Hugs for Brady Foundation Pediatric Cancer Research Lab
Research and Current Funding
Brain dysfunction is one example of chemotherapy-related toxicity that can affect children with cancer during, and long after, curative treatment. Survivors of childhood cancer are more likely than people who were never treated for cancer to exhibit decreased attention span, poor working memory, and problems with executive functions like cognitive flexibility and task shifting, impulse control, planning, focusing attention, and remembering complex instructions. We have investigated why this side effect happens to some patients but not other, by exploring the impact of inherited factors (genetic variants) and environmental factors (e.g. specific dietary components or social determinants of health). We measure biomarkers within blood and cerebrospinal fluid to identify early signs of brain injury, before cognitive deficits emerge. And we use an animal model to learn how chemotherapy damages the brain and to test treatments that can protect the brain from chemotherapy-induced damage.
Pathophysiology of chemotherapy-induced cognitive deficits in an animal model.
We administer chemotherapy at clinically-relevant doses to juvenile rats during a period of ongoing brain development, to mimic the treatment of young children diagnosed with acute lymphoblastic leukemia. Treated animals exhibit deficits in cognitive flexibility, visual memory, and spatial memory that persist into adulthood, at least a year after exposure to chemotherapy (Wen, Cole, et al. Neuropharmacology, 2022) as well as increased apoptosis, proliferation of neural precursors, and signs of neuroinflammation (Wen, Cole, et al. Neuropharmacology, 2022). We have previously found that NMDA antagonists are effective against methotrexate-induced cognitive deficits: dextromethorphan can ameliorate existing cognitive deficits (Vijayanathan, Cole, et al. Behavioral Brain Research, 2012), while concurrent administration of memantine can prevent it (Cole, et al. Clinical Cancer Research, 2013). Currently, we are exploring the role of altered blood-brain barrier function in chemotherapy-induced cognitive impairment, as well as the contribution of genetic variants, such as ApoE4.
- NIH/NCI R01-CA182284 (Principal Investigator) “Pathophysiology of Chemotherapy-Induced Cognitive Deficits in Juvenile Rats.” Annual Direct Support $207,500. Funding period: June 1, 2014-May 31, 2019.
- Rutgers Cancer Institute of New Jersey, 2018-
- Embrace Kids Foundation, 2018-
- Hugs for Brady Foundation, 2018-
Predicting cancer related cognitive impairment among children treated for acute lymphoblastic leukemia (ALL).
Cognitive function is being prospectively assessed among the 580 children enrolled on Dana Farber Cancer Institute ALL Consortium protocol 16-001, to document changes in function from baseline at 4 time points during the two years of chemotherapy, and one year after completion of therapy, using a computerized battery of cognitive assessments (Sands, Cole et al. Supportive Care in Cancer, 2016). Our laboratory will measure biomarkers of neuroinflammation, oxidative stress, and neurodegeneration within cerebrospinal fluid collected during treatment to determine which best predict treatment-related cognitive decline. We will also test whether common genetic variants (e.g. NOS3 894T; Cole, et al. J Clin Oncol 2015) are associated with increased evidence of neuroinflammation or cognitive decline.
- NIH/NCI R21-CA187226. (Principal Investigator) "Markers of Cognitive Decline During Treatment for Childhood ALL" Annual Direct Support $125,000. Funding period 9/1/2015 - 8/31/2018.
- NIH/NCI R01 CA220568 (Multi-Principal Investigator) “Identifying children with subclinical neurocognitive decline and susceptibility to oxidative damage during the early months of therapy for ALL” Annual direct support $563,152. Funding period 09/17/18-8/31/23.
Characterizing brain function among cancer survivors
In order to better understand the specific processing deficits contributing to poor cognitive functioning in pediatric cancer survivors, we are using a combination of non-invasive techniques to study brain functions: electroencephalography (EEG) and functional imaging (fMRI). We are studying survivors of both childhood ALL and solid tumors, and comparing brain functions with age matched controls(e.g. Brace, Cole, et al. Journal of Clinical and Experimental Neuropsychology, 2019). These studies are designed to identify the relative contributions of sensory processes, memory, and attentional mechanisms, and cortical-maturation delays to poor performance on standardized tests of cognition function. Our approach will lead to the development of a powerful set of tools for identifying children with persistent treatment-related changes in cognitive functioning due to exposure to toxic therapy, guiding interventions to alleviate cognitive deficits.
- NIH/NCI R01CA240360 (Multi-Principal Investigator) “Characterization of brain dysfunction during development in survivors of childhood acute lymphoblastic leukemia.” Annual direct support, $752,031. Funding period: March 1, 2020 – February 28, 2025.
- NIH/NCI R21CA262491-01 (Co-Investigator; PI: Baker TE) “Candidate mechanisms for chemotherapy-induced neurocognitive deficits in pediatric solid non-CNS tumor patients” Annual direct support, $125,000. Proposed funding period-7/1/21-6/30/23.
- Rutgers Brain Health Institute Pilot Grants Program in Neuroscience (Multi-PI) “Cognitive control deficits in childhood leukemia survivors: At the intersection of brain, behavior, and computation”. Annual Direct Support, $40,000. Funding Period, 1/24/19-1/23/20.