha Wise-Draper博士(血液学、肿瘤学、免疫学和HNC委员会成员)； 苏珊·威尔斯(委员会成员，高级研究员，有机化合物，质子和光子辐射，HNC)。 头颈部鳞状细胞癌(HNSCC)的治疗抵抗，HNSCC是HNC的一种， 这极大地增加了发病率和死亡率。由于打捞选择仍然有限，因此有一个 迫切需要开发新的治疗方法来延长HNSCC患者的生存时间。上一首 PI和其他人的研究表明，饮食中的抗氧化剂异硫氰酸酯化合物可以 使癌细胞对辐射和细胞因子敏感。异硫氰酸酯还可以保护正常细胞免受 辐射。该项目的长期目标是通过改善治疗反应来改善患者的预后。 这项提案的总体目标是测试异硫氰酸酯、苯基异硫氰酸酯(PEITC)在 与质子辐射相结合，会增加HNSCC细胞的DNA损伤和致死率。中环 假设质子辐射与PEITC的结合优于目前的护理标准 顺铂联合光子束治疗(XRT)。为了检验中心假说，我们 提出以下具体目标：1)研究PEITC如何增强质子辐射介导的细胞死亡 2)研究PEITC对正常头颈部细胞的辐射防护作用。发展中 由于对辐射无效，改善辐射反应的替代治疗策略意义重大 结果导致患者存活率下降。这一研究方案的创新之处在于它侧重于利用油井资源。 耐受性饮食抗氧化剂作为克服HNSCC和HNSCC辐射抗性的替代策略 采用尖端质子辐射。这一建议最终将提供洞察力和机械性 对制定替代治疗策略以克服放射治疗抵抗的认识 HNSCC患者以及潜在的其他癌症类型。

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.