# Molecular Mechanisms of Chemotherapy-Induced Cognitive Dysfunction

> **NIH NIH R50** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $154,543

## Abstract

Project Summary/Abstract
Cognitive dysfunction (“chemobrain”) is an important adverse sequel of cancer chemotherapy, the study of
which has been identified by the NCI as a poorly understood problem for which current management or
treatment strategies are limited or ineffective. Our preliminary data show that neuronal ryanodine
receptor/calcium release channels (RyR2) on the endoplasmic reticulum (ER) become oxidized and “leaky” in
mice treated with doxorubicin or methotrexate plus 5-FU. These mice exhibit cognitive dysfunction that can be
improved using a novel orally available small molecule drug (Rycal, S107) developed by the co-PI that fixes
leaky RyR2 channels. The goals of this application are to: (1) establish and characterize a murine model of
advanced human breast cancer that can be used to study whether intracellular calcium (Ca2+) leak via
oxidized neuronal RyR2 on the ER is a novel mechanism underlying cancer chemotherapy-induced
neurocognitive dysfunction; and (2) test whether the novel drug Rycal (S107) that fixes leaky neuronal RyR2
channels in vivo can prevent chemobrain. The proposed studies will have important clinical relevance as the
Rycal S107 is in the same chemical class as two closely related Rycals that are currently in clinical testing for
heart and muscle disorders, and to date both have excellent safety profiles. S107 has the advantage that it is
concentrated >10-fold in the brain. (Although S107 is patented by Columbia University, US 8,710,045,
04/29/14, the drug is available to all investigators and the applicant receives no proceeds from its sale). This
application is bolstered by preliminary data showing that commonly used chemotherapeutics cause cognitive
dysfunction in C57BL6 mice that can be prevented using the Rycal S107, and by our published data showing
that leaky neuronal RyR2 channels can cause stress-induced cognitive dysfunction (post-traumatic stress
disorder, PTSD) that can be ameliorated by oral treatment with S107. This application aims to make the
novel mechanistic link between chemobrain and PTSD - intracellular Ca2+ leak - and to test a potential
novel therapy that prevents this leak and prevents chemobrain. Research specialist, Dr. Mohammad, will
set up mouse models, with and without breast cancer, and establish the presence of cognitive dysfunction in
those models by testing several chemotherapeutic agents. Dr. Mohammad will perform the necessary
experiments with other team members, providing supervision and training support to maintain the high level of
research consistency and productivity required for project success.

## Key facts

- **NIH application ID:** 10305701
- **Project number:** 5R50CA243887-04
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Khalid S Mohammad
- **Activity code:** R50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $154,543
- **Award type:** 5
- **Project period:** 2019-09-09 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10305701

## Citation

> US National Institutes of Health, RePORTER application 10305701, Molecular Mechanisms of Chemotherapy-Induced Cognitive Dysfunction (5R50CA243887-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10305701. Licensed CC0.

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