Salk Institute and Sanford Burnham Prebys Medical Discovery Institute (SBP) scientists have developed a drug that prevents regrowth of cancer cells.
As a tumor grows, its cancerous cells ramp up an energy-harvesting process to support its hasty development. This process, called autophagy, is normally used by a cell to recycle damaged organelles and proteins, but is also co-opted by cancer cells to meet their increased energy and metabolic demands.
The recent finding identifies a small molecule drug that specifically blocked the first step of autophagy, effectively cutting off the recycled nutrients that cancer cells need to live.
Cells starved of nutrients activate the key molecule that kicks off autophagy, an enzyme called ULK1. Reuben Shaw, a senior author of the paper, professor in the Molecular and Cell Biology Laboratory at the Salk Institute and a Howard Hughes Medical Institute Early Career Scientist said, "The inhibitor will probably find the greatest utility in combination with targeted therapies."
Inhibiting ULK1 might snuff out some types of cancer by stifling a main energy supply that comes from the recycling process. A highly selective drug they named SBI-0206965, successfully killed a number of cancer cell types, including human and mouse lung cancer cells and human brain cancer cells, some of which were previously shown to be particularly reliant on cellular recycling.
"Inhibiting ULK1 would eliminate this last-ditch survival mechanism in the cancer cells and could make existing anti-cancer treatments much more effective," says Matthew Chun, one of the study's lead authors and a postdoctoral fellow in the Shaw lab at Salk.
Indeed, combining SBI-0206965 with mTOR inhibitors made it more effective, killing two to three times as many lung cancer cells. The only drugs that currently block cell recycling work by targeting the cell organelle known as the lysosome, which functions at the final stage of autophagy.
Comparing equivalent concentrations of the lysosomal drug chloroquine with SBI-0206965, in combination mTOR inhibitors, the scientists found that SBI-0206965 was better than chloroquine at killing cancer cells.
The group is now testing the drug in mouse models of cancer. "An important next step will be testing this drug in other types of cancer and with other therapeutic combinations," says Shaw.