Molecularly Targeted Radiosensitization of Locally Advanced Cancers

项目概要（总体） 除非原发肿瘤治愈，否则癌症无法治愈。对于局部晚期或不可切除的患者 对于初次手术不是一种选择的疾病，放射治疗（RT）结合全身性药物， 成为标准治疗。这是因为单独的全身治疗很少能治愈严重的疾病，但可以 显着提高RT的疗效，消除微观疾病。因此，作为系统治疗， 在不断改进的情况下，有效的本地控制变得越来越重要。虽然技术 计划和实施的改进降低了RT的毒性，RT剂量递增试验， 总的来说，未能改善结果。这个SPORE提案的首要假设是， RT与靶向局部晚期癌症分子驱动因素的全身治疗将改善患者的预后。 治疗的结果。该SPORE提案的目标是通过体外和体内试验来验证这一假设 针对抗辐射关键机制的临床前研究。我们的研究将推动试点临床试验 这将确定II期试验的条件，产生初步的反应评估，并测试临床前 通过相关研究提出假设。这一目标将通过三个具体目标来实现。目标1将 确定是否原发性放射抵抗，隐匿性转移性疾病的存在，以及缺乏 免疫原性可以通过使用PARP抑制剂增加辐射诱导的DNA损伤来靶向， 免疫检查点阻断（ICB）。我们在临床前和临床研究中测试了这种策略， RT和durvalumab治疗胰腺癌。目标2将确定是否由于独特的肿瘤的辐射抗性 可以靶向代谢，具体地，升高的嘌呤水平。我们在临床前和 使用FDA批准的嘌呤耗竭CNS渗透剂霉酚酸酯治疗胶质母细胞瘤的临床研究 莫非替（MMF）。目的3将确定是否辐射抵抗由于细胞周期控制和激活异常 使用CDK 4/6抑制剂可以在具有完整视网膜母细胞瘤蛋白（RB）的肿瘤细胞中靶向DNA修复。我们 在临床前研究和治疗局部晚期ER+女性的临床试验中验证这一假设 (and，在未来，如果得到临床前数据的支持，三阴性）乳腺癌使用RT与并发 Abemaciclib。这些项目将得到五个核心的支持：行政，转化病理学， 生物统计学和计算生物学，临床试验和放射增敏。我们有着悠久的历史， 纵向翻译：我们先前在这三种疾病中的早期试验已经进展到多机构， 我们不知道还有其他小组可以进行临床前和临床综合研究 这有一个显着的机会，降低发病率和死亡率的三个常见和 难以通过增加肿瘤的RT敏感性和免疫原性来治疗癌症， 使用临床上可用的试剂靶向它们的分子驱动剂。

PROJECT SUMMARY (OVERALL) Cancer cannot be cured unless the primary tumor is cured. For patients with locally advanced or unresectable disease for whom initial surgery is not an option, radiation therapy (RT) combined with a systemic agent has become the standard treatment. This is because systemic therapy alone can rarely cure gross disease, but can significantly improve the efficacy of RT and eliminate microscopic disease. Therefore, as systemic therapies continue to improve, the need for effective local control becomes increasingly important. Although technical improvements in planning and delivery have decreased the toxicity of RT, RT dose escalation trials have, in general, failed to improve outcome. The overarching hypothesis of this SPORE proposal is that combining RT with systemic therapy that targets the molecular drivers of locally advanced cancers will improve the outcome of treatment. The goal of this SPORE proposal is to test this hypothesis through in vitro and in vivo preclinical studies targeting key mechanisms of radiation resistance. Our studies will motivate pilot clinical trials that will define the conditions for phase II trials, yield an initial assessment of response, and test the preclinical hypotheses through correlative studies. This goal will be achieved through three specific aims. Aim 1 will determine if primary radiation resistance, the presence of occult metastatic disease, and a lack of immunogenicity can be targeted by increasing radiation-induced DNA damage using a PARP inhibitor with immune checkpoint blockade (ICB). We test this strategy in preclinical and clinical studies combining olaparib, RT, and durvalumab in pancreatic cancer. Aim 2 will determine if the radiation resistance due to unique tumor metabolism, specifically, elevated purine levels, can be targeted. We test this hypothesis in preclinical and clinical studies of glioblastoma using the purine depleting CNS-penetrant FDA approved agent mycophenolate mofetil (MMF). Aim 3 will determine if the radiation resistance due to aberrant cell cycle control and activated DNA repair can be targeted in tumor cells with intact retinoblastoma protein (RB) using CDK4/6 inhibitors. We test this hypothesis in preclinical studies and in a clinical trial treating women with locally advanced ER+ (and, in the future, if supported by preclinical data, triple negative) breast cancer using RT with concurrent abemaciclib. These projects will be supported by the five cores: Administrative, Translational Pathology, Biostatistics & Computational Biology, Clinical Trials, and Radiosensitization. We have a strong history of vertical translation: our prior early phase trials in these three disease have progressed to multi-institutional trials We do not know of another group that can carry out integrated preclinical and clinical studies which have a significant chance of decreasing the morbidity and mortality of three common and difficult to treat cancers by increasing the RT sensitivity and immunogenicity of tumors through targeting their molecular drivers using clinically available agents.