Emerging evidence suggests that childhood cancer survivors treated without central nervous system (CNS)
directed therapies are at significant risk for neurocognitive impairment that is associated with decreased social
attainment and quality of life. However, the underlying biological mechanisms of neurocognitive impairment in
this population are poorly understood limiting our ability to prevent or alleviate these adverse outcomes. Long-
term survivors of childhood cancer have a higher frequency of frailty and chronic health conditions than sibling
controls suggesting cancer therapy may accelerate the physiological and biological aging process, which may
lead to neurocognitive impairment. Studies in the general population indicate systemic inflammation and
oxidative stress increase with age and are associated with increased morbidity, mortality, and cognitive decline.
Inflammation and oxidative stress are also important regulators of telomere length and epigenetic changes which
have been associated with neurocognitive impairment in aging non-cancer populations. These biomarkers have
yet to be extensively examined in childhood cancer survivors treated without CNS directed therapies. The
objective of this K99R00 is to identify aging-related biological predictors of neurocognitive impairment and
subsequent decline in order to inform the design of future interventions using existing data and biospecimens
from 300 HL survivors and 200 community controls in the St. Jude Lifetime cohort. Specifically, the K99 phase
aims to examine cross-sectional associations between markers of inflammation, oxidative stress,
immunosenescence, and cellular aging (telomere length and epigenetic age acceleration) with neurocognitive
impairment in long-term Hodgkin lymphoma survivors (HL). The R00 phase will expand on these findings by first
describing the trajectory of neurocognitive decline in long-term HL survivors and then by examining longitudinal
associations between these biomarkers and subsequent neurocognitive decline. Further, these studies will
provide data on the influence of modifiable risk factors (e.g. exercise, smoking, nutrition) on these biomarkers to
inform future development of interventions to mitigate neurocognitive impairment in cancer survivors. Dr.
Williams is an emerging translational cancer control epidemiologist focused on underlying pathophysiologic and
biologic mechanisms of neurocognitive function in cancer survivors. The K99R00 allows Dr. Williams to develop
expertise in 1) neurobiology and cancer biology and treatment specific to HL, 2) aging-related biomarkers and
molecular epidemiology, 3) complex statistical methods and 4) clinical and behavioral intervention trials. Dr.
Williams' mentoring team has extensive expertise in neurocognitive assessments, neuropathology, molecular
epidemiology, childhood cancer, and statistical methods. St. Jude Children's Research Hospital is an
international leader in cancer control and survivorship and provides a resource-rich training environment for Dr.
Williams. The combined training and research plan will ensure Dr. Williams' transition to independence by
providing the skills and preliminary data to successfully compete for future R01-level grants.
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