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，在高 LET 方面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。 我们的“PDA 小鼠医院”以及 布鲁克海文国家研究实验室和我们的放射学研究中心产生的高 LET 带电粒子束 哥伦比亚加速器设施（RARAF）旨在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死亡来增强。 HIRT 代表了改善 (PDA) 生存的有希望的治疗机会，非常令人鼓舞 碳离子和吉西他滨联合治疗局部晚期 PDA 后报告的生存结果。 与其他放射治疗方式相比，高 LET 辐射沉积的能量更加密集 导致复杂的 DNA 损伤、簇状活性氧 (ROS) 形成和损伤 HIRT 产生的簇状 ROS 与细胞杀伤明显相关，然而，PDA 上调。 ROS 解毒途径，可能会减轻辐射对肿瘤细胞的杀伤作用。 最近表明，药物抑制胱氨酸输入可以对抗 PDA 对内源性 ROS 的抗性， 引发 PDA 细胞系和肿瘤中的铁死亡，并导致显着提高的存活率 原生 PDA 肿瘤小鼠的铁死亡所依赖的脂质过氧化的效率， 随 LET 变化，表明结合优化 HIRT 克服铁死亡抵抗可能 证明这是一种有效的 PDA 治疗方法。 因此，我们的中心假设是，PDA 中的 HIRT 效应是 LET 依赖性的，并且可以通过以下方式增强： 药物诱导铁死亡的目的是了解和量化 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 我们的第二个目标是了解 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引起类似的 这些终点的产量——这一结论可能会彻底改变重离子放射治疗。 我们的小鼠照射将在布鲁克海文的 NSRL 设施中使用定制的扩展重离子束。 然而，受辐射小鼠肿瘤内的 LETD 分布覆盖的 LET 范围比 我们将评估这些研究得出的结论是否正确。 分别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，通过重述 RARAF 的相关终点，RARAF 是我们的临床前重离子辐照设施，其中单 用于细胞照射的 LET 光束范围为 10 至 200 keV/μm。