The new three-year grant will allow Scripps Florida scientists to develop high-throughput screening tests to identify and optimize inhibitors of the “autophagy pathway,” the principal recycling center of the cell, which is especially active during times of stress or nutrient loss. During autophagy, various cell components, including damaged proteins and mitochondria, are delivered to the lysosome, which is essentially a bag of enzymes that breaks down cellular waste.
Autophagy is critical to cell survival and defects in the pathway can lead to a number of disorders, including some neurodegenerative and muscular diseases.
“We have shown that impairing autophagy can improve the efficacy of anti-cancer drugs, helping to overcome drug resistance,” Cleveland said. “Although there’s a lot of interest in generating compounds to act on specific components of the pathway, none exist now. The new grant will, hopefully, help us begin to remedy that situation.”
Duckett added, “Our studies have shown that impairing the autophagy pathway increases the sensitivity of cancer cells to conventional therapeutics, so this is a highly practical and productive approach to developing potential treatments.”
With the new funding, the scientists will develop a novel biochemical test to identify inhibitors of the UNC-51-like kinase (Ulk1), a critical on-off switch that regulates the pathway. Once identified, these small molecules will also help scientists improve their basic understanding of autophagy, its relationship to cancer, and its use as a target that could enhance the action of conventional anti-cancer therapeutics.
John Cleveland, professor and chair of the Department of Cancer Biology, and Derek Duckett, associate scientific director of the Translational Research Institute at Scripps Florida, will act as co-principal investigators.