Princeton team disables long-targeted gene behind spread of major cancers

Princeton team disables long-targeted gene behind spread of major cancers
Scientists have discovered a compound that takes aim at a gene central to the metastasis of many major cancers
Scientists have discovered a compound that takes aim at a gene central to the metastasis of many major cancers
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Scientists have discovered a compound that takes aim at a gene central to the metastasis of many major cancers
Scientists have discovered a compound that takes aim at a gene central to the metastasis of many major cancers

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.

Metastatic cancer is a key focus for researchers and with good reason, as it is actually the primary cause of death from the disease. While surgery or chemotherapy might be effective at eliminating an initial tumor, cells that have broken away can discreetly make their way around the body and give rise to new tumors, months or even years later.

“Metastatic breast cancer causes more than 40,000 deaths every year in the US, and the patients do not respond well to standard treatments, such as chemotherapies, targeted therapies and immunotherapies,” says Minhong Shen, member of the Princeton team behind the new discovery. “Our work identified a series of chemical compounds that could significantly enhance the chemotherapy and immunotherapy response rates in metastatic breast cancer mouse models. These compounds have great therapeutic potential.”

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.

“There was a lot of excitement,” Kang says. “‘Wow, we found a metastasis gene related to poor outcomes in patients! What next? Can we target it?’ That was the big question, because at the time, nobody knew how this obscure, little-known gene worked. It had no similarity to any other known human protein. We didn’t know if it was important to normal physiology.”

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.

“So basically, in most major human cancers, this gene is essential for cancer progression and all the terrible things associated with cancer, and yet it doesn’t seem to be important for normal development,” says Kang. “Mice can grow and breed and live normally without this gene, so we knew this would be a great drug target.”

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.

“In 2014, we showed what happens if you knock out a gene at birth,” Kang says. “This time, we show that after the tumor has already fully developed into full-blown, life-threatening cancer, we can eliminate the function of this gene. We found that whether you do it genetically or pharmacologically using our compound, you achieve the same outcome.”

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. 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.

“Now, with this drug, we reactivate the alarm system,” Kang says. “In normal tissues, healthy cells are usually not under stress or presenting signals that can be recognized as foreign by the immune system, so this is why MTDH is not essential for normal tissues. In essence, MTDH is a quintessential ‘cancer fitness gene’ that is uniquely required by malignant cells to survive and thrive.”

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. While noting that they are only just scratching the surface in terms of what it could do, they hope to be ready for clinical trials on human patients in two to three years.

“In the two papers we are publishing back-to-back today, we identify a compound, show it is effective against cancer, and show that it is very, very effective when combined with chemotherapy and immunotherapy,” says Kang. “Even though metastatic cancers are scary, by figuring out how they work – figuring out their dependency on certain key pathways like MTDH – we can attack them and make them susceptible to treatment.”

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

Source: Princeton University

I have known many people who were successfully treated for their primary tumors,but later succumb to metastasis.I wonder if rheumatoid arthritis involves something like MTDH,and it is lacking in people suffering arthritis,prompting the body to attack normal joint tissue.
Wow. This is huge news if they can turn it into a human-friendly treatment. And do so relatively quickly.
Ornery Johnson
As a former scientist researching cancer, I love to hear about progress in the fight that presents the possibility for broad applicability, strong efficacy and low host toxicity.
Wow. If this is confirmed through clinical trials, if I'm not mistaken this process possibly could be the greatest achievement yet towards fighting this disease. That the process seems to work for all forms of cancer or most is doubly amazing. Wish this would have been discovered a few yrs ago. Could have saved my dad from being slowly eaten alive by pancreatic cancer. Difficult to watch someone slowly die and not be able to do anything. This should be front page news.
I remember hearing about Metadherin years ago. I'm glad they did brute force research and have found a "silver bullet" that may pack a one-two punch on established tumors that may or may not have metastasized! Yes, it is great that in mice studies the new compound to disrupt the MTDH and SND1 connection, but the "possible 2-3 year start of clinical trials" is not that great.

Still - when the initial findings were reported back in 2006, we thought the studies were going to result in breakthroughs within 5 years. 15 years later they know more about the mechanism of action, but we are still years away from clinical trials in humans. Being able to use poisons to treat tumors currently protected with MTDH would improve our current chemotherapy success rates significantly! So many patients have to deal with good news followed by recurrances years later. Hopefully Princeton's research is finally coming to fruition! I hope so!
I'm 50. I can't tell you how happy I am to read about breakthroughs like this that *might* apply to someone like me in the future.
Thomas Origamus
Presumably, the gene and molecule have some purpose other than metastasis, and that is the real trick - does preventing the gene from functioning have negative effects?
Where are all the large charities? Their money and contacts can make this happen faster.