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New Treatment for Lung Cancer Shines in Preclinical Trials

Blocking fat production in lung cancer cells could halt tumor growth, according to a new study from the Salk Institute for Biological Studies. 

Like most cells, cancer cells create molecules to help fuel their division. Blocking the development of lipids, commonly known as fatty acids, within cancer cells could starve them of the fuel they need to divide and build tumors. The study, published Sept. 19 in the journal Nature Medicine, examined the effects of blocking ACC, an enzyme critical to lipid synthesis. 

Lung cancer is the second-most commonly diagnosed cancer in the United States, but is the leading cause of cancer death. According to the Centers for Disease Control, more than 212,500 people in the United States were diagnosed with lung cancer in 2013, the most recent year for which statistics are available. That same year, 156,176 people died from the disease. 

Treatments for lung cancer include surgery, chemotherapy, radiation therapy and targeted drugs that block the growth and spread of cancer cells. 

For years, researchers had hypothesized that they could treat cancer by chemically inhibiting enzymes involved in creating lipids within the cell. Studies done in cell culture, with cells grown in controlled laboratory environments, had been promising. 

The problem with previous cell culture studies, however, was that lipids also come into the body through a person’s diet, explained Professor Reuben Shaw of the Molecular and Cell Biology Laboratory at the Salk Institute, who led the research. “It was just completely unclear how much the ability of each of the cancer cells to make their own lipids mattered.” 

To remove that uncertainty, scientists would have to study lipid inhibitors in living bodies, but the technology wasn’t available until recently.

That changed, Shaw said, when a Boston based company, Nimbus Therapeutics, developed the first a new lipid inhibit. “For the first time, effectively in history,” he said, “one could begin to test such hypotheses.” 

The molecule Nimbus had developed could shut off an enzyme called Acetyl-CoA Carboxylase, or ACC, which is critical to lipid synthesis. Through a biological process, ACC produces malonyl-CoA, a chemical compound that other researchers have identified as a potential target for treating cancer, particularly breast cancer.

With the new molecule from Nimbus, called ND-646, Shaw and his team could start further up the chain and they were able to do so using live mice. Working in in collaboration with the University of California, San Diego, Schrodinger, a chemical simulation software company, and Nimbus, the team performed two different types of studies. In one, they used genetically engineered mice and activated a genetic switch that would cause the mice to develop lung cancer. 

“You can spontaneously get isolated cells within the lung that recombine,” Shaw said. “It grows in its normal location and spreads the way it normally would. 

“There are increased metabolic demands from cancer cells because they undergo rapid division,” Shaw said. “They need to make two of everything within the cell in a much shorter time period than normal cells.”  

With this type of study, scientists have a more realistic model. The cells are growing in their natural environment and treatments can be impacted by the natural workings of the mouse’s body. 

In the second type of study, Shaw and his team took lung cancer cells that had been established in culture and then transplanted them into the lungs of a live mouse. In both models, the mice were given ND-646 orally. 

Their results were positive. In mice treated with ND-646, lung cancer tumors shrank to one-third their previous size. Researchers also investigated the performance of ND-646 in combination with carboplatin, a common chemotherapy drug. The combination resulted in suppression of 87 percent of tumors. For comparison, carboplatin alone resulted in a 50-percent suppression rate. 

“We have never seen anything even close to that level of reduction of tumor burden in these genetic models,” Shaw said. “That's why we're so encouraged.”

But Shaw said that treating lung cancer is just the first step. It’s possible that ND-646 might be effective against other cancers as well, particularly breast cancer. Breast cancer affects more than 230,800 women and 2,000 men annually, according to the Centers for Disease Control. 

Amidst the hopeful news, Shaw offered a word of caution and a call to action for researchers: “In really aggressive tumors, resistance will arise; we should just assume that it will. If we know that’s likely to happen we should start now.”