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: 10322155
• 负责人: Sally A. Amundson
• 金额: $ 50.51万
• 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/10322155
• 关键词: 3D ultrasound; Address; Aftercare; Biology; Carbon ion; Cell Death; Cell Line; Cell Proliferation; Cells; Cessation of life; Charge; Clinical; Combined Modality Therapy; Complex; Custom; Cysteine; Cystine; DNA Damage; Dependence; Deposition; Development; Distant Metastasis; Dose; Drug Metabolic Detoxication; Engineering; Generations; Genetically Engineered Mouse; Glutathione; Goals; Heavy Ions; Helium; High-LET Radiation; Hospitals; Human; Immune; Immune response; Infiltration; Ionizing radiation; Ions; Knowledge; Laboratories; Linear Energy Transfer; Link; Lipid Peroxidation; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Microscopic; Modality; Molecular; Mus; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; 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; base; cell killing; clinically relevant; cost effective; gemcitabine; high-LET heavy ion therapy; imaging capabilities; improved; improved outcome; in vivo; irradiation; laboratory facility; mouse model; neoplastic cell; pancreatic cancer cells; pancreatic neoplasm; particle beam; pre-clinical; radiation response; 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 放射生物学，胰腺癌研究和高质量物理学。它利用工程PDA（胰腺） 我们的“ PDA小鼠医院”的小鼠模型和成像功能以及 在Brookhaven的NSRL和我们的放射学研究中产生的高电荷颗粒梁 哥伦比亚的加速器设施（RARAF）解决了重离子放射疗法的中心假设 （HIRT）PDA的效果是让依赖性的，可以通过药物诱导铁铁作用来增强。 Hirt代表了改善（PDA）生存的有前途的治疗机会，非常令人鼓舞 在局部晚期PDA的碳离子和吉西他滨治疗结合后，报告了生存结果。 与其他放射疗法相比，高质量辐射沉积能量密度要高得多 导致复杂的DNA损伤，簇状的活性氧（ROS）形成，并改变了损伤 信号。但是，hirt的群集ROS产生显然与细胞杀死有关，但是PDA更新 ROS排毒途径，可能导致通过辐射杀死肿瘤细胞的减轻。我们的实验室有 最近表明，药物抑制胱氨酸进口计数器对内源性ROS的抗性， 触发PDA细胞系和肿瘤中的铁毒性死亡，并显着提高了 自自PDA肿瘤轴承小鼠。脂质过氧化的效率，在其上取决于脂肪的效率 LET的多样性，表明与优化的Hirt结合使用耐铁毒性耐药性可能 证明了PDA治疗的有力方法。 我们的核心假设是，PDA中的Hirt效应是依赖的，可以通过 药物诱导铁铁作用。目的是了解和量化PDA套件相关的终点 在针对小鼠肿瘤定制的扩展重型离子光束中使用最先进的PDA鼠标模型 暴露，没有药理学诱导铁铁作用。我们的第二个目标是了解LET PDA套件相关端点的依赖性：首先找到最佳剂量平均let（letd） 与这些端点相对应，其次是评估临床氦离子束是否可能引起相似的 这些终点的产量 - 这一结论可能会彻底改变重离子放射疗法。 我们的鼠标辐照将在布鲁克黑文的NSRL设施中使用定制的延长重离子梁。 但是，受辐照的小鼠肿瘤内的letd分布覆盖的范围要小得多 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是 仍然在较高的莱特和降低较低的情况下分别有效与临床碳离子和氦离子的相关性 Hirt，通过概括我们的临床前重离子辐射设施Raraf的相关端点，其中 让细胞辐照的光束可从10到200 keV/m。