Project Details
Description
PROJECT SUMMARY
Chemotherapy-induced cognitive dysfunction (referred to as chemobrain) negatively impacts cancer
survivors and has emerged as a significant medical problem. To date, no effective treatment exists due to the
limited understanding of the mechanisms that drive chemotherapy-induced cognitive impairments. To provide
effective therapeutic strategies for this emergent medical problem, this application aims to answer Provocative
Question #12: What are the molecular and cellular mechanisms that underlie the development of cancer
therapy-induced severe adverse sequelae? While the underlying molecular pathways vulnerable to
chemotherapy-induced neurotoxicity are not well understood, recent results from our laboratory indicate the
Nampt-mediated NAD+ pathway is a promising therapeutic target for chemobrain. Using the platinum-based
chemotherapy compound cisplatin, we demonstrate its efficacy in suppressing the nicotinamide phosphoribosyl
transferase (Nampt)-mediated NAD+ metabolic pathway. Cisplatin-mediated suppression of Nampt-NAD+
metabolism leads to neurogenic dysfunction of the adult mouse hippocampus and memory impairments.
Remarkably, we found that by increasing NAD+ levels via administration of the NAD+ precursor nicotinamide
mononucleotide (NMN), we can effectively reverse cisplatin-induced deficits in neuronal dendrite morphology
and memory function, thus emphasizing the therapeutic potential of NAD+ metabolism in amelioration of
chemobrain. Based on these observations, our central hypothesis is that increasing Nampt or NAD+ levels
prevent cisplatin-induced impairments in neuronal and cognitive function. Our findings represent a novel
therapeutic strategy for chemobrain. To test this novel hypothesis, Aim 1 will determine whether increasing
NAD+ levels through NMN supplementation can improve cisplatin-induced deficits in neuronal and cognitive
function in both young and aged mice. In addition, our translational proposal will ensure the safety of NMN, as we
will determine if NMN has a detrimental impact on anti-neoplastic activity of cisplatin using patient-derived
xenograft (PDX) mouse models. Subsequently, Aim 2 will elucidate if genetically increasing Nampt levels can
prevent impairments in neuronal morphology and cognitive function. We will also evaluate if P7C3, a Nampt
enzyme activity enhancer, can improve cisplatin-induced chemobrain in young and aged mice. Our proposed
work will provide critical pathophysiological mechanisms and improve our understanding of the Nampt-mediated
NAD+ metabolic pathway in order to improve chemotherapy-induced cognitive dysfunction. Ultimately, the
findings will provide a framework by which safe and effective therapeutic strategies may be utilized in patients
undergoing cancer treatment so as to minimize or reverse neuronal and memory dysfunction.
Status | Finished |
---|---|
Effective start/end date | 8/8/19 → 7/31/24 |
Funding
- National Cancer Institute: $399,247.00
- National Cancer Institute: $397,500.00
- National Cancer Institute: $386,339.00
- National Cancer Institute: $386,340.00
- National Cancer Institute: $399,247.00
- National Cancer Institute: $399,249.00
- National Cancer Institute: $394,227.00
- National Cancer Institute: $136,017.00
- National Cancer Institute: $116,447.00
- National Cancer Institute: $136,019.00
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