Impact of research on AMP-activated protein kinase on the instigation of clinical trials testing the effect of the diabetes drug metformin on reducing cancer incidence and on the development of new therapeutics for diabetes and metabolic syndrome.
Submitting Institution
University of DundeeUnit of Assessment
Biological SciencesSummary Impact Type
TechnologicalResearch Subject Area(s)
Biological Sciences: Biochemistry and Cell Biology
Summary of the impact
In 2003, researchers at the University of Dundee identified the tumour
suppressor LKB1 as a critical upstream activator of AMP-activated protein
kinase (AMPK), which provided the first link between AMPK and cancer.
Metformin, the front-line therapy for type-2 diabetes, was already known
to exert its beneficial effects through AMPK. An interdisciplinary
collaboration at the University examined the link between metformin and
cancer, and reported in 2005 that diabetics taking metformin had a reduced
incidence of cancer. The impact has been clinical trials worldwide testing
the benefit of metformin for cancer treatment, and development of
therapeutics by pharmaceutical companies targeting this pathway.
Underpinning research
In 1987, Prof. Grahame Hardie FRS (Professor of Cellular
Signalling at the College of Life Sciences) first defined AMP-activated
protein kinase (AMPK) as a protein kinase that inactivated acetyl-CoA
carboxylase (ACC) and HMG-CoA reductase. In a series of seminal papers
published between 1988 and 1996, he elucidated the regulation of AMPK by
adenine nucleotides and phosphorylation, identified the critical
phosphorylation sites on ACC and on AMPK (still universally used as
biomarkers for AMPK activation today), developed the peptide substrate
used for its assay (still in wide use), and identified AMPK as a
heterotrimeric complex with a catalytic α subunit and regulatory 03b2 and
03b3 subunits. AMPK is now known to be a key player in regulating energy
balance at both the cellular and whole-body levels, placing it at centre
stage in studies of obesity, metabolism and diabetes (1).
In 1996, Prof. Hardie showed that another protein kinase was required to
activate AMPK by phosphorylating threonine-172 within the kinase domain on
the α subunit (2). In 2003, by mining the yeast genome, he identified
three protein kinases acting upstream of the yeast orthologue of AMPK (3).
The closest mammalian relative to these was LKB1, previously identified as
a tumour suppressor responsible for an inherited cancer syndrome
(Peutz-Jeghers syndrome). With Prof. Dario Alessi FRS (Professor
of Signal Transduction at the College of Life Sciences), Prof. Hardie made
the crucial discovery that LKB1 was the elusive upstream kinase required
to phosphorylate threonine-172 on AMPK (4). It has been subsequently found
that LKB1 is mutated in many spontaneous cancers, including 30% of
non-small cell lung cancers and 20% of cervical cancers; this may promote
tumourigenesis by removing the restraining influence the LKB1-AMPK pathway
normally has on cell growth and proliferation.
The crucial link between LKB1 and AMPK made by Hardie and Alessi
stimulated an interdisciplinary collaboration with Prof. Andrew Morris
FRSE FMedSci (Professor of Diabetic Medicine and Dean of Medicine at
the University of Dundee). The finding that LKB1 activated AMPK was
intriguing given that AMPK was known to be activated in cells by the
widely used diabetic drug, metformin. This gave rise to the hypothesis
that AMPK activation by metformin could decrease the incidence of cancer.
Professor Morris, an expert in the use of informatics to study the
epidemiological and molecular aetiological basis of diabetes and its
complications, tested this hypothesis using unique record linkage
databases developed in Tayside, Scotland: a diabetes clinical information
system (DARTS) and a database of dispensed prescriptions (MEMO). The
results of the epidemiological survey, published in the British Medical
Journal, revealed that diabetics taking metformin were 30% less likely to
develop any form of cancer than those on other medications (5). In follow
up experimental work by Prof. Alessi, metformin and other AMPK activators
were also found to delay the onset of tumourigenesis in cancer-prone mice
(6). These studies sparked huge interest worldwide both in the use of
metformin for cancer prevention and treatment, and in new drug development
programmes to find novel activators of AMPK.
References to the research
1. Hardie, D.G., Carling, D. and Carlson, M. (1998) The
AMP-activated/SNF1 protein kinase subfamily: metabolic sensors of the
eukaryotic cell? Ann. Rev. Biochem. 67, 821-855 (doi:
10.1146/annurev.biochem.67.1.821) (Citations 956, Scopus Nov 2013)
2. Hawley, S.A., Davison, M., Woods, A., Davies, S.P. Beri, R.K.,
Carling, D. and Hardie, D.G. (1996) Characterization of the
AMP-activated protein kinase kinase from rat liver, and identification of
threonine-172 as the major site at which it phosphorylates and actvates
AMP-activated protein kinase. J. Biol. Chem. 271, 27879-27887.
(doi:10.1074/jbc.271.44.27879) (Citations 504, Scopus Nov 2013)
3. Sutherland, C.M., Hawley, S.A., McCartney, R.R., Leech, A., Stark,
M.J., Schmidt, M.C. and Hardie, D.G. (2003) Elm1p is one of three
upstream kinases for the Saccharomyces cerevisiae SNF1 complex. Curr.
Biol. 13, 1299-1305. (doi:10.1016/S0960-9822(03)00459-7)
(Citations 146, Scopus Nov 2013)
4. Hawley, S.A., Boudeau, J., Reid, J.L., Mustard, K.J., Udd, L., Makela,
T.P. Alessi, D.R., and Hardie, D.G. (2003) Complexes
between the LKB1 tumour suppressor, STRADα/03b2 and MO25α/03b2 are
upstream kinases in the AMP-activated protein kinase cascade. J. Biol. 2,
28. (doi:10.1186/1475-4924-2-28) (Citations 792, Scopus Nov 2013).
5. Evans, J.M., Donnelly, L.A., Emslie-Smith, A.M., Alessi, D.R.
and Morris, A.D. (2005) Metformin and reduced risk of cancer in
diabetic patients. BMJ. 330, 1304-1305.
(doi:10.1136/bmj.38415.708634.F7) (Citations 577, Scopus Nov 2013).
6. Huang, X., Wullschleger, S., Shpiro, N., McGuire, V.A., Sakamoto, K.,
Woods, Y.L., McBurnie, W., Fleming, S. and Alessi. D.R. (2008)
Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in
PTEN-deficient mice. Biochem. J. 412, 211-221.
(doi:10.1042/BJ20080557) (Citations 142, Scopus Nov 2013).
Details of the impact
Beneficiaries (the benefit/impact):
(a) Pharmaceutical companies (the identification of AMPK agonists as cancer
prophylactic and potential therapeutic agents, as well as for diabetes)
(b) Diabetes patients (patients in Phase II clinical trials who have
benefited from Imeglimin
TM)
(c) Cancer patients (patients in Phase II clinical trials who have benefited
from metformin or other AMPK agonists in their therapy)
Impacts:
Drug Development campaigns by Pharma for novel AMPK activators
Research by the University of Dundee not only identified the components
and regulation of the AMPK signalling cascade, but also defined AMPK as a
key energy sensor with a central role in metabolism, diabetes and, more
recently, cancer. The impact of AMPK research at Dundee can be evidenced
by the publishing of 57 patents from 22 different organisations,
describing small molecule activators of AMPK. This, in turn, has led to
the initiation of several major drug discovery campaigns and clinical
trials, including:
Poxel, a spin-off from Merck-Serono in 2009, has developed
both a new indirect activator of AMPK called ImegliminTM, as
well as a direct activator of AMPK that is in pre-clinical development
(1). ImegliminTM is currently undergoing Phase II clinical
trials to test the benefit of additive effects of ImegliminTM
with metformin. In 2012, Phase IIa clinical trials showed that ImegliminTM
displays a superior benefit : risk profile compared with metformin in type
2 diabetes patients (2), and Phase II results recently released by Poxel
suggest that ImegliminTM showed increasing effectiveness as an
add-on therapy to Sitagliptin in patients inadequately controlled by
Sitagliptin monotherapy.
Mercury Pharmaceuticals Inc has developed new compounds to
activate AMPK for the treatment of prostate cancer (3). The company is
evaluating these compounds in an established animal model of human
prostate cancer and initial results are very promising. In addition to
prostate cancer, genetic markers in 30%-50% of non-small cell lung
carcinomas, 40% of colon cancers and over 50% of malignant melanomas
suggest that AMPK activators developed by Mercury Pharmaceuticals Inc will
have efficacy in these indications. In 2010, the company signed an
exclusive agreement with Debiopharm Group for the development and
commercialisation of a small molecule activator of AMPK (Debio 0930) for
treatment of type 2 diabetes (4).
Betagenon, performed a drug discovery programme to develop
novel direct AMPK agonists (5). In 2008, the pharmaceutical company
Antisoma announced that they had licensed rights to develop and
commercialise Betagenon's AMPK activators in cancer indications.
Clinical trials of metformin for cancer treatment and prophylaxis
The identification by the Dundee team that the tumour suppressor LKB1 is
the upstream kinase that activates AMPK, together with the finding that
metformin decreases cancer incidence in diabetic patients, has had a major
impact on the cancer field, especially as metformin is orally available,
has no long-term safety issues and is available as a generic drug. This
has driven 52 case-controlled clinical trials worldwide (many between
2008-2013) with an enrollment of over 7,000 people in 10 different
countries. As an example, these trials include one started in 2010 as the
first large-scale international clinical trial testing the effects of
metformin administered for 5 years on both recurrence and survival in
early-stage breast cancer (6). These kinds of trials will establish
whether the stratification of patients with AMPK-inactivation in their
cancers will benefit from AMPK-activating drugs and also assess whether
existing chemotherapy and radiotherapy regimens may be enhanced by
combining them with treatments that modulate AMPK. Thus far, two pilot
studies, in 2011 and 2012, have demonstrated a positive effect of
metformin in women with newly diagnosed breast cancer awaiting surgery
(7-8): short-term preoperative metformin was well-tolerated and resulted
in clinical, biomarker and cellular changes consistent with beneficial
anti-cancer effects.
As of 2013, there are 13 Phase I, 37 Phase II and 2 Phase III trials
underway examining the effect of metformin in a variety of cancers such as
pancreatic, prostate, colorectal, and breast cancer (see http://clinicaltrials.gov/)
and as of October 2013, metformin appears promising as a preventive agent
for ovarian and hepatic cancers. Whilst anecdotal, Lewis Cantley, Director
of the Beth Isreal Cancer Center, Harvard Medical School, said of the
drug: "Metformin may have already saved more people from cancer deaths
than any drug in history".
Sources to corroborate the impact
- Further information can be found on the Poxel website http://www.poxel.com/pipeline
- Pirags V., Lebovitz H. and Fouqueray P. (2012). Imeglimin, a novel
glimin oral antidiabetic, exhibits a good efficacy and safety profile in
type 2 diabetic patients. Diabetes Obes Metab. 14, 852-858 (doi:
10.1111/j.1463-1326.2012.01611.x).
- Further information can be found on the Mercury Pharmaceuticals Inc
website
http://www.mtipharm.com/
- Details of the Debiopharm — Mercury agreement, and the Debio 0930
compound can be found at http://www.mtipharm.com/news/pr20090408.htm.
- Further information can be found on the Betagenon website http://www.betagenon.com/
- A Phase III Randomized Trial of Metformin Versus Placebo on Recurrence
and Survival in Early Stage Breast Cancer Principal Investigator: 2028Dr
Pamela J. Goodwin, Mount Sinai Hospital, New York. ClinicalTrials.gov
Identifier: NCT01101438
http://clinicaltrials.gov/ct2/show/NCT01101438
- Niraula, S., Dowling, R.J., Ennis, M., Chang, M.C., Done, S.J., Hood,
N., Escallon, J., Leong, W.L., MCready, D.R., Reedijk, M., Stambolic,
V., and Goodwin, P.J. (2012) Metformin in early breast cancer: a
prospective window of opportunity neoadjuvant study. Breast. Cancer.
Res. Treat. 135, 821-830. (doi: 10.1007/s10549-012-2223-1)
- Hadad, S., Iwamoto, T., Jordan, L., Purdie, C., Bray, S., Baker, L.,
Jellema, G., Deharo, S., Hardie, D.G., Pusztai, L., Moulder-Thompson,
S., Dewar, J.A., and Thompson, A.M. (2011) Evidence for biological
effects of metformin in operable breast cancer: a pre-operative,
window-of-opportunity, randomized trial. Breast. Cancer. Res. Treat. 128,
783-794 (doi: 10.1007/s10549-011-1612-1)