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，在高let领域具有互补的专业知识