Project Details
Description
PROJECT SUMMARY
The receptor tyrosine kinase HER2 is amplified or overexpressed in approximately 25% of breast cancers and
is associated with tumor aggressiveness and poor prognosis. While the FDA-approved therapy trastuzumab has
been shown to have substantial clinical benefit, more than 60% of patients with HER2+ cancer do not respond
to it, and nearly all others who initially respond inevitably develop acquired resistance, underscoring the existing
unmet need for new therapeutic approaches for this disease. Recently, we identified a previously unanticipated
metabolic vulnerability of HER2 breast cancers, including the ones resistant to trastuzumab, in overreliance on
mitochondrial creatine kinase 1 (MtCK1) and by extension creatine phosphate shuttle for energy supply. We
demonstrated that a known substrate analog cyclocreatine, converted by MtCK1 into phosphocyclocreatine that
in turn acts as an inhibitor of creatine phosphate pathway, suppresses trastuzunab-resistant HER2 PDX tumor
growth, thus providing proof of concept for small molecule therapeutic intervention. We hypothesize that
pharmacological agents inhibiting MtCK1 will offer a novel much needed line of defense against HER2+ tumors
as well as other tumors dependent on MtCK1 for survival such as EVI1+ AML. To test this hypothesis we propose
to identify first-in-class small molecule inhibitors of MtCK1 using high-throughput large-scale screening (Aim 1),
hit confirmation (Aim 2) and hit profiling and validation (Aim 3). The completion of our project will result in
identification of compounds inhibiting creatine phosphate shuttle in HER2 cancers. We expect that the
knowledge, developed strategies, and chemical probes will ultimately enable the development of innovative
therapeutic approaches to combat HER2 breast and potentially other cancers.
Status | Finished |
---|---|
Effective start/end date | 5/8/20 → 4/30/23 |
Funding
- National Cancer Institute: $496,612.00
Fingerprint
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.