MYC, a gene with high cancer-initiating potential, is overexpressed in over 40% of breast cancers.

While MYC programs breast cancer cells to build more macromolecules (anabolic metabolism), it also creates a metabolic vulnerability by making them more sensitive to a type of cell death known as apoptosis.

Research Director Juha Klefstrom, PhD, University of Helsinki, Finland, has worked for a long time to exploit this apoptosis-sensitising effect of MYC in the battle against the cancer.

Klefstrom and his research group found that, because of this vulnerability, cancer cells can be attacked with a "drug cocktail" that includes the diabetes drug metformin and venetoclax, a BCL-2 protein inhibitor that can induce apoptosis in cancer cells.

Their results were published in Nature Communications.

The group identified metformin in a search for drugs that could boost the apoptosis-inducing action of venetoclax.

Venetoclax has been approved to treat certain leukaemias but not yet for the treatment of breast cancer.

"This drug combo exploits specific metabolic vulnerabilities that high levels of MYC create in tumour cells. Metformin and venetoclax, when given together, killed breast tumour cells in culture and blocked tumour 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", Dr Klefstrom explained.

However, the researchers soon discovered that the metformin plus venetoclax treatment only held tumours in check as long as the mice with implanted breast tumours were actively being treated with the drugs; once the treatment was stopped, the tumours grew back.

The study showed that tumours were initially filled with tumour-killing lymphocytes; however, after the treatment they largely vanished and the remaining killer cells expressed PD-1, which is a marker of immune cell exhaustion.

To help the immune cells better fight the tumour, the researchers developed a new treatment strategy.

First, they hit breast tumours with apoptosis-inducing drugs metformin and venetoclax to reduce the tumour size and to wake up killer lymphocytes.

After the primary tumours were surgically removed, the mice were then treated with a triple combination: metformin, venetoclax and a PD-1-targeted antibody, which is used in immunotherapies to keep killer cells active in the long-term. 

"With this combination, the survival of mice carrying implanted tumours was extended dramatically in comparison to mice that were treated with only single or double combinations", Klefstrom states.

Klefstrom highlights that this is a wonderful example of a translational study fundamentally aimed at taking research from bench to bedside. 

The first author of the study, Dr Heidi Haikala noted: "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 PhD project. We are very excited about our findings and hope that they will translate to benefit breast cancer patients."

"This is a great example of how scientists in academia, leveraging highly specialised tumour models and applying their unique insights, can contribute to the discovery of potential new treatments for people with cancer. It is also a testament to the great research being done in smaller countries like Finland," stated Joel Leverson, Ph.D., a Senior Scientific Director at AbbVie and one of the senior authors in the study.

"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.

Source: University of Helsinki