Chemotherapy-induced cognitive deficit (?chemobrain?) is a major side effect of cancer treatment that fre- quently persists long into survivorship. There are no FDA-approved drugs for prevention or treatment of che- mobrain, and the underlying mechanisms are poorly understood. This application aims at filling this void and responds to provocative question #9: What are the molecular and/or cellular mechanisms that un- derlie the development of cancer therapy-induced severe adverse sequelae? Our previous work in models of ischemic brain damage demonstrated that nasally applied mesenchymal stem cells migrate into the brain to restore cognitive and sensorimotor dysfunction, by promoting endogenous repair mechanisms leading to restoration of brain structure and by suppression of neuro-inflammation. Our preliminary data show that cisplatin induces cognitive deficits in mice that are associated with decreased neurogenesis, abnormalities in white matter organization and dendritic spine integrity, and impaired mito- chondrial respiration. Preliminary data indicate that mesenchymal stem cells (MSC) administered intranasally travel into the brain, restore the cognitive deficits and normalize mitochondrial function. Preliminary in vitro data indicates that MSC transfer healthy mitochondria to neurons damaged by cisplatin. Our working hypothesis is that cisplatin induces cognitive deficits by causing persistent mitochondrial damage leading to neuroinflammation, stem cell depletion, abnormalities in white matter organization and dendritic spine integrity, and impaired synaptic connectivity. We propose that nasally administered MSC re- verse CICI by restoring mitochondrial function and suppressing neuroinflammation. To test our hypothesis we will pursue the following Specific Aims:
Aim 1 : Treat CICI by intranasal administration of MSCs;
Aim 2 : Determine whether nasally administered MSCs migrate into the brain to promote endogenous repair mecha- nisms;
and Aim 3 : Determine the mechanisms underlying the effect of cisplatin and MSC on the brain. This study is innovative because: a) we will be the first to fully analyze CICI in the mouse at the neuroim- aging, cellular, mitochondrial and inflammatory levels; b) the potential to restore CICI by nasal administration of MSC has not been tested; c) the hypothesis that MSC transfer mitochondrial to damaged neurons in vivo has not been tested; c) successful completion of this study will identify key molecular mechanisms underlying chemobrain; and d) we will provide proof of principle that chemobrain can be repaired. This project is significant because chemobrain is a common side effect of cancer treatment that often per- sists into survivorship and reduces quality of life. We have already performed extensive safety studies in mice treated with MSC for ischemic brain damage. Successful completion of this project will provide the first step toward a treatment for brain damage and associated functional impairments caused by chemotherapy for tu- mors outside the nervous system or by other cancer treatments, including radiation therapy for brain tumors.

Public Health Relevance

The proposed project responds to RFA-CA-15-008, Provocative Questions #9, What are the molecular and/or cellular mechanisms that underlie the development of cancer therapy-induced severe adverse sequelae? Chemobrain is a major adverse side effect of cancer treatment that often lasts long into survivorship and for which preventive or curative FDA-approved treatments do not exist. We propose to test the hypothesis that chemobrain in a mouse model is caused by mitochondrial damage and that intranasally administered mesenchymal stem cells migrate into the brain to restore cognitive function by mitochondrial transfer, suppression of inflammation, and normalization of the growth-factor milieu in the brain.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA208371-05
Application #
10006060
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Bakos, Alexis Diane
Project Start
2016-09-01
Project End
2021-08-31
Budget Start
2020-09-01
Budget End
2021-08-31
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Hospitals
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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Lacourt, Tamara E; Vichaya, Elisabeth G; Chiu, Gabriel S et al. (2018) The High Costs of Low-Grade Inflammation: Persistent Fatigue as a Consequence of Reduced Cellular-Energy Availability and Non-adaptive Energy Expenditure. Front Behav Neurosci 12:78
Chiu, Gabriel S; Boukelmoune, Nabila; Chiang, Angie C A et al. (2018) Nasal administration of mesenchymal stem cells restores cisplatin-induced cognitive impairment and brain damage in mice. Oncotarget 9:35581-35597
Ma, Jiacheng; Huo, XiaoJiao; Jarpe, Matthew B et al. (2018) Pharmacological inhibition of HDAC6 reverses cognitive impairment and tau pathology as a result of cisplatin treatment. Acta Neuropathol Commun 6:103
Chiu, Gabriel S; Maj, Magdalena A; Rizvi, Sahar et al. (2017) Pifithrin-? Prevents Cisplatin-Induced Chemobrain by Preserving Neuronal Mitochondrial Function. Cancer Res 77:742-752