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.

这项建议汇集了一支独特的跨学科团队，在High-Let领域拥有互补的专业知识 放射生物学、胰腺癌研究和高LET物理学。它利用了工程化的PDA(胰腺 导管腺癌)小鼠模型和成像能力 布鲁克海文NSRL产生的高LET带电粒子束和我们的放射学研究 哥伦比亚大学的加速器设备(RARAF)解决了重离子放射治疗的中心假设 (Hirt)在PDA中的作用是不依赖的，并且可以通过药物诱导铁性下垂来增强。 Hirt代表着一个有希望的提高(PDA)存活率的治疗机会，非常令人鼓舞 报告了局部晚期PDA的碳离子和吉西他滨联合治疗后的生存结果。 与其他放射治疗方式相比，高LET辐射的能量储存密度要高得多。 导致复杂的DNA损伤、聚集的活性氧物种(ROS)的形成和改变的损伤 发信号。Hirt产生的聚集性ROS明显与细胞杀伤有关，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力。我们的实验室有 最近发现，抑制胱氨酸进口的药理作用可以对抗PDA对内源性ROS的耐药性， 在PDA细胞系和肿瘤中触发铁链死亡，并显著提高患者的存活率 自体PDA荷瘤小鼠。铁下垂所依赖的脂质过氧化的效率， 随着LET的不同而不同，这表明结合优化的Hirt可以克服铁性下垂抵抗 事实证明，这是治疗PDA的有效方法。 因此，我们的中心假设是，PDA中的Hirt效应是依赖的，并可以通过 药物诱导铁性下垂。目标是了解和量化与PDA-HIRT相关的端点 在为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性下垂。我们的第二个目标是了解LET PDA-HIRT相关终点的相关性：首先寻找最佳剂量平均LET(LETD) 与这些终点相对应，第二，评估临床氦离子束是否会引起类似的 这些终点的产额--这一结论可能会给重离子放射治疗带来革命性的变化。 我们的鼠标辐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，照射小鼠肿瘤内的LETD分布覆盖的LET范围比 Hirt治疗的典型人类肿瘤。我们将评估从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仍然有效 Hirt，通过概括RARAF的相关端点，我们的临床前重离子照射设施，在那里单 可提供10到200keV/m的用于蜂窝照射的LET束流。