Drexel University College of Medicine investigators have discovered two drug-like molecules that show early promise to shrink brain tumors caused by metastatic breast cancer. Their research in a mouse model, published in the journal Frontiers in Pharmacology, represents the first successful attempt to target a key metabolic enzyme in brain cancer cells to reduce tumor size.
The research centers the activity in the brain that fosters tumor growth: the conversion of acetate into the molecule called acetyl-CoA, which is known to play a role in biochemical reactions in carbohydrates, proteins, and metabolism to help produce energy. To do this acetyl-CoA uses an enzyme called acetyl-CoA synthetase 2 (ACSS2).
Leveraging the understanding of this process that aids brain tumor growth, the Drexel researchers sought to find molecules that could both cross the blood-brain barrier and bind to ACSS2 to block its function and shrink tumors.
Mauricio Reginato, PhD, senior author of the study and chair of the department of biochemistry & molecular biology at Drexel, said: “Currently available inhibitors aren’t very good, or don’t get to the brain. This work is still in very early stages, but we’re finding that these novel compounds are crossing the blood-brain barrier and effectively starving tumors of a key energy source.” This barrier has long been a challenge for effective cancer treatments, as it limits the ability of drugs reaching their target within the brain.
To search for promising compounds, the team employed advanced computer models to screen for drug compounds that could overcome this barrier. Their approach led to the identification of two promising compounds called AD-5584 and AD-8007. Both selectively killed cancer cells and blocked tumor growth in animal models, as well as reduced acetyl-CoA and lipids that cancer cells depend on for survival and growth.
“Our predictive computational models helped us identify two ACSS2 inhibitors that exhibited stability and important drug-like properties from a pool of other molecules,” said Alexej Dick, MD, an assistant professor at the Drexel University College of Medicine. “We could verify our computational pipeline’s success and predictive power in the lab and saw a good correlation with our predictions. This is critical and very helpful for further developing those drugs into a clinically relevant range.”
The team also tested combining these newly identified inhibitors with radiation using brain cancers cells and found they also worked well to destroy the tumors while also blocking additional tumor growth.
“We are currently planning to test whether these new drugs can turn breast cancer brain metastasis into a ‘hot’ tumor and thus synergize with immune therapy and radiation in preclinical models,” Reginato said.
Building on these findings, the investigators will now seek to refine the two compounds with an eye toward initiating clinical trials to test their safety and potential toxicity of the ACSS2 inhibitors. They will also study dosing levels to help optimize treatment with an aim of reducing the radiation treatments.
About 10% to 15% of stage IV breast cancer patients develop brain metastasis and more than eight out of 10 patients with brain metastasis are diagnosed with end-stage disease within a year following their diagnosis. These new findings could lead to the development of new drugs to effectively treat this subset of cancer patients.
