Blocking the synthesis of fat molecules, which are required to build plasma membranes and other cellular structures, may be a promising therapeutic approach to halt cancer’s growth, a new study suggests.
The study, “Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models,” published in Nature Medicine, shows that blocking a critical enzyme required for lipid synthesis, Acetyl-CoA Carboxylase (ACC) significantly reduces cancer growth in mouse models of lung cancer, and can enhance the response to standard platinum-based chemotherapy.
When cells proliferate, new plasma membranes and cellular organelles need to be produced to be included in the emerging cells. Usually, cells uptake free lipids from the bloodstream to build these cellular membranes, but the increased cell proliferation of cancer cells, which requires very high amounts of lipid molecules, often leads to the reactivation of the lipid synthesis pathways.
“Cancer cells rewire their metabolism to support their rapid division,” Reuben Shaw, a professor at the Salk Institute, whose lab has made significant progress in establishing the ties between cancer and metabolic processes, said in a press release. “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.”
In this study, Shaw and his colleagues partnered with Nimbus Therapeutics, a biotech company that had been developing a small molecule to inhibit ACC, a critical enzyme in the lipid metabolism. Although other researchers had hypothesized that shutting down lipid metabolism could be key to halting cancer progression, this was the first time the theory was tested.
“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 Rosana Kapeller, chief scientific officer at Nimbus Therapeutics and a co-author of the paper. “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.”
The researchers tested the ACC inhibitor, called ND-646, in multiple non-small cell lung cancer (NSCLC) mouse models, which showed marked inhibition of tumor growth. In fact, compared to untreated animals, the inhibitor decreased the tumor mass by nearly two-thirds. And when ND-646 was paired with Paraplatin (carboplatin), a chemotherapy agent commonly used in NSCLC patients, the results were even more striking: 87 percent of tumors were suppressed, compared to 50 percent when mice were treated with Paraplatin alone.
Importantly, researchers revealed that the ND-646 and chemotherapy combination seemed to leave healthy cells unharmed, even though it dramatically induced the death of cancer cells.
“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,” said Shaw, who holds the William R. Brody Chair at the Salk Institute.
“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,” he said.
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