Gluing proteins together kills cancer super selectively

Scientists have demonstrated a creative new way to kill cancer cells effectively, with few side effects. Gluing two particular proteins together tricks the tumors into destroying themselves.

Cells in our bodies naturally die off in a process called apoptosis, to be replaced by others. But when something goes wrong with that process, some cells can continue growing out of control – a condition we know as cancer.

Certain genes have the potential to mutate into oncogenes, which are a major driver of cancer. Often, these oncogenes are related to cell proliferation and disposal, so affected cells can evade apoptosis. Understandably, oncogenes and the proteins they encode are a common target for cancer treatments, but the new study, from researchers at Stanford, tackles the problem from a different angle.

“Since oncogenes were discovered, people have been trying to shut them down in cancer,” said Roman Sarott, co-first author on the study. “Instead, we’re trying to use them to turn signaling on that, we hope, will prove beneficial for treatment.”

The Stanford team targeted an oncogene protein called BCL6, which is implicated in diffuse large cell B-cell lymphoma. Mutated BCL6 will sit on DNA right near specific genes that promote apoptosis, keeping them switched off so the cancer cells can continue to grow and divide unchecked.

To counter this, the scientists developed a kind of molecular glue that binds BCL6 to another protein, CDK9. This one activates genes, and in this case it switches back on the apoptosis-associated genes that BCL6 is suppressing. In lab tests, this technique worked to kill off lymphoma cells with high potency.

“The idea is, Can you turn a cancer dependency into a cancer-killing signal?” said Nathanael Gray, co-senior author of the study. “You take something that the cancer is addicted to for its survival and you flip the script and make that be the very thing that kills it.”

This particular protein pairing is very selective to diffuse large cell B-cell lymphoma. That means that unlike radiation and chemotherapy, this technique doesn’t seem to affect healthy cells. In tests in mice without cancer, no major negative side effects were seen – although it does also attack some healthy immune cells.

In another experiment, the team tested the molecule against 859 different types of cancer, and the only one it killed was diffuse large cell B-cell lymphoma. The researchers plan to try to alter the mechanism to target other known cancer-causing proteins, such as Ras, which is implicated in several forms of the disease.

While it’s certainly an intriguing mechanism, it’s important to note that it’s still in the very early stages. The team is currently testing the compound in mice with diffuse large cell B-cell lymphoma, with hopes that the general idea could eventually be applied to treat a wide range of cancers with extreme selectivity.

If all goes well, the whole-body assault that comes with radiation or chemotherapy could eventually become a thing of the past.

The research was published in the journal Science.

Source: Stanford University