Metformin, an inexpensive, globally used diabetes drug that only costs about ¥90 per day, may create major changes in cancer treatment. The research group led by Dr. Yoshitaka Narita, Director of the Neurosurgery and Neuro-Oncology Department, National Cancer Center Hospital, and Professor Chihumi Kitanaka of the Yamagata University Faculty of Medicine has begun a phase II clinical trial in patients with glioblastoma, the most aggressive form of melanoma, to test the efficacy that standard treatments and metformin administration have in suppressing recurrences of the cancer. According to Dr. Narita, "Metformin only costs about ¥33,000 (about $240) even if it is administered for an entire year. We did not receive cooperation from pharmaceutical companies, so we are implementing the phase II trial with support from AMED. Good, low-cost products should be on the market worldwide, so we would like to proceed to phase III trials and link this to drug repositioning."
Cancer cells include cancer stem cells and non-stem cancer cells (so-called normal cancer cells), and, because cancer stem cells are highly resistant to radiotherapy and other treatments, the few cancer stem cells that remain even after surgery, radiotherapy, or drug administration can proliferate and cause a recurrence of cancer.
In 2011, Professor Kitanaka and researchers at Yamagata University, through experiments using mice, discovered the FOXO3A gene that is involved in the transformation of cancer stem cells into non-stem cancer cells, and the following year Professor Kitanaka discovered that metformin had the effect of activating this gene and that it had a therapeutic effect on malignant brain tumor cells. In other words, if cancer stem cells are turned into ordinary cancer cells by metformin administration, then new cancer cells will not be able to form, and radiotherapy and chemotherapy will be effective. Professor Katakana said that "Previous studies have shown that metformin, when combined with conventional glioblastoma therapies, can be expected to reduce recurrences and prolong survival."
There are more than 150 types of primary brain tumors (tumors originating from the brain), and in 2016, the Japan National Cancer Registry data showed 28,210 new brain tumors, including 7,611 malignant brain tumors. Gliomas accounted for 16% of the malignant brain tumors, about 5,000 people, and of them glioblastoma has the lowest five-year survival rate, at about 15%, and is classified as an intractable cancer with the worst prognosis (grade 4). There are also cases of glioblastoma from grade 2-3 astrocytoma. In 2016 there were 2,073 individuals in Japan with glioblastoma, and it is classified as a rare cancer, affecting 1.63 people out of every 100,000 people.
Metformin, on the other hand, is a guanidine-like compound derived from the French lilac/goat's rue plant and since 1959 has been used as a treatment for type 2 diabetes in more than 100 countries, including Japan. It is an excellent therapeutic agent because it is insulin-independent, does not cause weight gain, and does not increase the risk of hypoglycemia. Epidemiological studies have reported that metformin reduces the risk of cancer morbidity and mortality in diabetic patients, and several clinical studies are underway.
Most of the randomized trials to date have been in advanced or metastatic cancers, and, while some have reported limited efficacy, others have tended to show efficacy in non-advanced cancers. The metformin doses have also varied, with only two trials exceeding 2,000 milligrams per day, both of which suggested efficacy. For glioblastoma, one randomized controlled trial (Korea) for cases of recurrences and a single trial (Canada) for first-episode cases are in progress.
The research group is focusing on the fact that metformin specifically acts on cancer stem cells. They will use 2,250 milligrams of metformin, a dose shown in phase I trials to be safe, will administer it to patients with primary glioblastoma at a time when the tumor volume is minimal, after initial treatments of surgery + radiation + the drug temozolomide (standard treatments), and will then evaluate the recurrence rate. Specifically, metformin will be administered alone for seven days after surgery, followed by temozolomide and metformin for five to 28 days, and then one year of metformin in combination with the initial dosage.
A total of 15 clinical trials will be conducted at five institutions: the National Cancer Center Hospital, the University of Tokyo, Yamagata University, Saitama Medical University International Medical Center, and the University of Tsukuba. The current standard treatment has a progression-free survival rate of 27% at 12 months, so if the progression-free survival rate in the clinical trial exceeds 50% then the trial will be deemed promising and will move to phase III trials.
According to Dr. Narita, "There are cases of people easily taking metformin for cancer prevention, and the Japan Diabetes Society has issued a document on the subject. After showing the scientific data, we will proceed with clinical trials so that it can be used for cancer treatment under the supervision of a doctor. If good results are obtained in the randomized phase III trials, then we would like to expand its application to other types of cancer."
This article has been translated by JST with permission from The Science News Ltd.(https://sci-news.co.jp/). Unauthorized reproduction of the article and photographs is prohibited.