Princeton Team Disables Long-Targeted Gene Behind Spread of Major Cancers

An anonymous reader writes: The mysterious ways cancer spreads through the body, a process known as metastasis, is what can make it such a difficult enemy to keep at bay. Researchers at Princeton University working in this area have been tugging at a particular thread for more than 15 years, focusing on a single gene central to the ability of most major cancers to metastasize. They’ve now discovered what they describe as a “silver bullet” in the form of a compound that can disable this gene in mice and human tissue, with clinical trials possibly not too far away.

This discovery has its roots in 2004 research in which Princeton scientists identified a gene implicated in metastatic breast cancer, called metadherin, or MTDH. A 2009 paper by cancer biologist Yibin Kang then showed the gene was amplified and produced abnormally high levels of MTDH proteins in around a third of breast cancer tumors, and was central to not just the process of metastasis, but also the resistance of those tumors to chemotherapy. Subsequent research continued to shed light on the importance of the MTDH gene, demonstrating how it is critical for cancer to flourish and metastasize. Mice engineered to lack the gene grew normally, and those that did get breast cancer featured far fewer tumors — and those tumors that did form didn’t metastasize. This was then found to be true of prostate cancer, lung cancer, colorectal cancer, liver cancer and many other cancers.

The crystal structure of MTDH shows the protein has a pair of protrusions likened to fingers, which interlock with two holes in the surface of another protein called SND1. This is “like two fingers sticking into the holes of a bowling ball,” according to Kang, and the scientists suspected if this intimate connection could be broken, it could go a long way to dampening the harmful effects of MTDH. “We knew from the crystal structure what the shape of the keyhole was, so we kept looking until we found the key,” Kang says. The team spent two years screening for the right molecules to fill these holes without any great success, until they landed on what they say is a “silver bullet.” The resulting compound plugs these voids and prevents the proteins from interlocking, with profound anti-cancer effects that resemble those seen in the MTDH-deficient mice from their earlier work. “The scientists say that MTDH assists cancer in two primary ways, by helping tumors endure the stresses of chemotherapy and by silencing the alarm that organs normally sound when a tumor invades them,” adds New Atlas. “By interlocking with the SND1 protein, it prevents the immune system from recognizing the danger signals normally generated by cancerous cells, and therefore stops it from attacking them. The team is now working to refine the compound, hoping to improve its effectiveness in disrupting the connection between MTDH and SND1 and lower the required dosage. [T]hey hope to be ready for clinical trials on human patients in two to three years.”

The research has been published across two papers in the journal Nature Cancer.

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