This $1,780,906 federal Project Grant award, titled "Identification of Novel Biomarkers and Therapeutic Strategies in Chemobrain," was provided by the National Cancer Institute under the Cancer Treatment Research program (CFDA 93.395). The objective is to investigate the role of the enzyme PARP1 in mediating chemotherapy-induced cognitive impairment (CICI) and evaluate the potential of PARP1 inhibition as a therapeutic intervention. Key research activities include: Testing the PARP1...
The U.S. National Institute of Neurological Disorders and Stroke (NINDS) awarded a $445,500 Project Grant under the Extramural Research Programs in the Neurosciences and Neurological Disorders (CFDA 93.853) federal grant program to the University of Cincinnati. This grant supports research to investigate the effects of the chemotherapeutic agent methotrexate on synaptic plasticity, with a focus on understanding sex-dependent differences that may contribute to cognitive deficits observed in...
This federal Project Grant award from the National Cancer Institute (CFDA 93.395 - Cancer Treatment Research) provides $225,101 to investigate the mechanisms underlying the increased risk of hematological malignancy in sickle cell disease (SCD). The research will: Perform gain and loss of function experiments to study the impact of oxidative stress-induced DNA damage on the development of clonal hematopoiesis and hematological malignancies in SCD mouse models compared to normal controls....
This $248,509 Project Grant award from the National Cancer Institute's Cancer Research Manpower program (CFDA 93.398) supports research conducted by The Children's Hospital of Philadelphia (CHOP) to better understand the pathophysiology of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) - severe side effects that can occur with chimeric antigen receptor T-cell (CAR-T) cancer therapies. The key objectives are to: 1) Identify the cellular and...
This federal Project Grant award from the National Cancer Institute (CFDA 93.395 - Cancer Treatment Research) provides funding to assess the efficacy and toxicity of T3 (thyroid hormone) as a potential treatment for medulloblastoma, the most common malignant brain tumor in children. The $219,351 award will support a 2-year research project with the following objectives: Evaluate the toxicity, pharmacokinetics, and pharmacodynamics of T3 in tumor-bearing mice. Examine the therapeutic efficacy...
This Project Grant award from the National Cancer Institute (CFDA 93.394 - Cancer Detection and Diagnosis Research) provides $1,474,236.00 to The Children's Hospital of Philadelphia (CHOP) and the University of Pennsylvania to characterize synaptic density changes in the brain following radiation therapy using a novel positron emission tomography (PET) imaging tracer. The key objectives are to: 1) establish quantitative PET imaging methods to measure regional changes in synaptic density in...
The National Cancer Institute (NCI) awarded a Project Grant under the Cancer Treatment Research program (CFDA 93.395) to The Ohio State University for a 5-year, $601,091 research project on "Damage-Associated Molecular Patterns in Chemotherapy Toxicity". The project aims to investigate the role of the inflammatory protein S100A9 in paclitaxel-induced peripheral neuropathy, a debilitating side effect experienced by many cancer patients receiving this common chemotherapy drug. Key...
This Project Grant award from the National Cancer Institute (NCI), under the Cancer Detection and Diagnosis Research program (CFDA 93.394), provides $670,904 to The Regents of the University of California, San Francisco (UCSF) from August 7, 2024 to July 31, 2029. The grant supports research aimed at developing combination metabolic therapy and advanced imaging techniques to improve outcomes for patients with diffuse midline glioma (DMG), a devastating form of pediatric brain cancer....
This Project Grant award from the National Cancer Institute (CFDA 93.395 - Cancer Treatment Research) will fund research at the University of California, San Francisco (UCSF) to investigate metabolic mechanisms of immunosuppression in diffuse midline gliomas (DMGs), a type of aggressive brain cancer in children. The $686,979 award will support studies to determine how the H3K27M mutation in DMGs upregulates the glycolytic enzyme PGK1, leading to increased citrate production that suppresses...
This $1,220,394 federal Project Grant award from the National Cancer Institute (CFDA 93.395 - Cancer Treatment Research) will support a comprehensive investigation into the acute and chronic neurological side effects of chimeric antigen receptor (CAR) T-cell therapy. The research team at Sloan-Kettering Institute for Cancer Research will conduct a multi-faceted study to characterize the molecular mechanisms, biomarkers, and neurological outcomes associated with immune effector cell-associated...
MECHANISTIC STUDY OF METHOTREXATE-INDUCED OXIDATIVE DISTRESS IN NEURONS AND THE CSF - PROJECT SUMMARY THE NEUROCOGNITIVE SIDE EFFECTS OF CANCER CHEMOTHERAPY IN PEDIATRIC PATIENTS ARE HEART-BREAKING; NOT ONLY MUST THESE CHILDREN DEAL WITH THE HARDSHIP OF THE DISEASE AND HARSH TREATMENT, BUT THEY OFTEN ALSO FACE NEUROCOGNITIVE IMPAIRMENTS THAT AFFECT THEIR PERFORMANCE IN SCHOOL AND THEIR DAILY LIFE AS CANCER SURVIVORS. THESE BRAIN TOXICITIES, NAMED "CHEMOBRAIN", OR CHEMOTHERAPY-RELATED COGNITIVE IMPAIRMENT (CRCI), INCLUDE IMMEDIATE SYMPTOMS (CONFUSION, MEMORY IMPAIRMENT, ATAXIA), AS WELL AS PROLONGED NEUROCOGNITIVE MALFUNCTIONS. THE GAP IN THE FIELD: NOT ENOUGH IS KNOWN ABOUT THE MOLECULAR MECHANISMS OF CHEMOTHERAPY-INDUCED TOXICITY. SPECIFICALLY, METABOLIC ABERRATIONS IN THE BRAIN THAT ENSUE FOLLOWING THERAPY WITH METABOLIC DRUGS SUCH AS THE ANTI-FOLATE MTX, A STANDARD OF CARE FOR CHILDHOOD LEUKEMIA, IS AN UNEXPLORED FIELD. TO BE ABLE TO OFFER SOLUTIONS TO CHEMOTHERAPY-INDUCED NEUROTOXICITY IT IS CRITICAL TO FIRST UNDERSTAND THE MOLECULAR MECHANISMS OF THE TOXICITY CAUSED BY COMMON CHEMOTHERAPIES. THEREFORE, THE GOAL OF THIS PROJECT IS TO ELUCIDATE TARGETABLE MECHANISMS THAT MEDIATE AND MODIFY CHEMOTHERAPY-INDUCED NEUROTOXICITY WITH FOCUS ON OXIDATIVE DISTRESS. HYPOTHESIS: A GOOD UNDERSTANDING OF THE MOLECULAR MECHANISMS OF CRCI IS REQUIRED TO BE ABLE TO OFFER PREVENTIVE CARE OR TREATMENT. PRELIMINARY DATA: WE APPLIED METABOLITE PROFILING OF MTX-TREATED MOUSE AND HUMAN CEREBROSPINAL FLUID (CSF) TO STUDY THE METABOLIC IMPACT OF THE DRUG AND REVEALED OXIDATIVE DISTRESS IN THE CSF AND THE CHOROID PLEXUS (CHP), THE ORGAN THAT PRODUCES THE CSF. WE FOUND THAT IN ADDITION TO DAMAGING THE CHP AND CSF, MTX ALSO CAUSED TOXICITY TO NEURONS IN THE HIPPOCAMPUS. HOWEVER, THESE FINDINGS OFFER SOME HOPE: THE CSF CAN SERVE AS A CONDUIT FOR THERAPY BECAUSE IT IS RELATIVELY ACCESSIBLE FOR CLINICAL INTERVENTION AND REACHES ALL PARTS OF THE BRAIN. INDEED, OUR DISCOVERY THAT MTX TREATMENT CAUSES REDUCTION IN CSF LEVELS OF THE SECRETED ANTIOXIDANT ENZYME SOD3, BOTH IN MICE AND IN MTX-TREATED PATIENTS, LED US TO TEST CSF-BASED THERAPY; CHP-TARGETED GENE THERAPY WITH EXOGENOUS SOD3 EXPRESSION REPLENISHES CSF'S PROTECTIVE CAPACITY, PREVENTING METABOLIC DAMAGE IN THE HIPPOCAMPUS AND EVEN RESCUES MTX-INDUCED BEHAVIORAL DEFICITS IN MICE. APPROACH: WE WILL TEST OUR HYPOTHESIS THAT THE CHP-CSF SYSTEM CAN BE HARNESSED TO ALTER THE BRAIN REDOX ENVIRONMENT TO REDUCE ADVERSE EFFECTS OF CHEMOTHERAPY ON NON- CANCEROUS BRAIN CELLS BY ASSESSING THE MECHANISMS BY WHICH CSF-SOD3 PROTECTS THE HIPPOCAMPUS FROM MTX-INDUCED TOXICITY (AIM 1), BY STUDYING THE ROLE OF NITRIC OXIDE (NO) AND PEROXYNITRITE IN THE MTX-INDUCED OXIDATIVE DAMAGE IN CHP CELLS AND NEURONS (AIM 2), AND BY TESTING IF RESUMING OXIDATIVE BALANCE IN THE CSF CAN BE ACHIEVED BY PERIPHERAL AND BRAIN-SPECIFIC INJECTION OF ANTIOXIDANTS, AND WHETHER THESE ARE SUFFICIENT TO MITIGATE OXIDATIVE DAMAGE TO CHP AND HIPPOCAMPUS (AIM 3). IMPACT: OUR STUDY WILL REVEAL ACTIONABLE TOOLS TO MITIGATE THE NEUROLOGICAL DAMAGE INDUCED BY MTX, AND OTHER CHEMOTHERAPIES, AND THE IMMEDIATE POTENTIAL OF ANTIOXIDANTS CO-ADMINISTRATION WITH CHEMOTHERAPY FOR AMELIORATION OF CRCI AND IMPROVED SURVIVORSHIP.