In all types of cancer, there are molecules that accelerate uncontrollable and deadly growth. What would happen if scientists could target those molecules with others that would cause the cells to self-destruct? What if what drives the survival of cancer could instead activate the program for its destruction?
A few years ago, during a walk in a sequoia forest near his home in the Santa Cruz mountains, this idea became an epiphany for Gerald Crabtree, a developmental biologist at Stanford University. “I rushed back home,” he recalled, excited by the idea and thinking about how to bring it to fruition.
Now, in an article published on July 26th in the journal Nature, Crabtree, one of the founders of Shenandoah Therapeutics, a cancer drug developer, along with Nathanael Gray, a professor of chemical and systems biology at Stanford, and their colleagues report that they achieved what he envisioned on that walk. Although the concept is far from being a drug that can be administered to cancer patients, it could be a target for drug developers in the future.
“It’s fantastic,” said Jason Gestwicki, a professor of pharmaceutical chemistry at the University of California, San Francisco. “It turns something that cancer needs to stay alive into something that kills it, like switching your vitamins for poison.”
Louis Staudt, director of the Center for Cancer Genomics at the National Cancer Institute, said, “This could be a new way for cancer to act against itself.” Staudt wrote an editorial to accompany Crabtree’s article.
Once the treatment is further developed, he added, “I would love to test it in a clinical trial with our patients who have exhausted all other options.”
In laboratory experiments with cells from a blood cancer called diffuse large B-cell lymphoma, the researchers designed and built molecules that hooked onto two proteins: BCL6, a mutated protein on which the cancer depends for aggressive growth and survival, and a normal cell protein that activates any gene it approaches.
The new construct, a dumbbell-shaped molecule, is unlike anything seen in nature. The BCL6 protein, at one end of the dumbbell, guides the molecule to the genes for cell death that are part of each cell’s DNA and used to eliminate cells that are no longer needed. But when a person has diffuse large B-cell lymphoma, the BCL6 protein deactivates those genes for cell death, making the cells nearly immortal.
When the dumbbell, guided by the BCL6 protein, approaches the death-inducing genes, the normal protein at the other end of the dumbbell arms those death-inducing genes. Unlike other processes in the cell that can be reversed, activation of the death-inducing genes is irreversible.
The new strategy could improve the challenging task of using drugs to block all molecules that include a BCL6 protein. To kill cells with dumbbell-shaped molecules, it is sufficient to change the wiring of only a portion of the molecules with the BCL6 protein.
According to Crabtree, the concept could work for half of all types of cancer, which have known mutations that give rise to proteins that drive growth. And since the treatment is based on the mutated proteins produced by cancer cells, it could be highly specific and not affect healthy cells.
Crabtree explained the two areas of discovery that made this work possible. One is the discovery of “driver genes,” several hundred genes that, when mutated, drive cancer progression.
The second is the discovery of pathways that lead to cell death. According to Crabtree, these pathways are used to eliminate cells that, for some reason, rebel; there are around 60 billion cells per day in each individual.
The goal was to make the pathways that drive the growth of cancer cells communicate with the silenced pathways that drive cell death, something they would not normally do.
When the hybrid molecule reached the DNA of the cells, it not only activated the genes for cell death but also did something else. The molecule with the BCL6 protein led the hybrid molecule to other genes that the cancer had silenced. The hybrid molecule reactivated those genes, creating internal chaos in the cell.
“The cell had never experienced anything like this,” Staudt said.
“The molecule with the BCL6 protein is the organizing principle of these cancer cells,” he explained. When its function is completely disrupted, “the cell loses its identity and says, ‘Something very bad is happening here. I better die.'”
But the main effect of the experimental treatment was to activate the genes for cell death, Crabtree noted. “That is the therapeutic effect,” he said.
The group tested their hybrid molecule on mice, where it appeared to be safe. But, as Staudt pointed out, “humans are very different from mice.”
Stuart Schreiber, professor of chemistry and chemical biology at Harvard University and former collaborator of Crabtree, agrees that the work is “exciting.” But he issued a warning.
What Crabtree has created “is not yet a drug; it still has a long way to go,” he said.