"When cancers recur, they activate not just one type of survival protein, but many," explains Walensky, whose laboratory has extensively studied the cell-death system and makes compounds to manipulate it for research and therapeutic purposes.
"It's as if relapsed cancers 'learned' from their initial exposure to chemotherapy such that when they come back, they put up a variety of formidable barriers to apoptosis," he adds. "To reactivate cell death in refractory hematologic cancers, we need new pharmacologic strategies that broadly target these obstacles and substantially lower the apoptotic threshold."
When cancers specifically rely on one or two survival proteins, treating them with selective BCL-2 inhibitors can be very effective at eliminating the cancer cells' survival advantage. But relapsed cancers often evade such agents by deploying a battery of alternate survival proteins, so what's needed, Walensky says, are "next-generation" compounds that can block a wider range of survival proteins without jeopardizing normal tissues.
In the current research, the scientists built a chemically-reinforced peptide containing the death-activating BH3 domain of an especially potent killer protein, BIM, which is able to tightly bind with and neutralize all of the BCL-2 family survival proteins. This 'stapled' peptide, which incorporates the natural structure and properties of BIM BH3, not only disables the survival proteins, but also directly activates pro-death BCL-2 family proteins in cancer cells, making them self-destruct. Importantly, non-cancerous cells and tissues were relatively unaffected by the treatment.
"The diversity of BCL-2 family survival proteins blunts
|Contact: Bill Schaller|
Dana-Farber Cancer Institute