Targeting the Oncometabolism with Mitochondria-directed Chemicals
Abstract
SIGNIFICANCE: Breast cancer is the most prevalent form of cancer affecting women and second only to lung cancer as the leading cause of cancer mortality in females. Although therapeutic and diagnostic improvements have reduced the overall mortality from breast cancer, over 40,000 women still die of breast cancer each year in the USA alone. Most of these deaths are because of the relapse of breast cancer after the conclusion of clinical treatment. Tumors that recur have a high probability to develop resistance to drugs currently available as well as to progress towards metastatic disease. One important characteristic of these tumors is that they display the metabolic uncoupling between glycolysis and mitochondrial respiration indicating that targeting this metabolic peculiarity of most aggressive and most lethal tumors may be of utility to help women unlikely to respond to the standard of care. APPROACH: We discovered that the enzyme calmodulin kinase II (CaMKII) is mechanistically involved as well as may serve as a biomarker to identify tumors with metabolic uncoupling. Also, that at least at the cellular level, breast cancer types that develop chemoresistance can be effectively targeted via CaMKII inhibition. Hence, we propose to develop CaMKII inhibition as a new strategy to treat breast cancers displaying an established molecular signature of chemoresistance. SCIENTIFIC IMPACT: This application will address a novel mechanism of metabolic uncoupling in cancer cells. It was noted more than 80 years ago that as tumors progress, they become more reliant on glycolysis for energy production. More recent studies showed that the notion of a switch from mitochondria-based to glycolysis-based metabolism is incomplete to explain the metabolic reprogramming driving tumorigenesis and that a dysregulation of the mechanisms coupling these two pathways would be more adequate. However, how the uncoupling between glycolysis and mitochondria-respiration happens remains incompletely understood and this has limited progress in the field. CLINICAL IMPACT: Though CaMKII inhibitors are currently available, the global or untargeted inhibition of CaMKII can cause safety issues significant enough to limit this strategyÕs clinical utility. To overcome this problem we introduce a new proprietary chemical (SMA-011) which inhibits CaMKII in tumors while preserving CaMKII activation in normal cells. This is because SMA-011 is a pro-drug accessible to all mitochondria in the body but that needs iron to be converted to the active anti-cancer compound. Free-iron that can be bound by SMA-011 exists in cancer cell mitochondria but not in healthy cells. This is likely to increase the selectivity of SMA-011 against tumor cells. The enhanced selectivity of SMA-011 towards inhibiting CaMKII in cancer cells is likely to make it a safe and efficacious alternative for a subset of highly lethal breast cancers which fail the standard of care.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- May 20, 2019
- Source ID
- W911NF1910287
Entities
People
- Marcelo G. Bonini
Organizations
- Army Contracting Command
- Medical College of Wisconsin
- United States Army