New technology boosts potency of Targeted Cancer Therapy

In work that heralds a new, more potent form of targeted therapy for cancer, Dana-Farber Cancer Institute scientists have devised a chemical technology that doesn't just disable malevolent proteins in tumor cells, as current agents do, but destroys them. The strategy uses tumor cells' own protein-chopping machinery to break down and dispose of proteins that drive cancer growth. When tested in laboratory samples of leukemia cells and in animals with human-like leukemia, the approach caused cancer cells to die much more quickly than with conventional targeted therapies.
Researchers developed the strategy as a way to develop inhibitors of "undruggable" proteins and overcome drug resistance, a common shortcoming of targeted therapies. Resistance arises when tumors that originally responded to a particular therapy manage to circumvent the drug's effects and resume their growth. "One of the reasons resistance occurs is that cancer-related proteins often have multiple functions within the cell, and conventional targeted therapies inhibit just one or a few of those functions," said the paper's senior author, James Bradner, MD, an oncologist and chemist at Dana-Farber. "Conventional drugs allow the targeted protein to adapt to the drug, and the cell finds alternate routes for its growth signals. "We began designing approaches that cause the target protein to disintegrate, rather than merely be inhibited," he continued. "It would be very powerful if we could chemically convert an inhibitor drug into a degrader drug."The team tested the technology - which they dubbed "degronimids",in laboratory samples of leukemia cells. They began with the drug JQ1, which inhibits BRD4, a protein that orchestrates the expression of cancer growth genes. They built an adapter out of phthalimide - a chemical derivative of the drug thalidomide - and attached it to JQ1. The phthalimide was designed to bind snugly to a protein-degrading enzyme E3 (called Cereblon), making it ideal as a trailer hitch. When investigators treated the leukemia cells with a JQ1-and-phthalimide "conjugate" called dBET1, the BRD4 protein within the cells was degraded in less than an hour."We're very excited that this chemical technology may offer a way to improve many cancer drug molecules, and of course this strategy has implications beyond cancer for the treatment of other life-threatening diseases," Bradner said.