Antineoplastic properties of metformin in EB-associated aggressive cutaneous squamous-cell carcinoma

Patients with the rare and incurable genetic skin disease RDEB (recessive dystrophic epidermolysis bullosa) have a very high risk of developing aggressive skin cancer and dying prematurely. The results of a recent study suggest that the antidiabetic drug metformin may be effective in inhibiting both types of energy production in the malignant cells and thus influencing tumor growth.

As part of this research work, Dr. Tobias Welponer, Salzburg, was awarded the LEO Pharma Young Researcher Award ÖGDV. In a double interview, we spoke with him and his colleague Dr. Josefina Pinon Hofbauer, Salzburg, about the results, which are particularly important from a research point of view, and asked what can be derived from them for future therapeutic options.

What are the most surprising results from a research point of view?

Josefina Pinon Hofbauer: When we started the project we had several hypotheses. We hypothesized that RDEB-SCC would display altered cell energetics profiles compared to non-malignant keratinocytes and that, in particular, they would display a higher respiratory acti-vity. Following on this, we hypothesized that treatment with the mitochondrial complex I inhibitor metformin would decrease proliferation of these tumor cells. Finally, to show translational feasibility, we hypothesized that in an in vivo tumor model metformin treatment would result in an increase in overall survival. We’re happy to say that we could confirm all three hypotheses in our study.

What were the particular challenges associated with your research work? Why did you choose this topic?

Tobias Welponer: RDEB-SCC is a very rare and aggressive tumour entity for which there is currently limited information and there are no treatment options with sustainable efficacy. The main challenge was to identify novel pathways that can be exploited for anti-tumour therapy and for which translation into clinical practice is feasible in this fragile patient cohort. Therefore, the potential treatment targets would need to be addressed by a compound with good safety. In a further step the potential therapy would need to go into clinical trial stage. In view of the urgent therapeutic need we aimed for an agent that is already available to avoid the time-consuming development of new products. Repurposing of approved drugs with good safety data appeared to be the best option for our intentions.

Is there something that you already transfered into you own dermatological practice? What conclusions can be drawn about the current state of use in clinical practice? When can we expect further results that can be transfered into the individual practice?

Tobias Welponer: We are currently evaluating in preclinical models, whether metformin can be safely given to EB patients. As it slows tumour growth by inhibition of energy production in cells, a negative impact on wound healing needs to be ruled out considering chronic wounding in RDEB patients. This requires testing in preclinical models with loss of collagen 7 as observed in RDEB patients resulting in severe phenotypes. This is particularly challenging as these models are technically complex and time-consuming. After this step we can elaborate on possible fields of application in clinical practice, e.g. for prevention of SCC development in RDEB patients.

What is special about the clinical picture of epidermolysis bullosa (EB) from the point of view of patients, doctors and researchers?

Tobias Welponer: EB is a very rare skin disease with increased skin fragility, in which minor trauma can induce blister formation and wounding. Aside from generalized wounding, dressing changes and skin care ar burdensome and time-consuming. Expression of defective proteins in extracutaneous organs further aggravate the disease course. It is impressive how patients and their families deal with this significant disease burden. As researchers and doctors, we find it difficult to understand the suffering of patients, despite our close involvement. We admire how patients cope with the disease and are happy when we can help. It is always a great success for us to see our patients grow, enjoy life and manage school and work. These are achievements that are a source of great motivation and encouragement for us.

What role do fragile skin in general, proteins, cell energetics profiles and other factors play in the malignant transformation?

Josefina Pinon Hofbauer: Because of their fragile skin, RDEB patients are highly susceptible to repeated wounding. Additionally, the loss of Collagen VII, which is the affected protein in this form of EB, critically impairs normal wound healing. This results in persistent open wounds, which are characterized by ongoing inflammation and repair processes that are not only energy-intensive but also tumor-promoting. Thus, all these factors are intricately connected. It has been said that “tumors are wounds that do not heal”. This paradigm is poignantly illustrated in RDEB, where tumors develop in the areas of chronic, non-healing wounds.

What are possible links between the inhibition of both respiration and glycolysis with the tumor control?

Josefina Pinon Hofbauer: What we could nicely demonstrate in our real-time metabolic assays is that both mitochondrial respiration and glycolysis were increased in RDEB-SCC cells in culture compared to healthy non-malignant keratinocytes. They also showed a level of plasticity, meaning that they could adapt and switch between these two energy-producing pathways as needed. The implication of those observations is that you would need to inhibit both pathways simultaneously to achieve meaningful tumor control.

How does Metformin inhibits respiration and glycolysis in RDEB SCC and what are the consquences?

Josefina Pinon Hofbauer: That’s a good question and one we cannot answer yet. We don’t know the exact mechanisms by which metformin inhi-bits respiration and glycolysis in RDEB-SCC. This will require a molecular profiling of the treated cells, which we have not yet done. Right now we can only make assumptions from what is known in the literature. We know that metformin is a mitochondrial complex I inhibitor and can therefore directly inhibit mitochondrial respiration and ATP production in this way.

How important is the finding that you observed a delay in tumor onset and slower tumor growth with metformin treatment resulting in a 29% increase in overall survival?

Josefina Pinon Hofbauer: This particular tumor model is quite aggressive, which is part of the reason why we chose it. In an aggressive tumor model, where rapid progression is typical, any intervention that leads to a delay in tumor onset and reduces the rate of tumor growth can be considered a substantial finding. The 29% increase in overall survival is particularly noteworthy as it implies a potential clinical benefit and underscores the importance of exploring metformin as a part of cancer treatment strategies, especially for cancers that exhibit high metabolic activity. This could lead to improved management options for patients with such aggressive tumors, potentially enhancing both survival and quality of life.

What conclusions can be drawn from the research results with regard to pharmaceutical products and future therapy?

Tobias Welponer: Our methodological approach with a priori computational analyses of published data with the purpose to exploit already approved therapies could be used for other rare diseases to bypass time- and resource-consuming drug development. This might help directing research efforts and selecting feasible treatment options in fragile patient cohorts already at an early stage. This could speed up treatment development by repurposing drugs and might be a first step towards individualized medicine.

What research topics would you like to see more commitment to?

Tobias Welponer: Firstly, we will continue our research work on metformin. Aside from this, we want to deepen our understanding of this complex disease, as many aspects are yet unknown. One aspect are gastrointestinal symptoms and mucosal involvement of EB patients. We already know that the mucosa of the intestine is affected by mutations in this disease. However, the extent is fairly unknown as clinical investigations would be infeasible for these patients. If we could identify a potential treatment target to improve gastrointestinal symptoms, we hope to alleviate severity of the disease course.

Are there any stakeholders, companies/sponsors or other scientists we can mention in this context?

Tobias Welponer: Debra Austria is a donor-organized patient organization which, together with the Department of Dermatology and Allergology, has established the EB Center in Salzburg. This has made it possible to improve the treatment of EB patients in Austria on several EB levels.

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