Within every cancer, there are molecules that drive the deadly and uncontrolled growth. What if these molecules could be linked to others that trigger self-destruction in cells? Could the very factors that allow cancer to survive be used to activate its own destruction?
Dr. Gerald Crabtree, a developmental biologist at Stanford, had this idea during a walk in the redwoods near his home. Enthusiastic about the concept, he immediately started planning ways to make it a reality.
In a recent paper published in the journal Nature, Dr. Crabtree, along with Nathanael S. Gray and their colleagues from Foghorn Therapeutics, reported that they have successfully executed this idea. Although it is still a long way from being a viable drug for cancer patients, it holds potential as a future target for drug developers.
The significance of this accomplishment is evident. Jason Gestwicki, a professor of pharmaceutical chemistry at the University of California, San Francisco, described it as “very cool,” likening it to transforming a vitamin into a poison that kills cancer cells.
Dr. Louis Staudt, director of the Center for Cancer Genomics at the National Cancer Institute, called this a “potentially new way to turn cancer against itself.” He expressed his interest in testing it in clinical trials for patients who have exhausted all other treatment options.
In laboratory experiments using cells from a type of blood cancer called diffuse large B-cell lymphoma, the researchers designed and created molecules that connected two proteins: BCL6, a mutated protein crucial for the aggressive growth and survival of the cancer, and a normal cell protein capable of activating adjacent genes.
The resulting molecule, shaped like a dumbbell and unique to nature, utilized the guidance of BCL6 to reach cell-death genes present in every cell’s DNA. These genes are responsible for eliminating unnecessary cells. However, in diffuse large B-cell lymphoma, BCL6 turns off these cell-death genes, rendering the cells effectively immortal.
When the dumbbell-shaped molecule, guided by BCL6, approached the cell-death genes, the normal protein at the other end of the dumbbell triggered these genes. Unlike other cellular processes that can be reversed, activating cell-death genes is an irreversible action.
This approach proves more effective than attempting to block all BCL6 molecules with drugs. Rewiring a portion of BCL6 molecules using the dumbbell-shaped molecules is sufficient to induce cell death.
Dr. Crabtree believes that this concept could potentially apply to half of all cancers that have known mutations in proteins driving their growth. Furthermore, since the treatment specifically targets the mutated proteins produced by cancer cells, it could spare healthy cells, making it highly specific.
Two key discoveries made this breakthrough possible. The first involved identifying “driver genes” responsible for fueling cancer’s spread. The second discovery focused on the pathways involved in cell death. By connecting the cancer-driving pathways with silenced cell-death pathways, the researchers were able to trigger internal chaos within the cancer cells.
Dr. Staudt explained that BCL6 serves as the organizing principle for these cancer cells. When its function is disrupted, the cells lose their identity and recognize that something is gravely wrong, leading to self-destruction.
Although the experimental treatment appeared safe in mice, humans are a different story, as Dr. Staudt pointed out. The team still has a long way to go before this becomes a viable drug.
While the work of Dr. Crabtree and his colleagues is undeniably exciting, caution is necessary. It is essential to remember that the current creation is not yet a drug and requires further development.
In conclusion, this groundbreaking research opens up new possibilities in the fight against cancer. By leveraging the molecules driving cancer’s growth to activate cell death, scientists may have discovered a potential strategy to turn cancer against itself.
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