Timeframe: 2019 – 2023
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
Study overview: 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. As a result, 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 causes of tumor formation is a potential opportunity. Accordingly, the main components of this funding renewal include:
- 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.