This application is responsive to the NCI Provocative Question #9 (RFA-CA-15-008). 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.

Public Health Relevance

Our preliminary data suggest that 'leaky' Ca2+ release channels are associated with chemobrain-induced cognitive dysfunction; mice subjected to chemotherapy showed posttranslational modifications of neuronal RyR channels consistent with intracellular calcium leak and exhibited altered behavior and impaired cognitive function. From our pilot and previous studies we hypothesize that intracellular Ca2+ leak represents a key pathology that impairs memory storage and alters signaling in the brain required for normal behavior (and contributes to chemobrain). A novel drug called a rycal that we have developed which prevents intracellular Ca2+ leak will be tested in mouse models to determine whether it can prevent chemobrain-induced cognitive dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA206025-03
Application #
9486907
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Horowitz, Todd S
Project Start
2016-05-10
Project End
2021-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Kushnir, Alexander; Santulli, Gaetano; Reiken, Steven R et al. (2018) Ryanodine Receptor Calcium Leak in Circulating B-Lymphocytes as a Biomarker in Heart Failure. Circulation 138:1144-1154
Zalk, Ran; Marks, Andrew R (2017) Ca2+ Release Channels Join the 'Resolution Revolution'. Trends Biochem Sci 42:543-555