Cancer treatment would make cells destroy themselves – 09/08/2023 – Health

Inside every cancerous tumor are molecules that encourage deadly, uncontrollable growth. What if scientists could attach these molecules to others to make cells destroy themselves? Could the very engines of cancer survival turn on the program of its destruction instead?

This idea came as a revelation to developmental biologist Gerald Crabtree of Stanford University a few years ago when he was walking among redwood trees near his home in the Santa Cruz Mountains.

“I ran home,” he said, excited by the idea and thinking of ways to put it into practice.

Now, in an article published July 26 in the journal Nature, Crabtree —founder of Shenandoah Therapeutics, which is developing cancer drugs—along with Nathanael Gray, professor of biochemistry and systems biology at Stanford, and their colleagues, report that accomplished what Crabtree envisioned during that walk. While the concept is still a long way from being a drug that can be given to cancer patients, it could be a goal for drug developers in the future.

“It’s really cool,” commented Jason Gestwicki, a professor of pharmaceutical chemistry at the University of California San Francisco. “The idea is to convert something the cancer cell needs to stay alive into something that kills it. It would be like converting your vitamin into a poison.”

Louis Staudt, director of the Center for Oncological Genomics at the National Cancer Institute, said: “This is a potentially new way of turning cancer against itself.” Staudt wrote an editorial to accompany Crabtree’s article.

He said that once the treatment has been developed, “I’m going to be very excited to be able to try it in a clinical trial with our patients who have exhausted all other options.”

In laboratory experiments with cells from a type of blood cancer, diffuse large B-cell lymphoma, researchers designed and built molecules that bound two proteins: BCL6, a mutated protein on which the cancer depends to grow aggressively and survive, and a normal cellular protein that activates whatever genes it approaches.

The new construction, a dumbbell-shaped molecule, is unlike anything seen in nature. NCL6, at one end of the dumbbell, steers the molecule toward the cell-death genes that are part of every cell’s DNA and are used to eliminate cells that are no longer needed. But when a person has diffuse large B-cell lymphoma, BCL6 turned off these cell-death genes, essentially making the cells immortal.

When the alter, guided by BCL6, approaches the cell death genes, the normal protein present at the other end of the alter activates these death genes. Unlike other cellular processes that can be reversed, activation of cell death genes is irreversible.

The new approach could represent an improvement over the daunting task of using drugs to block all BCL6 molecules. With the dumbbell-shaped molecules, it only takes a fraction of the BCL6 molecules to rebind to kill cells.

The concept has the potential to work on half of all cancers, those with known mutations that generate proteins that promote growth, Crabtree said. And because the treatment depends on the mutated proteins produced by the cancer cells, it can be extremely specific, sparing healthy cells.

Crabtree explained the two areas of discovery that made the work possible. One is the discovery of so-called “driver genes”—several hundred genes that, when mutated, drive the spread of cancer.

The second area is the discovery of cell death pathways. These pathways, Crabtree said, “are used to eliminate cells that for one reason or another have started to act out of control”—as in the case of 60 billion cells per day in each individual.

The issue was getting the pathways that promote cancer cell growth to communicate with the muted pathways that drive cell death, something that would not normally occur.

When the hybrid molecule found its way into the cells’ DNA, it not only turned on cell-death genes, it did more. BCL6 led the hybrid molecule to other genes that cancer had silenced. The hybrid molecule reactivated these genes, creating internal chaos in the cell.

“The cell never went through this,” said Staudt.

“BCL6 is the organizing principle in these cancer cells,” he explained. When its function is completely disrupted, “the cell loses its identity and says, ‘Something very wrong is going on here. The best thing I can do is die.'”

But, Crabtree said, the main effect of the experimental treatment was to activate cell death genes. “That’s the therapeutic effect,” he said.

The group tested their hybrid molecule in mice, in which it appeared to be safe. But Staudt pointed out that “humans are very different from mice.”

Stuart Schreiber, a professor of chemistry and biochemistry at Harvard University and a collaborator with Crabtree on previous work, described the work as “exciting” but had a caveat.

What Crabtree created, he said, “is not a drug. It has a long way to go to be one.”

^{Translated by Clara Allain}