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ADVANCES IN DRUG DEVELOPMENTC u r r e n t D e v e l o p m e n t s i n O n c o l o g y D r u g R e s e a r c h Michael Pollak, MD
Alexander Goldfarb Research Chair and Professor
Department of Oncology
Department of Medicine
McGill University
Montreal, Canada
H&O Please provide an overview of metformin.
studies of diabetic patients with cancer. A number of What is known about its mechanism(s) of action? observational studies reported decreased cancer incidence and cancer-related mortality in patients with diabetes MP Metformin is an oral biguanide commonly used in
who were receiving standard doses of metformin (1500 to the management of type 2 diabetes mellitus. Guanidine 2250 mg/day in adults). In 2005, a report in the BMJ by is a natural substance found in certain plants, and bigu- Evans and colleagues demonstrated a reduced risk of sub- anides are based on this chemical structure. Although the sequent cancer diagnosis in diabetics who were receiving precise mechanism of metformin’s antineoplastic activity metformin vs those patients not receiving the drug; the is not well defined, it has been proposed to involve activa- protective effect increased with greater metformin expo- tion of the liver kinase-B1 (LKB1) and AMP-activated sure. Other studies involving multiple forms of cancer protein kinase (AMPK) pathway. Metformin inhibits have reported reduced cancer risk in diabetics receiving mitochondrial respiratory chain complex I, which leads treatment with metformin vs no metformin treatment, as to decreased intracellular ATP and an increase in the ratio well as lower cancer-related mortality in patients receiving of intracellular AMP to ATP. Owing to this change in the metformin compared with those receiving other standard energy status of the cell, the LKB1/AMPK pathway is diabetic therapies. However, in other studies of diabetic activated, in turn phosphorylating TSC2, which results cancer patients, metformin use was not associated with in inhibition of mTORC1 signaling and downregula- benefit. Thus, the need for additional clinical research is tion of energy-consuming processes in an attempt to crucial in order to fully appreciate the impact of metfor- maintain cellular energy homeostasis. Through its activity min on cancer recurrence and survival.
on hepatocytes, metformin may indirectly inhibit tumor cell proliferation. This results in decreased hepatic glu- H&O What are areas of concern regarding
cose secretion and ultimately decreased serum insulin, a retrospective studies of diabetic patients treated known mitogen for a subset of cancer cells. H&O What led to the current interest in the
MP Dozens of retrospective studies claim to show that
use of metformin for cancer prevention and diabetic patients who receive metformin have a lower risk of cancer or better cancer prognosis than patients with diabetes who do not receive metformin. These studies, MP The potential for application of metformin in oncol-
however, are controversial and lacking in definitive proof. ogy was first recognized in retrospective epidemiologic Rather, they are best regarded as hypothesis-generating 594 Clinical Advances in Hematology & Oncology Volume 11, Issue 9 September 2013 studies. In a critique published in 2013 in Diabetes Care, or carefully controlled. It is essential that ongoing and Suissa and associates highlighted important methodologic future studies include strong embedded correlative concerns with many of these studies, namely time-related research components, with evaluation of host and tumor factors to identify potential predictors of metformin benefit and, more importantly, to allow for an enhanced H&O What have laboratory models
understanding of the relative contributions of indirect insulin-mediated and direct insulin-dependent metfor- min action. The absence of pharmaceutical industry MP Laboratory models were undertaken to follow up on
interest in metformin has led to less coordination of the pharmacoepidemiologic clues of metformin. Perhaps research activities than what is commonly seen in anti- surprisingly to some observers, these models have consis- cancer drug development. Consequently, it is essential tently demonstrated metformin’s antineoplastic activity. for the research community to ensure that this function However, the overarching issue with these models is that is fulfilled and that a major focus on clinical translation many use concentrations of metformin that are consider- and relevance emerges in future research.
ably higher than those used in diabetes treatment. H&O What do you think the future holds?
H&O Why else should these clues be interpreted
MP The clues regarding metformin and other bigu-
anides are tantalizing, but some of the ongoing trials are MP There are very exciting clues from laboratory studies
based on incomplete data regarding dosing, therapeutic and population studies that metformin may improve can- combinations, and predictors of efficacy. Almost all clin- cer outcomes or lower cancer risk. However, it is crucial ical trials are testing conventional doses used in patients to conduct more laboratory and clinical studies in order to with diabetes, which may not be optimal for applica- find the optimal dose, to understand in what disease situ- tions in oncology. The first generation of clinical trials ations the drug may be most beneficial, and to determine may be followed by a second generation of trials that if metformin itself or a metformin derivative would be consider these issues. Trials of novel biguanides also may be expected in the future, if the private sector invests in drug development in the area. Currently, there are a H&O How can future clinical trials of metformin
number of clinical trials evaluating the use of metformin as a cancer therapy, including studies in prostate, breast, colorectal, endometrial, and pancreatic cancer. Together MP Clearly, further studies are necessary to clarify the
with new pathophysiologic investigations, these studies role of this agent in cancer prevention and therapy. should help to further elucidate the role of metformin as Moving forward, research should aim to identify key patient and tumor factors that govern metformin sensi- tivity, which is critical for the design of clinical trials and Suggested Readings
the identification of patients best suited for metformin treatment. Given that metformin has a favorable toxicity Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ. 2005;330(7503):1304-1305. profile, is relatively inexpensive, and has shown antipro- Goodwin PJ, Stambolic V, Lemieux J, et al. Evaluation of metformin in early liferative activity both in vitro and in vivo in preclinical breast cancer: a modification of the traditional paradigm for clinical testing of studies, researchers should be encouraged to carry out anti-cancer agents. Breast Cancer Res Treat. 2011;126(1):215-220.
additional clinical trials on this agent. Unlike newly Pollak MN. Investigating metformin for cancer prevention and treatment: the end synthesized drug candidates, the use of metformin is of the beginning. Cancer Discov. 2012;2(9):778-790. not controlled by a pharmaceutical company with intel- Pollak MN. The insulin and insulin-like growth factor receptor family in neoplasia: lectual property rights. This is one of the reasons why an update. Nat Rev Cancer. 2012;12(3):159-169.
there are more than 100 trials of metformin ongoing in Suissa S, Azoulay L. Response to Yang and Chan. Metformin and the risk of cancer: time-related biases in observational studies. Diabetes Care. 2012;35:2665- oncology. However, not all of these are well designed 2673. Diabetes Care. 2013;36(6):e88.
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Source: http://www.hematologyandoncology.net/files/2013/09/ho0913_dd1.pdf