Early last December, dermatologist and physician-scientist Stefan Schieke, MD, published ground-breaking research in the journal Cell Reports (view article on PubMed) that could lead to the effective treatment of lymphoid cancers. These findings from Schieke Lab have immediate clinical relevance and are already advancing to the early stages of clinical trials
Schieke and his research fellow (at time of publication) now Assistant Scientist (November 1st 2021), Hamidullah Khan, PhD, were initially inspired by preliminary data suggesting that the ‘wonder drug’ Metformin could work as an anti-cancer agent, and decided to see whether it would also work against lymphoma and lymphocytic leukemia. For the uninitiated, Metformin has long been a treatment for Type 2 Diabetes, with recent studies showing that it has anti-cancer, and even lifespan-extending, effects. It was a logical step to test it against lymphoma and leukemia cells.
But initial tests using Metformin against lymphoid cancers suggested that the cancerous cells were resistant – they kept growing in culture and in mice.
Metformin’s primary function is to target a specific protein in mitochondria, called “respiratory chain complex 1,” which is key to cell metabolism. “By blocking that protein’s function, you block the function of the mitochondria, with downstream effects curtailing metabolism as well as other critical cellular functions, which might explain its wide potential applications.”.
Yet Metformin didn’t shut down leukemia and lymphoma cells’ metabolism, even though it was successfully shutting down respiratory chain complex 1.
“That really made us ask the more sophisticated question,” says Schieke, “How do the cancer cells evade Metformin and the mitochondrial dysfunction it should cause? What are the specific mechanisms that allow this resistance, and can we target those to sensitize these cancer cells to the drug Metformin?”
With further investigation, Schieke and his lab discovered that the leukemia and lymphoma cells treated with Metformin were bypassing respiratory chain complex 1, and successfully metabolizing glucose outside the mitochondria. At a high level, Schieke likens this to the human diet:
“You can survive on eating different foods: you run out of meat and so you switch to potatoes. This metabolic flexibility gives any organism a distinct survival advantage – but metabolic flexibility in cancer cells is a problem because it means we can’t easily target them with a single metabolic drug.”
In this case, Metformin shuts down the aforementioned protein, respiratory chain complex 1, causing the metabolic pathways to be rewired in a process known as the Warburg effect. This effect allows glucose that is usually fed to the mitochondria to instead be converted into lactate for direct consumption by the cell, bypassing the mitochondria entirely. The change in fuel preference is known by researchers as “metabolic flexibility.” The switch causes the cancer cells to become critically dependent on glucose, eliminating the ability to process and thrive on different fuels such as amino acids and fatty acids in addition to glucose.
On the face of it, making the cancer cells dependent on glucose as a source of fuel opens up a path to treatment—by starving those cells of glucose. However, such a method would be very hard to use with actual patients, who still require glucose for the non-cancer cells in their bodies. Instead, Schieke decided to focus his research on the mechanism that induces metabolic flexibility itself.
Schieke and Khan discovered how lymphoid cancer cells adapted to metformin by activating the Warburg effect. Once Metformin took effect, the mitochondria would release a stress signaling molecule called “reactive oxygen species” (mROS), which in turn activates a well-known and highly conserved molecule, “hypoxia-inducible factor 1 alpha” (or HIF-1α). HIF-1α enhances the Warburg effect, allowing the cancer cell to continue to grow despite Metformin’s effect.
This metabolic adaptation to Metformin is unique among cancer cells, and it explains why leukemias and lymphomas have never been susceptible to the drug. Moreover, it is also unique to malignant lymphocytes – normal lymphocytes from healthy patients do adapt to Metformin, but they do so using a different pathway.
Schieke’s discovery might give us a new way to treat lymphoid cancers, all of which are non-curable. A drug that inhibits HIF-1α already exists, but it wasn’t deemed particularly effective, and so had “fallen off the clinical map.” Schieke’s research showed that a one-two-punch treatment was effective: First, suppress HIF-1α to block the metabolic adaptation to mitochondrial dysfunction; Next, treat with Metformin to kill the cancerous cells, which can no longer adapt.
Schieke and Khan’s next step was to confirm their data in freshly isolated leukemia cells from patients with chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL). Their validation tests using these fresh cells both in cell lines and in mice made it clear that there was potential for clinical trials:
“Based on cell culture and animal studies, this might provide a treatment with low toxicities. Normal lymphocytes are not affected – the treatment is highly selective for the cancer cells – and both of the drugs are already well tolerated in clinical trials and, in the case of Metformin, in common use. We are hoping it will be less toxic than chemo.”
Schieke is now working with the UW Carbone Cancer Center and the lymphoma group with Christopher Fletcher and Vaishlee Kenkre to test his experimental treatment in clinical trials.
“What really makes this job so cool is figuring out biological mechanisms at the bench that could be the foundation for new treatments, and that we are able to roll it over to the Cancer Center which can make the clinical testing happen.”