Blocking fat to block cancer

Interrupting acetyl-CoA carboxylase in lipid synthesis has been found to suppress, shrink tumors

Kelsey Kaustinen
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Most people are familiar with mitochondria as the “powerhouse” of the cell, the main source of energy, but fat also plays a role in keeping things running. Cells produce their own fat molecules, which are used to build plasma membranes and other critical structures.
However, as with many other cellular mechanisms, this can be used by and contribute to cancer. Because cancer cells are constantly growing and dividing, they require a lot of energy, which includes fat molecules.
“Cancer cells rewire their metabolism to support their rapid division,” noted 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.”
Shaw and his team worked with Nimbus Therapeutics, which discovers and develops small molecules to treat a variety of diseases. In particular, the company is developing a molecule to shut off an enzyme called acetyl-CoA carboxylase, or ACC, which plays a key role in lipid synthesis.
“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,” he added. “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.”
The team explored that inhibitor's effects in several extensive large-scale tests in animal models of cancer and transplanted human lung cancer cells, and got even more striking results. ND-646, the inhibitor in question, caused tumor mass to shrink by about two-thirds compared to untreated animal models. Additionally, when it was combined with carboplatin—one of the standard treatments for non-small cell lung cancer, it damages DNA—they saw 87 percent of tumors repressed, compared to 50 percent when treated with carboplatin alone.
“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.”
Even better, despite the strong effects, the combination didn't seem to impair normal cells; Robert Svensson, a Salk research associate and first author, commented that “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.”
This work appeared in a paper titled “Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models, which was published in Nature Medicine.
SOURCE: Salk Institute press release

Kelsey Kaustinen

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