Timeframe: 2019 – date
Goal: Investigate the potential of heat shock protein 70 (Hsp70) and mitogen-activated protein kinases (MAPKs) as therapeutic options for FLC
Principal Investigator: John Scott, PhD, Edwin G. Krebs-Speights Professor of Cell Signaling and Cancer Biology, and Chair, Department of Pharmacology
Precision medicine approaches have identified the underlying genetic defect in FLC as a deletion in chromosome 19. Consequently, FLC patients produce a unique protein in which an important part of heat shock protein 40 (DNAJ) is fused to a key cellular enzyme called protein kinase A (PKAc). This chimeric protein, DNAJ-PKAc, is expressed in FLC tumors where it hijacks normal cellular processes, leading to cancer.
It is believed that DNAJ-PKAc brings together unique combinations of cellular enzymes that cause FLC. These protein complexes activate the biochemical pathway downstream from the fusion protein, deregulating cell proliferation. Thus, drugs that target such key protein combinations represent a therapeutic opportunity. In a past study, the University of Washington team discovered drug pairs that halt the growth of genetically modified liver cells that mimic the human cancer. Their experimental plan is to test a new concept in drug treatments for FLC. Rather than blocking the action of the DNAJ-PKAc protein kinase enzyme itself, they will use combinations of FDA-approved drugs and/or drugs already in clinical testing that neutralize proteins associated with this chimeric enzyme. In particular, they believe that combinations of drugs targeting proteins that bind tightly to DNAJ-PKAc, such as heat shock protein 70 (Hsp70) and mitogen-activated protein kinases (MAPKs), will offer a viable therapeutic option. They hope that such a pharmacological approach and the use of repurposed FDA-approved drugs will expedite a cure for FLC.
During the past funding cycle, the study team discovered drug combinations that target “signaling island” in FLC tumors that harbor DNAJ-PKAc. Eliminating these oncogenic focal points is a new frontier in FLC research. Accordingly, there are three main components of this funding renewal:
- Using innovative pharmacological approaches to determine which part of DNAJ-PKAc causes cancer.
- Advancing towards clinical trials any promising drug combinations that target DNAJ-PKAc signaling islands.
- Working in partnership with FCF to inform patients and families of the latest breakthroughs in translational research.