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.

项目摘要（总体）除非原发性肿瘤治愈，否则无法治愈癌症。适用于本地高级或无法切除的患者初始手术的疾病是选择的疾病，辐射疗法（RT）与全身剂相结合成为标准处理。这是因为仅系统性治疗几乎无法治愈严重的疾病，但是可以显着提高了RT的功效并消除了微观疾病。因此，作为全身疗法继续改善，对有效的地方控制的需求变得越来越重要。虽然是技术性的计划和交付的改善降低了RT的毒性，RT剂量升级试验已在将军，未能改善结果。该孢子提议的总体假设是结合针对局部晚期癌症分子驱动因素的全身疗法的RT将改善治疗的结果。该孢子建议的目的是通过体外和体内检验该假设临床前研究针对辐射抗性的关键机制。我们的研究将激发飞行员临床试验这将定义II期试验的条件，对响应进行初步评估，并测试临床前通过相关研究假设。这个目标将通过三个特定目标实现。目标1意志确定原发性辐射是否是否存在，神秘转移性疾病的存在以及缺乏可以通过使用PARP抑制剂与具有辐射诱导的DNA损伤来靶向免疫原性免疫检查点封锁（ICB）。我们在结合Olaparib的临床前和临床研究中测试了这一策略，胰腺癌中的RT和Durvalumab。 AIM 2将确定是否由于独特的肿瘤引起的辐射阻力代谢，具体是嘌呤水平升高，可以针对。我们在临床前和使用嘌呤耗尽的CNS-PENETRANT FDA批准剂Mycophenaly的胶质母细胞瘤的临床研究 Mofetil（MMF）。 AIM 3将确定是否由于异常细胞周期控制引起的辐射阻力并激活 DNA修复可以使用CDK4/6抑制剂在具有完整的视网膜细胞蛋白（RB）的肿瘤细胞中。我们在临床前研究和治疗局部晚期ER+的妇女的临床试验中检验该假设（并且，将来，如果得到临床前数据的支持，则三重阴性）使用RT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，临床试验和放射敏化。我们有很强的历史垂直翻译：我们先前在这三种疾病中的早期试验已发展为多机构我们不知道可以进行综合临床前和临床研究的试验有很大的机会降低三个共同的发病率和死亡率，难以通过提高肿瘤的RT敏感性和免疫原性来治疗癌症使用临床上可用的药物针对分子驱动器。