Molecularly Targeted Radiosensitization of Locally Advanced Cancers

项目总结(总体) 除非原发肿瘤被治愈，否则癌症是无法治愈的。适用于局部晚期或不能切除的患者 对于那些不能进行初始手术的疾病，放射治疗(RT)结合全身治疗已经 成为标准的治疗方法。这是因为单靠系统疗法很少能治愈肉眼疾病，但却能。 显著提高放射治疗的疗效，消除微观疾病。因此，作为系统性治疗， 随着情况继续改善，对有效的地方控制的需要变得越来越重要。尽管技术上 计划和交付方面的改进降低了RT的毒性，RT剂量递增试验在 将军，没能改善结果。这个孢子提议的首要假设是，结合 以局部晚期癌症分子驱动因素为靶点的全身放射治疗将改善 治疗结果。这一孢子提议的目标是通过体外和体内来检验这一假说。 针对辐射抵抗关键机制的临床前研究。我们的研究将推动试点临床试验 这将定义第二阶段试验的条件，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 确定是否存在初级辐射抵抗、是否存在隐匿性转移疾病以及是否缺乏 可通过使用PARP抑制剂增加辐射诱导的DNA损伤来靶向免疫原性 免疫检查点阻断(ICB)。我们在结合奥拉帕利的临床前和临床研究中测试这一策略， RT、Durvalumab在胰腺癌中的应用。目标2将确定是否由于独特的肿瘤而产生的辐射抗性 代谢，特别是嘌呤水平的升高，可以作为靶点。我们在临床前和临床试验中测试了这一假设 FDA批准的脱嘌呤类中枢神经系统药物霉酚酸酯治疗胶质母细胞瘤的临床研究 莫非替尔(MMF)。AIM 3将确定辐射抵抗是否由于细胞周期的异常而被控制和激活 使用CDK4/6抑制剂可以针对视网膜母细胞瘤蛋白(RB)完整的肿瘤细胞进行DNA修复。我们 在临床前研究和治疗局部晚期ER+的女性的临床试验中验证这一假设 (将来，如果得到临床前数据的支持，三重阴性)乳腺癌采用RT联合同期治疗 阿贝米卡利布。这些项目将得到五个核心的支持：行政、转化性病理学、 生物统计学与计算生物学、临床试验和放射增敏。我们有很强的历史 垂直翻译：我们之前对这三种疾病的早期试验已经进展到多机构 我们不知道还有另一组人可以进行临床前和临床综合研究 它们很有可能降低三种常见和非传染性疾病的发病率和死亡率 通过提高肿瘤的放射敏感性和免疫原性来治疗癌症 使用临床上可用的药物来定位他们的分子驱动因素。

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.