Hyperbaric Oxygen Therapy to Mitigate Childhood Radiation-Induced Neurocognitive and Skeletal Toxicity: Multimodality Evaluation in a Young Rodent Model
Abstract
Background: While radiation therapy (RT) is an integral component of pediatric cancer management, RT is also the most common cause of lifelong toxicity in childhood cancer survivors (CCS). The effects of RT on the central nervous system (brain) and musculoskeletal system (bones and muscle growth) can cause intellectual disabilities, brain damage, and growth deformities that can significantly impair the long-term health and quality of life of CCS. Hyperbaric oxygen therapy (HBOT) is a treatment in which a person breathes 100% oxygen while exposed to increased atmospheric pressure (2-3 atmospheres), for 1.5 to 2 hours for 20-40 sessions. HBOT has been shown to improve cerebral blood flow, stimulate angiogenesis, restore impaired brain metabolism, reduce inflammation, and reverse RT induced changes in tissues. There is clinical and laboratory evidence to show that HBOT may reduce these side effects of RT. Hypothesis: HBOT may decrease the damaging effects of RT on intellectual brain and musculoskeletal growth in children with cancer. We propose to test this hypothesis in a pediatric-age matched mouse model treated with varying combinations of RT and HBOT in a randomized study utilizing a comprehensive advanced diagnostic panel including neurocognitive (intellectual), physical (measurements), advanced imaging (scans), molecular (genes), serum biomarker (blood tests), and pathology (microscopic changes in cells and tissues) end points. Aims Aim 1: Determine the impact of HBOT on Neurocognitive functioning of pediatric age-matched mice following whole brain RT (10Gy in one fraction) utilizing neurocognitive (intellectual) testing in mice randomized to six treatment arms. Aim 2: Determine the impact of HBOT on Skeletal development of pediatric age-matched mice following whole hind limb RT (20Gy in 1 fraction to entire one hind limb) utilizing physical (using calipers) and computed tomography (CT) scan-based measurements of limb length and diameter in mice randomized to six treatment arms. Aim 3: Discover novel biomarkers that may define the effects and their mechanisms following treatment using HBOT and RT on the brain and muscles/bones using a variety of tests including advanced imaging (magnetic resonance imaging MRI, CT, positron emission tomography PET scans), pathology (microscope), serum biomarkers (blood tests) and genomic alterations in mice randomized to six randomized arms in Aims 1 and 2. Design: We will use pediatric age-matched (4-6 weeks old) C57Bl6 mice for this study. These animals will be randomly assigned to one of six treatment arms described in Table. Innovation: (i). This is the most detailed study of HBOT effects on RT-induced intellectual and bone growth damage using a variety of diagnostic tests described above. (ii). Use of a pediatric age-matched animal model. (iii). We will study both early and late (6 months) evaluation of RT/HBOT effects that will be of clinical relevance to pediatric oncology. Impact: Currently there are no treatments available to reduce the radiation damage induced in children with cancer. In order to fulfil this unmet need, we assembled an expert multidisciplinary team to comprehensively study the mechanistic correlation of HBOT/RT effects. We hope that such this study will promote future clinical research using HBOT. The study team includes leaders in pediatric oncology who will be able to facilitate the adoption and translation of this research to the clinic. Military Relevance: Having a child suffer from cancer is one of the most traumatic experience a human being can endure. While modern cancer treatments provide great hope to parents for a cure, the side effects of these treatments can result in lifelong complications. Military Service Members and their families will likewise suffer the trauma of having their children grow up with emotional, intellectual, and physical deformities that can permanently affect their ability to gain empl
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210822
Entities
People
- John Kalapurakal
Organizations
- Northwestern University
- United States Army