It is estimated that 1 in 8 women in the U.S. will develop breast cancer over the course of their life. Even though the disease is following a descending trend in number of cases, it remains the most common form of malignancy among women. Now, researchers from Finland may have found a way of turning the disease against itself.
In more than 40% of cases, patients exhibit an overexpression of the MYC gene. While MYC helps breast cancer cells generate more macromolecules, it also creates a metabolic vulnerability by making them more sensitive to a type of cell death known as apoptosis.
Research Director Juha Klefstrom, Ph.D., University of Helsinki, has uncovered a way of exploiting this vulnerability using a “drug cocktail” which Metformin (diabetes drug) and Venetoclax, a BCL-2 protein blocker that can trigger apoptosis (programmed cell death).
“This drug combo exploits specific metabolic vulnerabilities that high levels of MYC creates in tumor cells. Metformin and venetoclax, when given together, killed breast tumor cells in culture and blocked tumor growth in breast cancer animal models. Furthermore, the drugs efficiently killed authentic breast cancer tissue donated by breast cancer patients. The breast cancer samples were obtained fresh from surgeries performed in Helsinki University Hospital”, explained Dr. Klefstrom.
While initial results were successful, the team noticed that the effect was only exhibited during treatment. The lymphocytes were able to kill tumors but they shortly disappeared and the remaining killer cells expressed PD-1, a marker of immune cell exhaustion.
To counteract this issue, researchers changed their approach. They used Metformin and Venetoclax to reduce the tumor size and wake up the killer lymphocytes and then surgically removed them. Post operation, they treated the mouse models with a triple combination of Metformin, Venetoclax and a PD-1-targeted antibody, which is used in immunotherapies to keep killer cells active long-term.
“With this combination the survival of mice carrying implanted tumors was extended dramatically in comparison to mice that were treated with only single or double combinations”, noted Dr. Klefstrom.
She also highlighted that this project was a result of interdisciplinary teamwork involving many individuals, basic researchers, pathologists, surgeons, and oncologists.
“It’s quite amazing how we’ve been able to bring a discovery from the lab bench all the way to the doors of the cancer clinics within the time frame of one Ph.D.project. We are very excited about our findings and hope that they will translate to benefit breast cancer patients”.
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