Cutting the fat to treat cancer

Cells create their own fat molecules to build their plasma membranes and other critical structures. Now, researchers at the Salk Institute, along with academic and industry collaborators, have found a way to obstruct this instrumental process to stifle cancer’s growth, which they detailed in a paper published Sept. 19 in Nature Medicine. Like halting the delivery of supplies to a construction site, the approach stalls the molecular building blocks cancer needs to grow.

“Cancer cells rewire their metabolism to support their rapid division,” said Salk professor Reuben Shaw, whose lab has made significant progress in establishing the ties between cancer and metabolic processes. “Because cancer cells are more reliant on lipid synthesis activity than normal cells, we thought there might be subsets of cancers sensitive to a drug that could interrupt this vital metabolic process.”

Researchers had previously hypothesized that interrupting cells’ lipid assembly line could disable cancer, but it was only recently that they were able to disrupt the process and test this theory. Shaw’s team partnered with a Boston-based biotech, Nimbus Therapeutics, which discovers and develops small molecules in the hopes of treating a variety of diseases. The company was developing a molecule to shut off a critical player in lipid synthesis, an enzyme called acetyl-CoA carboxylase, or ACC.

According to Dr. Rosana Kapeller, chief scientific officer at Nimbus Therapeutics and a co-author of the paper, “Reuben Shaw and I have known each other for a long time, and because we were friends, I approached Shaw about four years ago to test Nimbus’ ACC inhibitor ND-646 on non-small cell lung cancers.”

Kapeller says ND-646 is an allosteric inhibitor of ACC, which blocks the dimerization of the ACC enzyme—it blocks fatty acid synthesis in the cells, and blocking endogenous lipogenesis inhibits the tumor cell growth.

“This confirms that shutting down endogenous lipid synthesis could be beneficial in some cancers and that inhibitors of the ACC enzyme represent a feasible way to do it,” said Kapeller. “We’ve taken a novel computational chemistry approach to designing high-potency allosteric inhibitors of this difficult enzyme, and we are very encouraged by the results.”

In multiple and extensive large-scale tests in both animal models of cancer and in transplanted human lung cancer cells, the results of ND-646 were far more promising than expected: tumor mass shrank by roughly two-thirds, compared to untreated animals. And when the researchers paired ND-646 with one of the common treatments for non-small lung cancer called carboplatin, the antitumor response was even greater: a dramatic 87 percent of tumors were suppressed, compared to 50 percent with the standard treatment of carboplatin alone.

“We found surprisingly well-tolerated dosing with some of these novel ACC inhibitors that have broad bioavailability and should not be far away from what would be needed to initiate clinical trials,” says first author Robert Svensson, a Salk research associate.

This combination of carboplatin (which damages DNA, a problem for rapidly dividing cells) and ND-646 (knocking out ACC and halting lipid synthesis) didn’t seem to impair normal cells even as it dramatically slowed cancer growth.

“For cancer agent trials, drugs are tried separately, but in real life, several drugs are usually used concurrently. Yes, ND-646 works well on its own, and it will work well as a single drug therapy, but it will likely work better in concert with other drugs. Carboplatin combined with ND-646 has already been proven to work well. If you have a drug that blocks endogenous lipogenesis, and you combine it with a drug that blocks ability to repair DNA, by putting these different mechanisms together you’ll hit your target in multiple ways, thereby making the drugs more effective in combination,” Kapeller tells DDNews.

“This is the first time anyone has shown that this enzyme, ACC, is required for the growth of tumors, and this represents compelling data validating the concept of being able to target fat synthesis as a novel anticancer approach,” added Shaw, who is the holder of the William R. Brody Chair at Salk. “The implications are that we have a very promising drug for clinical trials for subtypes of lung cancer as well as liver and other types of cancer. This represents a new weapon in the arsenal to fight cancer.”

“Nimbus’ ACC program has been acquired by Gilead, so Gilead now owns all of the ACC inhibitors we’ve developed,” says Kapeller. “Gilead is now the one who will be developing the drugs, and I believe they plan to take these drugs into clinical trials.”

The paper’s title is “Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small cell lung cancer in preclinical models.”

Gilead Sciences acquired Nimbus’ ACC inhibitor program in May 2016, including ND-646 and other ACC inhibitors for the treatment of non-alcoholic steatohepatitis and for the potential treatment of hepatocellular carcinoma and other diseases.