Molecularly Targeted Radiosensitization of Locally Advanced Cancers

局部晚期癌症的分子靶向放射增敏

基本信息

批准号：
10554470
负责人：
THEODORE S LAWRENCE
金额：
$ 206.62万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-14 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10554470
关键词：
Address Animals Astrocytes Biological Assay Biometry Breast Cancer Cell CDK4 gene Cell Cycle Regulation Clinical Clinical Research Clinical Trials Clinical assessments Combined Modality Therapy Computational Biology Conformal Radiotherapy Correlative Study Cytoplasm DNA DNA Damage DNA Repair Data Disease Dose Estrogen receptor positive FDA approved Future Glioblastoma Glutamine Goals Guanosine Triphosphate In Vitro Institution Interferons Knowledge Locally Advanced Malignant Neoplasm Malignant Neoplasms Malignant neoplasm of brain Malignant neoplasm of pancreas Metastatic breast cancer Microscopic Molecular Molecular Target Morbidity - disease rate Mus Normal tissue morphology Operative Surgical Procedures Outcome PARP inhibition Pathology Patients Phase Ib Clinical Trial Poly(ADP-ribose) Polymerase Inhibitor Preclinical Testing Primary Neoplasm Purines Radiation Radiation Induced DNA Damage Radiation Tolerance Radiation Toxicity Radiation therapy Radiosensitization Recording of previous events Reporter Research Resistance Retinoblastoma Protein Signal Transduction Systemic Therapy Testing Translations Treatment outcome Unresectable Woman Work X-Ray Computed Tomography advanced pancreatic cancer bioluminescence imaging cancer type early phase trial immune checkpoint blockade immunogenicity improved improved outcome in vivo individual patient inhibitor malignant breast neoplasm molecular targeted therapies mortality mycophenolate mofetil neoplastic cell pharmacologic phase II trial pre-clinical precision medicine preclinical study programmed cell death ligand 1 protein function radiation resistance randomized trial response standard care success triple-negative invasive breast carcinoma tumor tumor metabolism

项目摘要

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.

项目概要（总体）除非原发肿瘤被治愈，否则癌症无法治愈。对于局部晚期或无法切除的患者对于无法进行初始手术的疾病，放射治疗 (RT) 与全身药物相结合已成为可能成为标准治疗。这是因为单独的全身治疗很少能治愈总体疾病，但可以显着提高RT的疗效并消除微小疾病。因此，作为全身治疗持续改进，有效的局部控制的必要性变得越来越重要。虽然技术上计划和实施方面的改进降低了 RT 的毒性，RT 剂量递增试验已一般，未能改善结果。该 SPORE 提案的总体假设是结合放疗结合针对局部晚期癌症分子驱动因素的全身治疗将改善治疗结果。 SPORE提案的目标是通过体外和体内测试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定义 II 期试验的条件，对反应进行初步评估，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将确定原发性辐射抗性、隐匿性转移性疾病的存在以及缺乏使用 PARP 抑制剂可通过增加辐射诱导的 DNA 损伤来靶向免疫原性免疫检查点阻断（ICB）。我们在结合奥拉帕尼的临床前和临床研究中测试了这一策略， RT 和 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辐射抵抗新陈代谢，特别是嘌呤水平升高，可以作为目标。我们在临床前和临床前测试了这个假设使用FDA批准的嘌呤消耗中枢神经系统渗透剂霉酚酸酯治疗胶质母细胞瘤的临床研究莫非替尔（MMF）。目标 3 将确定辐射抗性是否由于细胞周期控制异常而激活使用 CDK4/6 抑制剂可针对具有完整视网膜母细胞瘤蛋白 (RB) 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+ 女性的临床试验中检验这一假设（并且，在未来，如果有临床前数据支持，三阴性）乳腺癌使用同步放疗 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。我们拥有悠久的历史垂直翻译：我们之前对这三种疾病的早期试验已经进展到多机构试验我们不知道还有哪个小组可以进行综合临床前和临床研究这有很大机会降低三种常见疾病和疾病的发病率和死亡率通过增加肿瘤的 RT 敏感性和免疫原性来治疗癌症是困难的使用临床上可用的药物来靶向其分子驱动因素。