Although most children with cancer are cured, treatment-related toxicity causes organ dysfunction. In some cases, the damage cn be permanent, interfering with quality of life in the decades following curative therapy for cancer. Our laboratory focuses on how the complex interplay between cancer therapy, host and environmental factors determines treatment-related organ toxicity. Although we study a variety of chemotherapeutic agents, our primary focus is the antifolate drug, methotrexate, used in the treatment of some of the more common childhood cancers, including acute lymphoblastic leukemia, non-Hodgkin lymphoma, and osteosarcoma.
To better understand the large interpatient variability in toxicity among children treated with identical chemotherapy regimens, we examine interpatient variation in environmental factors (e.g. intake of dietary nutrients or exposure to poverty) as well as host factors (genetic variants). We identified a common variant in thymidylate synthase associated with increased risk of bony toxicity (fractures or osteonecrosis) among children with acute lymphoblastic leukemia. We identified common variants in genes related to oxidative stress and/or neuroinflammation that were associated with significantly increased risk of exhibiting behavioral or neurocognitive deficits among survivors of childhood leukemia. And we have identified dietary deficiencies associated with acute treatment-related toxicity during therapy.
We use a rodent model of chemotherapy-induced cognitive deficits to study the underlying pathophysiology and test protective interventions in this preclinical model. We demonstrated that methotrexate, when administered at clinically-relevant doses, produces the expected changes in folate physiology within the central nervous system. By depleting reduced folate pools, methotrexate prevents the remethylation of homocysteine to methionine, allowing accumulation of homocysteine in the brain and spinal fluid. Downstream metabolites of homocysteine are sufficient to recapitulate the memory deficits observed after methotrexate, when they are injected into the central nervous system at concentrations seen after methotrexate. Critically, blocking these metabolites at the N-methyl-d-aspartate glutamate receptor prevents methotrexate-induced memory deficits, suggesting the same approach might prevent cognitive decline among children treated with the same drug. We are currently using this model to explore the contribution of oxidative stress within the central nervous system to chemotherapy-induced memory deficits or alterations in executive function.
Current NIH support is funding ta translational, longitudinal study of biomarkers within blood and cerebrospinal fluid collected prospectively from children undergoing therapy for acute lymphoblastic leukemia. We are prospectively testing whether biomarkers indicating altered folate physiology, oxidative stress, neuroinflammation, or subacute neurodegeneration predict treatment related neurocognitive decline from baseline. We will test whether the most predictive biomarkers change early during the two years of leukemia therapy, when a proactive intervention can prevent further damage. In addition, we are prospectively testing whether analyses of genetic variants can identify those subjects who are most susceptible to oxidative stress and/or neurocognitive decline.