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

项目总结/摘要 此应用程序是一个指导职业发展奖，以促进牙科，口腔和 颅面研究工作队（K 01）。我在验证一个假设，将膳食抗氧化剂与 质子放射治疗将改善头颈癌（HNC）患者的预后。该奖项将提供 我所需要的资源，以实现以下目标：（1）成为质子辐射的领先专家 以及改善HNC患者预后的新治疗策略。(2)为了完成研究 和职业发展活动中提出的这一申请。(3)提高知名度，指导和 促进研究人员谁是代表性不足或谁是从一个处于不利地位的背景， HNC领域。为了实现这些目标，我组建了一个多学科的导师团队， 补充专业知识。这些包括：（1）维尼塔塔基亚博士（主要导师，放射肿瘤学和HNC）， (2)Susan Waltz博士（共同主要导师，肿瘤生长，高级研究员，微环境和转移）， (3)Trisha Wise-Draper博士（委员会成员，血液肿瘤学，免疫学和HNC），（4）Dr. Susanne威尔斯（委员会成员，高级研究员，类器官，质子和光子辐射，和HNC）。 头颈部鳞状细胞癌（HNSCC）（HNC的一种形式）对治疗性治疗的耐药性， 这在很大程度上导致发病率和死亡率上升。由于救助方案仍然有限， 迫切需要开发新的治疗方法来延长HNSCC患者的生存期。先前 PI和其他人的研究表明，膳食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结局。 本提案的总体目标是测试异硫氰酸酯、苯乙基异硫氰酸酯（PEITC） 与质子辐射组合，在HNSCC细胞中产生增加的DNA损伤和致死性。中央 假设质子放射与PEITC的组合上级当前的护理标准 顺铂与光子束疗法（XRT）的组合。为了检验中心假设，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对正常头颈部细胞辐射损伤的保护作用。发展中 改善放射反应的替代治疗策略是重要的， 导致患者存活率降低。这项研究计划的创新之处在于，它侧重于充分利用- 耐受的，膳食抗氧化剂作为克服HNSCC辐射抗性的替代策略， 采用了尖端的质子辐射这一建议最终将提供洞察力和机制 了解如何开发替代治疗策略，以克服放射治疗抵抗， 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.