Researchers Develop New Method That Tricks Cancer Cells Into Killing Themselves

Our bodies divest themselves of 60 billion cells every day through a natural process called "apoptosis". So Stanford medicine researchers are developing a new approach to cancer therapy that could "trick cancer cells into disposing of themselves," according to announcement from Stanford's medical school: Their method accomplishes this by artificially bringing together two proteins in such a way that the new compound switches on a set of cell death genes... One of these proteins, BCL6, when mutated, drives the blood cancer known as diffuse large cell B-cell lymphoma... [It] sits on DNA near apoptosis-promoting genes and keeps them switched off, helping the cancer cells retain their signature immortality.

The researchers developed a molecule that tethers BCL6 to a protein known as CDK9, which acts as an enzyme that catalyzes gene activation, in this case, switching on the set of apoptosis genes that BCL6 normally keeps off. "The idea is, Can you turn a cancer dependency into a cancer-killing signal?" asked Nathanael Gray, PhD, co-senior author with Crabtree, the Krishnan-Shah Family Professor and a chemical and systems biology professor. "You take something that the cancer is addicted to for its survival and you flip the script and make that be the very thing that kills it...."

When the team tested the molecule in diffuse large cell B-cell lymphoma cells in the lab, they found that it indeed killed the cancer cells with high potency. They also tested the molecule in healthy mice and found no obvious toxic side effects, even though the molecule killed off a specific category of of the animals' healthy B cells, a kind of immune cell, which also depend on BCL6. They're now testing the compound in mice with diffuse large B-cell lymphoma to gauge its ability to kill cancer in a living animal. Because the technique relies on the cells' natural supply of BCL6 and CDK9 proteins, it seems to be very specific for the lymphoma cells — the BCL6 protein is found only in this kind of lymphoma cell and in one specific kind of B cell. The researchers tested the molecule in 859 different kinds of cancer cells in the lab; the chimeric compound killed only diffuse large cell B-cell lymphoma cells.
Scientists have been trying to shut down cancer-driving proteins, one of the researchers says, but instead, "we're trying to use them to turn signaling on that, we hope, will prove beneficial for treatment."

The two researchers have co-founded the biotech startup Shenandoah Therapeutics, which "aims to further test this molecule and a similar, previously developed molecule," according to the article, "in hopes of gathering enough pre-clinical data to support launching clinical trials of the compounds.

"They also plan to build similar molecules that could target other cancer-driving proteins..."