Researchers at the University of Helsinki, Finland, have found a new use for the diabetes drug metformin in a combination treatment that is effective against MYC-driven breast cancer.
Around half of breast tumors have increased levels of the MYC protein, an oncogenic transcription factor that is often overexpressed in cancers. Overexpression and amplification of the MYC gene have been linked to breast tumor progression and increased risk of relapse and death.
Even though MYC plays a role in furthering the progression of cancer, it also makes cancer cells vulnerable to apoptosis (programmed cell death). Some proteins of the BCL-2 family contribute to MYC's ability to promote apoptosis, whereas other proteins in the same family do the opposite: overexpression of BCL-2 or BCL-XL protects tumors from apoptosis without diminishing the tumor-promoting functions of MYC.
In an attempt to therapeutically reactivate MYC's apoptotic potential in tumors, scientists have developed small-molecule BH3 mimetics, which bind to and neutralize the anti-apoptotic members of the BCL-2 protein family. In mouse models of lymphoma, several BH3 mimetics, including the BCL-2/BCL-XL inhibitor ABT-737, its orally bioavailable derivative navitoclax, and the BCL-2 inhibitor venetoclax have successfully restrained disease development. BH3 mimetics have demonstrated even higher efficacy when used in combination with other therapies, including standard chemotherapy, proteasome inhibitors, and histone deacetylase inhibitors.
Building on this work, the researchers at the University of Helsinki used ABT-737 in a mouse model of Myc-driven breast cancer to explore the antitumor effects of inhibiting BCL-2 and BCL-XL. Although ABT-737 induced apoptosis and reduced tumor growth, it did not provide survival benefit when used as a monotherapy.
When the investigators sought out companion drugs that could enhance ABT-737's antitumor activity, they found that ABT-737 produced strong apoptotic capability when combined with agents that induce AMP-activated protein kinase activation. Metformin is one such agent, and the researchers found that metformin in combination with navitoclax or venetoclax efficiently inhibited tumor growth and caused immune cells to infiltrate the tumor.
"This drug combo exploits specific metabolic vulnerabilities that high levels of MYC create in tumor cells," explained Juha Klefstrom, PhD, Researcher Director in the Medical Faculty of the University of Helsinki and senior investigator of the study, which was published in Nature Communications. "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."
There was a drawback, however. These benefits only lasted so long as the drug combination was being administered. Once the drugs were withdrawn, the tumor regrew and demonstrated immune escape, the ability to bypass the immune system's attack.
The investigators solved this problem by creating a two-part treatment plan that began with metformin combined with venetoclax to induce apoptosis, followed by a regimen consisting of metformin, venetoclax, and immunotherapy treatment with a PD-1 (programmed cell death-1)–targeted antibody.
"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," stated Dr. Klefstrom.
The researchers note that this study, which involved a collaboration of basic researchers, pathologists, surgeons, and oncologists from the time of its inception, was aimed at taking research directly from the laboratory to a clinical setting. The study's lead author, Heidi Haikala, PhD, who is now a postdoctoral researcher at Harvard Medical School and the Dana-Farber Cancer Institute, emphasized this point: "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."
For More Information
Haikala HM, Anttila JM, Marques E, et al (2019). Pharmacological reactivation of MYC-dependent apoptosis induces susceptibility to anti-PD-1 immunotherapy. Nat Commun, 10:620. DOI:10.1038/s41467-019-08541-2
Image credit: Klefstrom Lab, University of Helsinki