A novel therapeutic approach developed at Stanford University leverages a chimeric molecule to induce self-destruction in diffuse large B-cell lymphoma cells. This innovative strategy involves linking two proteins, BCL6 and CDK9, which forces the cancer cells to activate multiple cell death signals simultaneously. The research, published recently, demonstrates promising preclinical results, showing high potency in killing lymphoma cells with minimal toxic side effects in healthy mice.
The team's molecule works by exploiting the natural presence of BCL6 and CDK9 proteins within the lymphoma cells. By forcing these proteins to interact, the molecule triggers a cascade of events that lead to cell death. Sai Gourisankar, PhD, a postdoctoral scholar and co-first author on the study, described the mechanism as "cell death by committee," emphasizing that once a cancer cell is dead, it reaches a terminal state.
Specificity and Efficacy
In laboratory tests, the molecule exhibited remarkable specificity, selectively killing diffuse large cell B-cell lymphoma cells among 859 different kinds of cancer cells. This specificity is attributed to the limited expression of BCL6 protein, which is primarily found in this type of lymphoma cell and a specific kind of B cell. The researchers also observed that the molecule, while killing off a specific category of healthy B cells in mice, did not cause obvious toxic side effects.
Overcoming Treatment Resistance
Cancer's ability to rapidly adapt to therapies that target only one weak spot often leads to treatment resistance. To address this, the researchers designed their molecule to activate 13 different apoptosis-promoting genes regulated by BCL6. The hope is that by simultaneously triggering multiple cell death signals, the cancer cells will not be able to survive long enough to evolve resistance. However, this hypothesis remains to be tested in further studies.
Future Directions
Crabtree and Gray, the lead researchers, have co-founded a biotech startup, Shenandoah Therapeutics, to further develop this molecule and a similar, previously developed molecule. The company aims to gather sufficient preclinical data to support the initiation of clinical trials. Additionally, the team plans to create similar molecules targeting other cancer-driving proteins, such as the oncogene Ras, which is implicated in various cancer types.
The study was supported by grants from the Howard Hughes Medical Institute, the National Institutes of Health, the Mary Kay Foundation, the Schweitzer Family Fund, the SPARK Translational Research Program at Stanford University, and Bio-X at Stanford University.
