Researchers have identified a gatekeeper protein that prevents pancreatic cancer cells from transitioning into a particularly aggressive cell type and also found therapies capable of thwarting those cells when the gatekeeper is depleted.
A team from MD Anderson describes in the journal Nature a series of preclinical experiments using patient-derived tumor xenografts (PDXs) and mouse models that point to potential treatments for patients with a rapidly-progressing and resistant subgroup of tumor cells.
“Pancreatic cancer cells are characterized by remarkable plasticity, cellular changes that make this malignancy so difficult to treat,” said first author Giannicola Genovese, M.D., instructor in Genomic Medicine.
Genovese and colleagues found, in a subset of tumor cells, after the original oncogenic driver fades, depletion of a gene called SMARCB1 results in a cellular change to mesenchymal status, a mobile and invasive cell state.
The team also found vulnerability for mesenchymal cells: they are overly reliant on accelerated protein production to meet increased metabolic needs.
“Inhibiting proteostasis in combination with standard of care chemotherapy was highly effective in killing these most aggressive subpopulations of pancreatic cancer,” Genovese said.
Identify, understand tumor cells to kill them
This led the team to look at a drug called AUY922, an inhibitor of heat shock protein 90, which blocks proteostasis — the creation, folding, distribution and degrading of proteins. Both as a single agent and combined with the chemotherapy gemcitabine, AUY922 increased the response rate and lengthened survival of mice whose tumors faithfully recapitulated key features of human pancreatic cancers.
A key challenge in treating cancer stems from molecular and genomic variability of tumor cells, which causes functional differences across cells that can fuel resistance to treatment.
“We are working to dissect the cell populations within tumors to attempt to understand the functional vulnerabilities of each, then to plan for more rational combinatorial treatment approaches,” said Giulio Draetta, M.D., Ph.D., professor of Genomic Medicine and director of MD Anderson’s Institute for Applied Cancer Science.
Draetta, who is corresponding author of the paper, noted that identifying the subpopulation of aggressive cells and establishing their vulnerability to proteostasis inhibitors allows a match of treatment to specific cell type. “This is truly functionally defined, personalized medicine.”
Read more about this discovery in the MD Anderson Newsroom.