Deflector Shield Drug Strategy Fights Resistant Leukemia, Lymphoma

In proof-of-concept studies in mice with transplanted, drug-resistant leukemia tumors, the compound alone inhibited cancer growth, and when paired with other drugs, showed synergistic anti-cancer activity, according to the researchers, led by Loren Walensky, MD, PhD, of Dana-Farber/Children’s Hospital Cancer Center (Boston, MA, USA).

Their study’s findings have been posted online by the Journal of Clinical Investigation. Dr. Walensky is the senior author and James LaBelle, MD, PhD, is the first author. A cell’s fate--whether and when it lives or dies--depends on a battle between “pro-death” and “anti-death” forces within the cell that serve as a check-and-balance system to maintain well-ordered growth. The system is regulated by the BCL-2 9 (B-cell lymphoma 2) family of proteins, which contains both pro-death and pro-survival members.

When cells are no longer needed or are damaged beyond repair, the body activates pro-death BCL-2 proteins to shut down mitochondria-- the power plants of the cell--resulting in a controlled cellular destruction known as apoptosis.

Many cell-killing cancer treatments work by triggering these “executioner proteins” to cause tumor cells to commit suicide in this fashion. But cancer cells can escape their death sentence-- and even become immortal--by hyper-activating the survival arm of the family; these proteins intercept the killer proteins and block their lethal mission. “When cancers recur, they activate not just one type of survival protein, but many,” explained Dr. 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. 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 tumors specifically rely on one or two survival proteins, treating them with selective BCL-2 inhibitors can be very effective at eradicating the cancer cells’ survival advantage. But relapsed cancers often evade such agents by deploying a battery of alternate survival proteins, so what's needed, Dr. Walensky noted, are next-generation compounds that can block a wider range of survival proteins without jeopardizing normal tissues.

In the current research, the scientists constructs 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 the antitumor activity of essentially all cancer treatments to some degree,” Dr. Walensky pointed out. “By using nature’s solution to broad targeting of the BCL-2 pathway with a stapled BIM BH3 peptide, our goal is to eliminate cancer's protective force field and enable the arsenal of cancer treatments to do their job.”

Related Links:
Dana-Farber/Children’s Hospital Cancer Center