Nav: Home

Combination treatment, diabetes drug and immunotherapy, may help to fight breast cancer

February 06, 2019

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-sensitizing 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. 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 leukemias but not yet for the treatment of breast cancer.

"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", Dr. Klefstrom says.

However, the researchers soon discovered that the metformin plus venetoclax treatment only held tumors in check as long as the mice with implanted breast tumors were actively being treated with the drugs; once the treatment was stopped, the tumors grew back. The study shows that tumors were initially filled with tumor-killing lymphocytes; however, after the treatment they largely vanished and the remaining killer cells expressed PD-1, a marker of immune cell exhaustion.

To help the immune cells better fight the tumor, the researchers developed a new treatment strategy. First, they hit breast tumors with apoptosis-inducing drugs metformin and venetoclax to reduce the tumor size and to wake up killer lymphocytes. After the primary tumors 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 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", Klefstrom states.

Klefstrom highlights that this is a wonderful example of a translational study fundamentally aimed at taking research from bench to bedside. The key people from the University of Helsinki and Helsinki University Hospital (HUS) - basic researchers, pathologists, surgeons and oncologists - were all involved at the earliest stages of the study.

The first author of the study Dr Heidi Haikala notes: "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 specialized tumor 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," states 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 concludes.
-end-
The collaborative study involved Juha Klefstrom, Satu Mustjoki and Timo Otonkoski groups at the University of Helsinki, FIMM, HUSLAB pathology, Helsinki University Hospital/HUS breast cancer surgery unit and HUS Comprehensive Cancer Center. Other key collaborators included University of Wurzburg, Germany, Oncotest GmbH (now part of Charles River Laboratories Inc.) and AbbVie, North Chicago.

University of Helsinki

Related Breast Cancer Articles:

Does MRI plus mammography improve detection of new breast cancer after breast conservation therapy?
A new article published by JAMA Oncology compares outcomes for combined mammography and MRI or ultrasonography screenings for new breast cancers in women who have previously undergone breast conservation surgery and radiotherapy for breast cancer initially diagnosed at 50 or younger.
Blood test offers improved breast cancer detection tool to reduce use of breast biopsy
A Clinical Breast Cancer study demonstrates Videssa Breast can inform better next steps after abnormal mammogram results and potentially reduce biopsies up to 67 percent.
Surgery to remove unaffected breast in early breast cancer increases
The proportion of women in the United States undergoing surgery for early-stage breast cancer who have preventive mastectomy to remove the unaffected breast increased significantly in recent years, particularly among younger women, and varied substantially across states.
Breast cancer patients with dense breast tissue more likely to develop contralateral disease
Breast cancer patients with dense breast tissue have almost a two-fold increased risk of developing disease in the contralateral breast, according to new research from The University of Texas MD Anderson Cancer.
Some early breast cancer patients benefit more from breast conservation than from mastectomy
Breast conserving therapy (BCT) is better than mastectomy for patients with some types of early breast cancer, according to results from the largest study to date, presented at ECC2017.
One-third of breast cancer patients not getting appropriate breast imaging follow-up exam
An annual mammogram is recommended after treatment for breast cancer, but nearly one-third of women diagnosed with breast cancer aren't receiving this follow-up exam, according to new findings presented at the 2016 Annual Clinical Congress of the American College of Surgeons.
Low breast density worsens prognosis in breast cancer
Even though dense breast tissue is a risk factor for breast cancer, very low mammographic breast density is associated with a worse prognosis in breast cancer patients.
Is breast conserving therapy or mastectomy better for early breast cancer?
Young women with early breast cancer face a difficult choice about whether to opt for a mastectomy or breast conserving therapy (BCT).
Breast density and outcomes of supplemental breast cancer screening
In a study appearing in the April 26 issue of JAMA, Elizabeth A.
Full dose radiotherapy to whole breast may not be needed in early breast cancer
Five years after breast-conserving surgery, radiotherapy focused around the tumor bed is as good at preventing recurrence as irradiating the whole breast, with fewer side effects, researchers from the UK have found in the large IMPORT LOW trial.

Related Breast Cancer Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Anthropomorphic
Do animals grieve? Do they have language or consciousness? For a long time, scientists resisted the urge to look for human qualities in animals. This hour, TED speakers explore how that is changing. Guests include biological anthropologist Barbara King, dolphin researcher Denise Herzing, primatologist Frans de Waal, and ecologist Carl Safina.
Now Playing: Science for the People

#SB2 2019 Science Birthday Minisode: Mary Golda Ross
Our second annual Science Birthday is here, and this year we celebrate the wonderful Mary Golda Ross, born 9 August 1908. She died in 2008 at age 99, but left a lasting mark on the science of rocketry and space exploration as an early woman in engineering, and one of the first Native Americans in engineering. Join Rachelle and Bethany for this very special birthday minisode celebrating Mary and her achievements. Thanks to our Patreons who make this show possible! Read more about Mary G. Ross: Interview with Mary Ross on Lash Publications International, by Laurel Sheppard Meet Mary Golda...