Drug Combination Could be New Step in Fighting Breast Cancer

Translational study of breast cancer therapy sought to ‘take research from bench to bedside.’

Researchers from the University of Helsinki have discovered a combination of drugs that, when enhanced with immune system-boosting anti-PD-1 therapy, created an effective and long-lasting therapeutic effect in mice. The combination uses the MYC oncoprotein in cancer cells, which in large quantities causes self—destruction to cancer cells.

MYC is a gene with a cancer-initiating potential and is overexpressed in more than 40% of breast cancers. Although MYC forces breast cancer cells to build more macromolecules, it also creates a metabolic vulnerability by increasing their sensitivity to apoptosis. Researchers discovered that this vulnerability allows a drug cocktail with the diabetes drug metformin and the BCL-2 protein inhibitor venetoclax to induce apoptosis in cancer cells.

Research director Juha Klefstrom, PhD, explained that the drug combination works by exploiting the metabolic vulnerabilities of the cell itself.

“Metformin and venetoclax, when given together, killed breast tumor cells in culture and blocked tumor growth in breast cancer animal models,” she said. “Furthermore, the drugs efficiently killed authentic breast cancer tissue donated by breast cancer patients.”

Upon experimentation with mice, researchers soon found that the metformin plus venetoclax treatment only maintained cancer cell death as long as the mice implanted with breast tumors were actively receiving the combination. According to the press release, the tumors were initially filled with tumor-killing lymphocytes, yet after treatment, they largely disappeared and the remaining cancer cells expressed PD-1, a marker of immune cell exhaustion.

To build a more successful strategy, the researchers first used the drug combination of metformin and venetoclax to reduce the tumor size and to wake up killer lymphocytes. After the primary tumors were surgically removed, they then treated the mice with the triple combination of metformin, venetoclax, and a PD-1-targeted antibody, which is used in immunotherapies to keep killer cells active long-term. Through this series of steps, the mice’s survival rate increased more drastically than previously seen.

"We finally have a drug combination that efficiently exploits MYC's apoptotic function and most importantly, these drugs can be tested in the clinic in real patients. We are currently working hard towards this next step," Klefstrom concluded.