Personalized treatment is a growing genre of cancer therapy. Researchers of the Salk Institute for Biological Studies and UCLA recently treated lung cancer with a specific metabolic mutation, KRAS LKB1 deficiency, with a derivative of a drug originally FDA approved for diabetic therapy, phenformin.
The LKB1 enzyme normally is activated in response to low cellular energy. The enzyme lets the cell know it is metabolizing inefficiently, so the cell can correct itself before starving to death. However, 20% of non-small cell lung cancers (NSCLC) have a mutation resulting in LKB1 inhibition or very little effective LKB1 produced. This is the second most common mutation in NSCLC. Following, “the tumor cell loses the ability to regulate its energy consumption, similar to a car losing its breaks,” David Shackelford.
The metabolic regulator phenformin attacks the mitochondria of affected cells and lowers the available energy. This pushes the cell into a state of needing LKB1 to correct its energy consumption. However, NSCLC lacking the LKB1 gene cannot correct and eventually apoptose, commit cellular suicide.
Using advanced stage lung cancer genetically modified mice with the mutation to the KRAS LKB1 gene (and similar KRAS mutations as controls), phenformin’s effect on tumor size and mouse survival was studied.
Mice given phenformin showed 30% decreased tumor area according to red pixel count of morphometric analysis after three weeks of treatment. In analyzing tumor cells specifically, their apoptotic rate was increased significantly. Therefore, the tumor cells were dying and shrinking cancer impact. Accompanying, an average of 35% increased survival of mice was seen when treated with phenformin in mice with the KRAS LKB1 mutation as seen in figure 5 A & B of the article.
The tumor reduction was definitely significant in the mice introduced to phenformin. It’s also noteworthy that phenformin had little to no effect on normal cells because they had functioning LKB1 and could correct any drug induced metabolic imbalance. This drug treatment would work well as an adjuvant to surgical removal of the bulk of tumors to clean out any remaining cancer.
Because phenformin is already FDA approved, clinical trials showing it’s anti-cancer effects in humans are all that is needed to bring this treatment to life. Pharmacies may see phenformin in the cancer treatment aisle sooner than most drugs even reach clinical trials.
David B. Shackelford1, Evan Abt, Laurie Gerken, Debbie S. Vasquez, Atsuko Seki, Mathias Leblanc, Liu Wei, Michael C. Fishbein, Johannes Czernin, Paul S. Mischel3, Reuben J. Shaw. LKB1 Inactivation Dictates Therapeutic Response of Non-Small Cell Lung Cancer to the Metabolism Drug Phenformin. Cancer Cell, 2013.