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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  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 ¡ª 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 , 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.