Radiation can be life-saving for a child with a brain tumor. But this therapy can also cause damage to the brain that leaves the child with deficits in cognitive function, including learning and memory challenges.
Now, thanks to funding from Medicine by Design, a University of Toronto scientist and her team are closer to finding a way to protect the brain from damage for children who must be treated with cranial radiation.
“We found that if we gave metformin, which is an approved, safe drug used to treat diabetes, as a pre-treatment in animal models, we could actually stop the damage from happening,” says Cindi Morshead, a professor and chair of the Division of Anatomy in the Department of Surgery at U of T.
This study, published today in Cell Reports Medicine, builds on previous work done with metformin. Last summer, Morshead and researchers from The Hospital for Sick Children (SickKids) showed that metformin administered after cranial radiation encouraged neurogenesis, or the process of making new neurons in the brain.
Morshead says that given the safety of metformin, this new research will hopefully proceed quickly to clinical trials. “Anything we can do to stop children from having these long-term impairments would be very positive.
For children with brain tumors who need cranial radiation, to be able to do something that would ensure their brain is damaged less in the first place, rather than try to repair it after the fact, would be life-changing for these children and their families.”
Notably, the previous metformin study, which looked at administering the metformin after the cranial radiation and once the damage had already occurred, found that the benefits of metformin were seen only in juvenile females. Morshead says that today’s study showed no sex-specific effect, which indicates that pre-treating children with Metformin could provide additional benefit.
Cognitive deficits from radiation can result from killing newborn neurons that underly learning and memory. Morshead says this study shows that metformin offers neuroprotection to animals who were given the drug prior to the cranial radiation.
“Radiation is an insult on the brain, and our study showed that we’re able to protect the micro environment because the metformin decreases brain inflammation. After the drug treatment, newborn neurons were not lost and could keep making new connections in the part of the brain that is important for olfactory memory.”
Morshead, whose lab is located at the Donnelly Center for Cellular and Biomolecular Research, says that, for this project, the researchers taught animals where to find a food reward based on a particular smell. One type of scent belonged to a dish that had a hidden treat, and another type of smell belonged to a dish that had no hidden treat. Only mice that had the metformin treatment before radiation could remember which scent was associated with the treat.
“It was really quite a striking effect. The ones that were not administered the metformin prior to radiation couldn’t remember the association,” Morshead says. “The ones that were given the metformin remembered the association weeks after the radiation. So we concluded that the mice that were not treated with the metformin had an impairment in long-term memory, and metformin protected against this impairment.”
This study is part of a large team project funded by Medicine by Design, led by Freda Miller, an adjunct scientist in the Neurosciences & Mental Health program at SickKids and a professor at the Department of Molecular Genetics, U of T. Miller’s research team, which includes eight labs at U of T and SickKids, is taking a wide-ranging approach to promoting self-repair in the brain and muscle. Miller and her colleagues at SickKids made the discovery that metformin had potential to be used for self-repair in the brain. Morshead’s metformin research builds on this original finding.
“I am excited by this paper since it describes a potential protective therapy for children who need cranial radiation,” says Miller, who is also a professor at the University of British Columbia. “And, just as importantly, the metformin story provides a classic example of why we need to support basic research, and why working in collaborative teams is essential.
The original finding that metformin recruits endogenous brain stem cells came from fundamental studies on how stem cells build the brain developmentally, and then it was moved forward to other models by highly interdisciplinary scientists like Dr. Morshead.”
Morshead credits funders including Medicine by Design for being strong supporters of this and other promising metformin work. “My lab—as well as the labs of Freda Miller and Don Mabbott at SickKids and others—are grateful to have the opportunity to do this research.
Being able to show these positive results using a drug that we know is safe, approved and accessible is really the best-case scenario. Our hope is that this is one day a low-risk solution for children who would otherwise be living with cognitive deficits after surviving a brain tumor.”
In addition to her work with Miller on this large team project, Morshead also leads another Medicine by Design project that’s focused on enhancing neuroplasticity in the brain, regenerating cells that are lost or damaged by a stroke.
Gliomas are the most common primary neoplasms of the central nervous system (CNS) and they constitute approximately 30–40% of these types of cancers [1,2]. In the case of malignant tumors, this percentage is even higher and amounts to as much as 80% [2,3]. Gliomas are derived from glial cells or glial precursor cells [
4]. For their proper description, the WHO (World Health Organization) created the Classification of Tumors of the Central Nervous System, dividing them into four groups in terms of malignancy [5,6]. High-grade gliomas (WHO grade III and IV gliomas) account for the vast majority of all primary tumors of the CNS. The most common and aggressive form of glioma is glioblastoma multiforme (GBM, WHO grade IV glioma). It is estimated that it constitutes 15% of diagnoses . Despite surgery, radiotherapy, and temozolomide chemotherapy (the main treatments for gliomas), the mean overall survival is about 14.6 months [8,9,10].
Metformin (MET), 1,1-dimethylbiguanide hydrochloride, is a biguanide drug that is used as the first-line medication in the treatment of type 2 diabetes. It suppresses gluconeogenesis in the liver, sensitizes peripheral cells to insulin, increases glucose uptake, inhibits mitochondrial respiration, and reduces glucose absorption by the gastrointestinal tract.
The last of these functions is responsible for the majority of side effects [11,12,13,14]. Metformin is a safe drug; it has had a long history of use and is used by millions of patients on a daily basis. Research suggests that metformin is not only a relatively safe drug in the non-diabetic patients’ group, but may also be associated with positive effects on the body such as weight loss or reduced cardiovascular risk [15,16,17].
Moreover, its regular use contributes to a decrease in the likelihood of stroke in patients with type 2 diabetes. It has also been proved to reduce mortality associated with cardiovascular disease [18,19]. The most dangerous complication of metformin is lactic acidosis; however, it rarely occurs in patients [20,21,22]. What is more, the majority of patients in whom it had developed had a history of independent risk factors for this condition .
However, no studies have yet been conducted to determine the exact risk of lactic and keto acidosis following the administration of the drug in a patient population with normal carbohydrate metabolism. Ongoing observations of the effect of metformin on non-diabetic individuals are presently at the recruitment stage (NCT03772964).
Currently, metformin is one of the most common oral anti-diabetic drugs registered for clinical use. It is widely used due to its relative safety, anti-hyperglycaemic activity, and bodyweight reduction influence . Recently, its potential influence on the pathogenesis of tumors has also been observed [25,26,27].
The use of metformin has been associated with better overall and progression-free survival of patients with high-grade glioma . Repurposing metformin as cancer treatment is already being tested in a range of clinical trials for a variety of cancers. The aim of the present study is to present a review of the literature on metformin as a potential treatment drug in high-grade gliomas (Table 1).
Table 1 – Currently registered clinical trials considering the use of metformin in glioma and cerebral tumors treatment.
|No.||Trial||Start Date||Estimate Completiton Date||Country||n||Title|
|1||NCT01430351||September 2011||September 2022||USA||144||Temozolomide, Memantine Hydrochloride, Mefloquine, and Metformin Hydrochloride in Treating Patients With Glioblastoma Multiforme After Radiation Therapy|
|2||NCT02496741||November 2015||December 2016||Netherland||20||Metformin And Chloroquine in IDH1/2-mutated Solid Tumors|
|3||NCT02040376||March 2014||December 2017||Canada||24||Placebo Controlled Double Blind Crossover Trial of Metformin for Brain Repair in Children With Cranial-Spinal Radiation for Medulloblastoma|
|4||NCT02149459||June 2014||July 2018||Israel||18||Treatment of Recurrent Brain Tumors: Metabolic Manipulation Combined With Radiotherapy (SMC 0712-13)|
|5||NCT02780024||March 2015||December 2020||Canada||50||Metformin, Neo-adjuvant Temozolomide and Hypo- Accelerated Radiotherapy Followed by Adjuvant TMZ in Patients With GBM|
|6||NCT03243851||November 2016||December 2019||Korea||108||Study on Low Dose Temozolomide Plus Metformin or Placebo in Patient With Recurrent or Refractory Glioblastoma (METT)|
|7||NCT03151772||January 2018||March 2021||Sweden||40||Bioavailability of Disulfiram and Metformin in Glioblastomas|
The Effect of Metformin on the Course of Cancer
Carbohydrate disorders pose a particularly serious issue in modern medicine. According to forecasts, by 2030, 439 million adults worldwide will have struggled with the problem of diabetes . These disorders also affect the occurrence of tumors. Chaichana et al., examined 182 patients with low-grade gliomas (WHO grade II) for the effect of persistent hyperglycaemia on treatment outcomes.
They have shown that it results in a decrease in patient survival and the increase in the frequency of relapses [29,30]. Similar results have been observed with high-grade gliomas as well as in studies conducted precisely on patients with GBM [30,31,32].
Type 2 diabetes, as well as obesity, has been identified as an independent factor of poor prognosis in patients with high-grade gliomas . This was also confirmed by studies carried out by Welch et al. They showed that, among patients suffering from GBM, the prognosis is worse in the presence of diabetes .
This indicates the possible potential role of drugs that lower blood glucose in glioma therapy. It is worth noting that anti-cancer treatment itself can affect carbohydrate metabolism. Steroids, including dexamethasone, are the primary medicines for preventing brain edema due to the presence of a tumor. One side effect of their use is hyperglycemia. In their observations of patients with newly diagnosed GBM, Derr et al., also confirmed the negative impact of high glucose values on patients’ prognosis.
At the same time, they drew attention to the fact that proper control of the doses of steroids taken makes it possible to limit the severity of hiperglycemia, thus contributing to the improvement of the clinical outcomes of patients . This shows how important it is to know exactly the pathomechanism of the cancer process as it allows physicians to effectively plan oncological treatment.
As mentioned before, metformin is among the drugs that lower blood glucose. The potential effect of the activity of metformin has been described in the pathogenesis of many cancers. Inhibition of tumor cells growth after metformin administration was observed, among others, in colon, breast, prostate, pancreatic cancer, leukemia, melanoma, lung, and endometrial carcinoma [6,35,36,37,38,39,40,41,42,43,44,45,46,47].
This effect was visible in both in vitro and in vivo experiments. Similar observations have been made for gliomas [48,49]. This applies to the inhibition of tumor cell proliferation as well as the inhibition of their differentiation and invasiveness [35,39,50,51,52,53,54,55]. It can also lead to the death of GBM cells as the result of apoptosis or autophagy [35,39,51]. The use of metformin may also increase the effectiveness of standard glioma therapies [50,51,56].
In studies conducted by Adeberg et al., on a cohort of 276 patients with primary GBM, longer progression-free survival was demonstrated in diabetic patients treated with metformin . This observation included only patients with GBM. Studies by Seliger et al., concerned 1093 patients with high-grade gliomas (also WHO III). Additionally, in this case, improved overall and progression-free survival in patients treated with metformin has been shown.
Interestingly, this relationship was only relevant to grade III gliomas. For grade IV, no relationship was found between metformin intake and the patients’ life expectancy . Similar results were obtained from another analysis also carried out by Seliger et al., In this case, they studied the effect of metformin use on 1731 patients with GBM.
Similarly, no significant relationship between the use of the drug as monotherapy and overall survival and progression-free survival has been demonstrated . The discrepancy of data from various experiments indicates the need for further observation on this issue.
Some researchers also indicate the potential for also using metformin in cancer prevention [59,60,61,62]. It has been noticed that, in patients with diabetes on long-term treatment with this drug, the chance of developing neoplasm is lower compared to the controls . However, the analysis by Seliger et al., showed no significant correlation between the occurrence of the disease and the earlier use of metformin in patients with gliomas . However, confirming this issue requires further research.
Metformin has a number of physicochemical characteristics that would promote its use in the treatment of brain tumors if its effectiveness were confirmed. The drug particles are characterized by their small size and amphoteric character, thus determining their hydrophilicity and high solubility in water. However, it also has a non-polar hydrocarbon chain, giving it its lipophilic properties. This makes it possible for metformin to bind to the lipid domains of cell membranes .
The ability of the drug to cross the blood-brain barrier has been demonstrated in studies conducted by Łabuzek et al., on a rat model. The authors checked how the oral administration of metformin changes its concentration in various regions of the brain, such as the frontal cortex, the olfactory bulb, the hypothalamus, the striatum, the pituitary gland, and the cerebellum.
They showed a high ability of metformin to cross the blood-brain barrier and redistribution in the central nervous system . Convergent results were also noted in observations of other authors [66,67,68]. This is an important property in the case of high-grade glioma because, due to its location, effective action within them requires overcoming the barrier, which is not achieved by many other drugs.
The widespread use of it in the world is also of great importance. Thanks to this, it has already been thoroughly tested for side effects and potential interactions with other drugs. This can potentially significantly reduce the time needed for the official implementation of metformin in standard patient
Metformin: Antineoplastic Mechanism
To this day, the complete mechanism of action of metformin on cancer cells has not been known. As mentioned earlier, it causes the inhibition of tumor cell proliferation and a decrease in the rate of cancer development, but the exact path leading to this effect is still a mystery . One of the reasons for this is the multidirectional signaling pathways stimulated by the presence of drug particles. Metformin can act both through adenosine monophosphate kinase protein (AMPK: dependent mechanism) and without AMPK (AMPK-independent) (Figure 1) [11,13].
. . . . . . .
At present, two main points of drug anti-tumor activity are indicated:
acting on mitochondria through oxidative stress, and
acting by regulating AMPK pathway activity [86,87].
More information: Daniel Derkach et al. Metformin pretreatment rescues olfactory memory associated with subependymal zone neurogenesis in a juvenile model of cranial irradiation, Cell Reports Medicine (2021). DOI: 10.1016/j.xcrm.2021.100231