Inside all cancers are molecules that promote lethal and uncontrolled growth. What if scientists could link those molecules to other molecules and cause cells to self-destruct? do you want?
The idea came to Dr. Gerald Crabtree, a developmental biologist at Stanford University, several years ago while taking a walk through a redwood forest near his home in the Santa Cruz Mountains.
“I ran home,” he said, excited about the idea and the plans to bring it to life.
Now, paper Dr. Crabtree, founder of Shenandoah Therapeutics, which is developing cancer drugs, and Nathanael S. Gray, a professor of chemical and systems biology at Stanford University, and colleagues Wednesday. Reported in Nature magazine. What did you imagine during the walk? While the concept is far from a drug that can be administered to cancer patients, it could be a target for drug developers in the future.
“This is pretty cool,” said Jason Gestwicky, a professor of medicinal chemistry at the University of California, San Francisco. “Just like you turn a vitamin into a poison, you turn what cancer cells need to stay alive into something that kills them.”
“This could be a new way to attack cancer itself,” said Dr. Louis Stout, director of the Center for Cancer Genomics at the National Cancer Institute. Dr. Stout writes: Editor Attached to Dr. Crabtree’s paper.
Once this treatment is further developed, “I would very much like to try it in clinical trials in patients who have exhausted all other options,” he added.
In a lab using cells from a blood cancer, diffuse large B-cell lymphoma, the researchers designed and built a molecule that connects the two proteins. BCL6 is a mutant protein that cancers depend on for aggressive growth and survival, and a normal cellular protein. When you get close, the genetic switch is turned on.
A dumbbell-shaped molecule, this new structure is unlike anything found in nature. BCL6, at one end of the dumbbell, is part of the DNA of all cells and directs molecules to cell death genes used to eliminate cells that are no longer needed. However, in people with diffuse large B-cell lymphoma, BCL6 disables these cell death genes, essentially immortalizing the cells.
When BCL6 guides the dumbbell toward the cell death gene, normal proteins at the end of the dumbbell activate the cell death gene. Unlike other processes in cells that can be reversed, turning on cell death genes is irreversible.
New approaches may improve the difficult task of using drugs to block all BCL6 molecules. In the case of dumbbell-shaped molecules, he only needs to rewire part of the BCL6 molecule to kill the cell.
The concept could work for half of all cancers known to have mutations that produce proteins that promote growth, Dr. Crabtree said. And because the treatment relies on mutated proteins produced by cancer cells, it has the potential to be highly specific without harming healthy cells.
Dr. Crabtree described two areas of discovery that made the research possible. One is the discovery of ‘driver genes’, the hundreds of genes that, when mutated, cause the spread of cancer.
The second is the discovery of intracellular death pathways. Crabtree said these pathways “are used to eliminate cells that have become abnormal for some reason” — 60 billion cells per person each day.
The quest is to connect pathways that promote cancer cell proliferation with silent pathways that promote cell death, something that is not normally done.
Once the hybrid molecule reached the cell’s DNA, it did more than just activate cell death genes. BCL6 induced hybrids to other cancer-silenced genes. The hybrid turned those genes back on, causing internal chaos within the cell.
“We’ve never experienced cells before,” Dr. Stout said.
“BCL6 is the organizing principle of these cancer cells,” he explained. When that function is completely destroyed, “the cell loses its identity and says, ‘Something very wrong is going on here.'” ”
But the main effect of the experimental treatment was to activate cell death genes, Dr. Crabtree said. “That’s the therapeutic effect,” he said.
The research group tested the hybrid molecule in mice and appeared to be safe. But Dr. Stout said, “Humans are very different from mice.”
The study is “exciting,” said Stuart L. Schreiber, a professor of chemistry and chemical biology at Harvard University and a former collaborator of Dr. Crabtree. But he gave a word of warning.
What Dr. Crabtree has created is “not a drug. It still has a long way to go,” he says.
