Linear energy transfer (LET) dependencies for understanding pancreatic tumor control and relevant molecular endpoints in support of RBE-based heavy-ion radiotherapy

用于了解胰腺肿瘤控制和支持基于 RBE 的重离子放射治疗的相关分子终点的线性能量转移 (LET) 依赖性

• 批准号: 10544320
• 负责人: Sally A. Amundson
• 金额: $ 51.2万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10544320
• 关键词: 3D ultrasound; Address; Aftercare; Artificial Endocrine Pancreas; Biology; Carbon ion; Cell Death; Cell Line; Cell Proliferation; Cells; Cessation of life; Charge; Clinical; Collimator; Combined Modality Therapy; Complex; Custom; Cysteine; Cystine; DNA Damage; Dependence; Deposition; Development; Distant Metastasis; Dose; Drug Metabolic Detoxication; Generations; Genetically Engineered Mouse; Glutathione; Goals; Heavy Ions; Helium; High-LET Radiation; Hospitals; Human; Immune response; Ionizing radiation; Ions; KPC model; Knowledge; Laboratories; Linear Energy Transfer; Link; Lipid Peroxidation; Local Therapy; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Microscopic; Modality; Molecular; Mus; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Physics; Protons; Radiation; Radiation therapy; Radiobiology; Radiology Specialty; Reactive Oxygen Species; Relative Biological Effectiveness; Reporting; Research; Resistance; Resolution; Roentgen Rays; Signal Transduction; Therapeutic; Time; Tumor Markers; United States National Aeronautics and Space Administration; advanced pancreatic cancer; animal imaging; anti-cancer; anticancer research; cell killing; clinically relevant; cost effective; gemcitabine; high-LET heavy ion therapy; imaging capabilities; immune cell infiltrate; improved; improved outcome; in vivo; irradiation; laboratory facility; meter; mouse model; neoplastic cell; pancreatic cancer cells; pancreatic ductal adenocarcinoma cell; pancreatic neoplasm; particle beam; pharmacologic; pre-clinical; radiation response; relative effectiveness; serial imaging; tumor; tumor growth; x-ray irradiation

This proposal brings together a unique interdisciplinary team with complementary expertise in high-LET radiobiology, pancreatic cancer research, and high-LET physics. It leverages the engineered PDA (pancreatic ductal adenocarcinoma) mouse models and imaging capabilities at our “PDA Mouse Hospital” together with the high-LET charged particle beams generated at Brookhaven’s NSRL and our Radiological Research Accelerator Facility (RARAF) at Columbia to address the central hypothesis that heavy ion radiotherapy (HIRT) effects in PDA are LET dependent and can be enhanced by pharmacological induction of ferroptosis. HIRT represents a promising therapeutic opportunity for improving (PDA) survival, with very encouraging survival results reported after combined carbon-ion and gemcitabine therapy for locally advanced PDA. Compared with other radiotherapy modalities the high-LET radiations deposit energy far more densely resulting in complex DNA damage, clustered reactive oxygen species (ROS) formation, and altered damage signaling. The generation of clustered ROS by HIRT is clearly linked to cell killing, however, PDA upregulates ROS detoxification pathways, potentially leading to mitigation of tumor cell killing by radiation. Our labs have recently shown that pharmacological inhibition of cystine import counters PDA resistance to endogenous ROS, triggering ferroptotic death in PDA cell lines and tumors, and resulting in significantly improved survival of autochthonous PDA tumor bearing mice. The efficiency of lipid peroxidation, upon which ferroptosis depends, varies with LET, suggesting that overcoming ferroptosis resistance in combination with optimized HIRT may prove a powerful approach for PDA treatment. Thus our central hypothesis is that HIRT effects in PDA are LET dependent and can be enhanced by pharmaceutical induction of ferroptosis. The goal is to understand and quantify PDA-HIRT relevant endpoints using state-of-the art PDA mouse models in extended heavy-ion beams customized for mouse tumor exposure, with and without pharmacological induction of ferroptosis. Our second goal is understanding the LET dependencies of PDA-HIRT relevant endpoints: First to find the optimal dose-averaged LET (LETD) corresponding to these endpoints, and second to assess whether clinical helium ion beams may induce similar yields of these endpoints – a conclusion that would potentially revolutionize heavy ion radiotherapy. Our mouse irradiations will use custom extended heavy-ion beams at Brookhaven’s NSRL facility. However, the LETD distributions within the irradiated mouse tumors cover a much smaller LET range than in typical human tumors treated with HIRT. We will assess whether the conclusions drawn from these studies are still valid at the higher LETs and lower LETs respectively of relevance for clinical carbon-ion and helium-ion HIRT, by recapitulating relevant endpoints at RARAF, our preclinical heavy-ion irradiation facility where mono- LET beams for cellular irradiations are available from 10 to 200 keV/m.

该提案汇集了一个独特的跨学科团队，他们在高LET领域具有互补的专业知识 放射生物学、胰腺癌研究和高LET物理学。它利用了工程PDA（胰腺 导管腺癌）小鼠模型和成像能力在我们的“PDA小鼠医院”与 布鲁克海文NSRL产生的高LET带电粒子束和我们的放射性研究 加速器设施（RARAF）在哥伦比亚，以解决重离子放射治疗的中心假设， （HIRT）在PDA中的作用是LET依赖性的，并且可以通过药物诱导铁凋亡来增强。 HIRT代表了改善PDA生存率的有希望的治疗机会， 碳离子和吉西他滨联合治疗局部晚期PDA后的生存结果。 与其他放射治疗方式相比，高LET辐射存款能量更密集 导致复杂的DNA损伤、活性氧簇（ROS）形成和损伤改变 发信号。通过HIRT产生簇状ROS与细胞杀伤明显相关，然而，PDA上调 ROS解毒途径，可能导致减轻辐射对肿瘤细胞的杀伤。我们的实验室 最近显示，胱氨酸输入的药理学抑制对抗PDA对内源性ROS的抗性， 引发PDA细胞系和肿瘤中的铁凋亡死亡，并导致显著改善的 原位PDA荷瘤小鼠。脂质过氧化的效率，依赖于铁凋亡， 随着LET的变化而变化，这表明克服铁凋亡抗性与优化的HIRT相结合， 证明了PDA治疗的有效方法。 因此，我们的中心假设是，在PDA中的HIRT效应是LET依赖性的，并且可以通过以下方式增强： 药物诱导的铁下垂。目的是了解和量化PDA-HIRT相关终点 在针对小鼠肿瘤定制的扩展重离子束中使用最先进的PDA小鼠模型 暴露，有和没有药物诱导的铁下垂。我们的第二个目标是理解LET PDA-HIRT相关终点的依赖性：首先找到最佳剂量平均LET（LETD） 对应于这些终点，其次评估临床氦离子束是否可能诱发类似的 这些终点的产率-这一结论可能会彻底改变重离子放射治疗。 我们的小鼠辐照将使用布鲁克海文NSRL设施的定制扩展重离子束。 然而，照射小鼠肿瘤内的LETD分布覆盖比照射小鼠肿瘤中小得多的LET范围。 用HIRT治疗的典型人类肿瘤。我们将评估这些研究得出的结论是否 在与临床碳离子和氦离子相关的较高LET和较低LET下仍然有效 HIRT，通过概括RARAAF的相关终点，我们的临床前重离子辐照设施， 用于细胞辐照的LET束可从10至200 keV/μ m获得。