Title: Exploiting mitochondrial heteroplasmy for cancer chemotherapy Roughly a third of patient cancers are heteroplasmic -- that is, individual cells harbor a mixture of genetically distinct mitochondrial genomes -- and a substantial fraction of these bear severe loss-of-function mutations affecting genes necessary for respiration. These mutations appear to be passengers rather than drivers of tumorgenesis, but our lab recently discovered that they can render cancer cell lines and xenografts more vulnerable to biguanides, mitochondrial inhibitors used to treat type 2 diabetes. Since heteroplasmy is relatively rare in normal tissues, these findings suggest that mitochondrial inhibitors may have a therapeutic window for treating heteroplasmic cancers, but specifically when and how this heteroplasmy may be exploited for treatment remains poorly understood. Additionally, our work showed that heteroplasmy is a reversible genetic defect, since heteroplasmic cells generally still contain wild-type copies of the mitochondrial genome, and that partial reversion is a route to drug resistance. This reduction of heteroplasmy is not a simple mutational processes, and its mechanisms are unknown. The proposed work aims to fill both of these gaps in current knowledge with a systematic study of how heteroplasmy affects susceptibility to a variety of relevant inhibitors and how these inhibitors may drive changes in heteroplasmy leading to drug resistance.

Public Health Relevance

Many cancers harbor mutations in mitochondrial DNA that render them more vulnerable to mitochondrial inhibitors, but specifically when and how these mutations may be exploited for treatment remains poorly understood. We plan to carry out a systematic study of how these mutations affects susceptibility to a variety of relevant inhibitors and of mechanisms to block paths to drug resistance.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA219859-01
Application #
9379150
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Espey, Michael G
Project Start
2017-09-01
Project End
2022-07-31
Budget Start
2017-09-01
Budget End
2018-07-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Whitehead Institute for Biomedical Research
Department
Type
DUNS #
120989983
City
Cambridge
State
MA
Country
United States
Zip Code
02142