Stanford Medicine researchers have developed a two-part molecule that turns a major driver of B-cell lymphoma against the cancer cells that depend on it. In mice, twice-daily treatment with the experimental compound caused aggressive lymphoma tumors to disappear within 11 days. The work advances a strategy the research team has been developing for years.
Instead of simply shutting down a cancer-promoting protein, the scientists designed a small molecule that connects it to another protein capable of activating the cell's built-in death program. The researchers believe this type of molecular rewiring could eventually have applications beyond lymphoma, including other cancers and some autoimmune diseases. "We're trying to essentially fight cancer with its cause -- taking the driving force of the cancer and then rewiring it to activate cell death mechanisms," said Gerald Crabtree, MD, the David Korn, MD, Professor in Pathology and a professor of developmental biology.
Crabtree shares senior authorship of the study, which was published in Cell, with Nathanael Gray, PhD, the Krishnan-Shah Family Professor and a professor of chemical and systems biology; Stephen Hinshaw, PhD, assistant professor of molecular and cellular physiology; and Michael Green, PhD, director of translational and laboratory research, lymphoma/myeloma at the MD Anderson Cancer Center. Graduate student Meredith Nix and postdoctoral scholar Sai Gourisankar, PhD, are the lead authors of the research. Diffuse large B-cell lymphoma is the most common form of non-Hodgkin lymphoma, a type of blood cancer.
In many cases, the disease is driven by a protein known as BCL6. In healthy immune cells, BCL6 attaches to DNA and temporarily shuts down genes that would normally stop cell growth or initiate cell death. This temporary suppression gives immune cells time to multiply during an immune response.
Once the immune threat has passed, other proteins modify BCL6 so that it can no longer silence those genes. The excess immune cells can then die through apoptosis, a controlled form of programmed cell death that allows the body to remove unneeded, damaged or cancerous cells without causing inflammation or harming nearby tissue. Problems arise when BCL6 remains permanently active.
In lymphoma cells, the protein can stay stuck in the "on" position, continually suppressing death-related genes and allowing malignant cells to keep multiplying. Crabtree, Gray and their colleagues wanted to do more than simply remove that suppression. Their goal was to push those same cell-death genes into a highly active state.
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