Drug Rescue and Repurposing: Marianne Koritzinsky
By: Marianne Koritzinsky
What drug are you investigating for its repurposing potential?
Our work so far has focused on metformin, which is a biguanide commonly prescribed for type II diabetes. In the treatment of diabetes, metformin works by reducing gluconeogenesis in the liver. This occurs because metformin inhibits mitochondrial activity, which in turn triggers metabolic adaptation in the liver cells.
For what new purpose is the drug being studied?
We are studying a specific role for metformin to enhance the response to radiotherapy during cancer treatment. We know that areas of poor oxygenation (hypoxia) in tumors limit the success of radiotherapy because hypoxic cells are radiation resistant. Hypoxia arises in part because the cancer cells close to blood vessels rapidly consume all the delivered oxygen, leaving nothing for cells further from the vessels. We therefore reasoned that if we can inhibit oxygen consumption, perhaps we would be able to increase the oxygen content of the tumors and make radiation therapy more efficient. Metformin was very interesting to us in this respect, since it was already known to inhibit mitochondrial respiration. Furthermore, it is a well-tolerated drug that has been taken by a large number of diabetics undergoing radiotherapy for cancer, so it is unlikely to cause severe side-effects when combined with radiation treatment.
What are the research findings?
We have grown tumors in mice and measured hypoxia by administering specific drugs (2-nitroimidazoles) that bind and mark hypoxic cells. The markers can be detected using fluorescent antibodies either by immunohistochemistry or flow cytometry. Markers can also be detected non-invasively by PET imaging, a technique that is increasingly being utilized also in the clinic to identify patients with hypoxic tumors. Using all these approaches, we found that if we gave the mice metformin, there was less hypoxia in the tumors. These better oxygenated tumors also showed increased response to radiation, as we would expect. These preclinical studies have therefore provided proof-of-principle that metformin can help reprogram the metabolism of cancer cells to decrease tumor hypoxia and enhance the efficacy of radiotherapy.
What do you hope is the future of the drug in this field?
There is already great general interest in metformin as an anti-cancer drug. Epidemiological and retrospective studies of diabetics have suggested that metformin might protect against cancer development and enhance response to chemotherapy. Metformin might therefore be beneficial for several independent reasons, and have application as an anti-cancer therapeutic in different contexts.
So far, there have been many efforts in the clinic to try to increase tumor oxygenation by supplying more oxygen. In these strategies, patients have been breathing high-oxygen or high-pressure gas during radiotherapy, or received blood transfusions or vasodilating agents. These approaches have worked to some extent, but are not very practical. The idea of patients rather taking metformin pills before or during radiotherapy is therefore very attractive.
We know that hypoxia is a poor prognostic factor in patients with head and neck, prostate and cervix cancer, so these are the sites we will pursue first. We are hoping to assess in non-diabetic patients whether metformin can decrease tumor hypoxia.
We started this project by investigating metformin, because it is such a commonly prescribed drug. However, other mitochondrial poisons could also have similar beneficial effects on tumor oxygenation. We are therefore pursuing other clinically available drug candidates that we think might be useful for this purpose.
What do you think is the future of drug rescue and repurposing?
Drug repurposing has enormous potential since it can shorten the way from laboratory to clinic substantially. This has certainly been realized in the cancer field, where large pharmacological screens are taking place across the world to identify drugs with anti-cancer properties that are currently used for other indications. Also, as we learn more about the mechanisms of action of specific drugs, we are able to expand this field in a hypothesis-driven approach. Metformin is a great example of the latter. Knowledge of its primary mechanism of action has accumulated over the last decades, although it has been known for centuries that French Lilac extracts which contains biguanides could relieve troublesome frequent urination–a symptom we recognize today as reflective of diabetes. Now we can use this mechanistic knowledge to propose novel applications for metformin in other diseases.
Marianne Koritzinsky, PhD, MSc
Department of Radiation Oncology
University of Toronto
Ontario Cancer Institute