# Identification of novel biomarkers and therapeutic strategies in chemobrain.

> **NIH NIH R01** · RUTGERS BIOMEDICAL AND HEALTH SCIENCES · 2024 · $593,617

## Abstract

PROJECT SUMMARY
While current treatment approaches can cure most children diagnosed with cancer, chemotherapy-induced
cognitive impairment (CICI) has emerged as a significant medical problem with a negative impact on quality of
life. Given that more children with cancer now survive into adulthood, identification of biomarkers that can
predict and/or mediate susceptibility to cognitive decline, in conjunction to novel therapeutic interventions to
treat CICI, are urgently needed. Poly (ADP-ribose) polymerase 1 (PARP1), the main nicotinamide adenine
dinucleotide (NAD+) consuming enzyme, is activated by DNA damage and causes cellular NAD+ degradation,
contributing to neurodegeneration. Similarly, our preliminary studies demonstrate that various
chemotherapeutics including methotrexate, cisplatin and paclitaxel cause neuronal DNA damage, resulting in
increased cleavage of PARP1 expression in the adult mouse hippocampus and human excitatory neurons.
Remarkably, we further show that PARP1 inhibition through administration of a potent PARP1/2 inhibitor,
veliparib effectively prevents cisplatin-induced anxiety-like behavior and neurogenic defects. Taken together,
these observations strongly suggest that hyperactivation of PARP1 by chemotherapy causes NAD+ loss to
further impair neuronal and cognitive function. Based on these together with the fact that methotrexate, which
is routinely used for childhood cancers, also increases cleaved PARP1 expression, potentially mediating
neurotoxicity, we hypothesize that methotrexate-induced PARP1 hyperactivation causes cellular NAD+ loss,
an effect that can be prevented by inhibition of PARP1 activity, and thus ameliorating CICI. In addition, given
that NAD+ loss has proven to be a promising biomarker for the age-related neurodegenerative conditions, we
also propose to test the hypothesis that NAD+ and its associated metabolites can be novel biomarkers to
predict and/or mediate CICI. To address these hypotheses, Aim 1 will test if veliparib prevents methotrexate-
induced cognitive impairment in tumor-free and primary T-cell acute lymphoblastic leukemia (T-ALL) juvenile
mouse models. In addition, given the importance of PARP1 signaling in cancer development, we will also
evaluate the impact of veliparib on tumor growth and chemotherapy’s anti-neoplastic activity using clinically
relevant T-ALL patient-derived xenograft (PDX) mice. Subsequently, using cell-type specific conditional PARP1
KO mice, Aim 2 will test which neural cell type is responsible for CICI. Moreover, we will also elucidate if NF-
kB-mediated cyclooxygenase-2 (COX-2) inflammatory signaling is a key downstream PARP1 effector driving
CICI. Lastly, Aim 3 will test if PARP1-dependent NAD+ metabolic pathway can be promising biomarkers that
can predict and/or mediate susceptibility to cognitive impairment in a cohort of ALL pediatric patients and
primary T-ALL juvenile mice. Our proposed translational work will provide critical mechanisms mediating CICI
and...

## Key facts

- **NIH application ID:** 10944092
- **Project number:** 1R01CA293210-01
- **Recipient organization:** RUTGERS BIOMEDICAL AND HEALTH SCIENCES
- **Principal Investigator:** Peter D. Cole
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $593,617
- **Award type:** 1
- **Project period:** 2024-06-26 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10944092

## Citation

> US National Institutes of Health, RePORTER application 10944092, Identification of novel biomarkers and therapeutic strategies in chemobrain. (1R01CA293210-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10944092. Licensed CC0.

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