THEY CALL IT "CANCER"
Researchers in Finland have discovered a drug combination that collaborates with the cancer cells' own MYC oncoprotein, which in large quantities causes self-destruction of the cancer cells.
When this combination is enhanced with immune system-boosting anti-PD-1 therapy, a more effective and long-lasting therapeutic effect can be seen in mice. These findings pave the way for new treatment combination strategies to harness the body’s natural defenses to fight "cancer".
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.
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Cancer tumor is always white, not green, blue or red
Invasive Breast Carcinoma (IBC)Images of invasive breast cancer:
Left: Pathology slide image of cancerous breast tissue, Right: Tumor (white area) in fatty breast tissue.
Images courtesy: C. Whitaker Sewell, MD - Professor of Pathology, Emory University School of Medicine. https://www.cancerquest.org/patients/cancer-type/breast-cancer_
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Carcinoma of the breast is the most common cancer in the Western world and accounts for 20% of all cancers in women in the UK, with 1 in 10 women developing breast cancer in their lifetime (the prevalence of the condition in males is significantly less).By TeachMeSeries Ltd (2019)
Invasive carcinoma of the breast can beclassified into:- Invasive ductal carcinoma (75-85%)
- Invasive lobular carcinoma (10%)
- Other subtypes (5%), such as medullary carcinoma or colloid carcinoma
Historically, ductal and lobular carcinomas were originally divided on the basis that ductal carcinomas arise in the ducts and lobular carcinomas arise in the lobules; it is now known that almost all breast carcinomas actually arise in the terminal duct lobular unit but this classification remains in use due to the different behaviour of the two subtypes.
“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.
Further information:
Research Director Juha Klefstrom, PhD, University of Helsinki
Email: juha.klefstrom@helsinki.fi
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.
Reference: Heidi M. Haikala, Johanna M. Anttila, Elsa Marques, Tiina Raatikainen, Mette Ilander, Henna Hakanen, Hanna Ala-Hongisto, Mariel Savelius, Diego Balboa, Bjoern Von Eyss, Vilja Eskelinen, Pauliina Munne, Anni I. Nieminen, Timo Otonkoski, Julia Schüler, Teemu D. Laajala, Tero Aittokallio, Harri Sihto, Johanna Mattson, Päivi Heikkilä, Marjut Leidenius, Heikki Joensuu, Satu Mustjoki, Panu Kovanen, Martin Eilers, Joel D. Leverson, Juha Klefström. Pharmacological reactivation of MYC-dependent apoptosis induces susceptibility to anti-PD1 immunotherapy. Nature Communications. DOI 10.1038/s41467-019-08541-2
Do You Have Candida? Take The "Spit Test"!
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Sugar - cause of Candida - Candida cause of Cancer - This video saved my Life
Click for video
Explanation...
Origin of your problems
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Do You Have Candida? Take The "Spit Test"!
Candidiasis is a very common infection caused by the Candida fungus,
and can affect your skin, nails, organs, genitals, throat, bloodstream and mouth.
This infection can affect both men and women, but it's more commonly found in women.
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