the dstt, a model for collaboration between academia and
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The DSTT, a model for collaboration between
academia and industry
Philip Cohen
MRC Protein Phosphorylation and Ubiquitylation Unit,
University of Dundee, Scotland
The attachment and removal of phosphate from proteins
is a simple mechanism for altering their function
protein kinase
proteinphospho-
protein
(modified
function)
protein
phosphatase
P
• Since the first kinase inhibitor (Gleevec) was approved for CML in
2001, 29 other kinase inhibitors, have been approved for clinical use,
nearly all in the field of cancer
• Kinases account for 50-70% of all the cancer drug discovery
programmes in the pharmaceutical industry.
• The global market for kinase therapies was $29 billion per annum in
2011 and is expected to reach $45 billion per annum by 2016
• Over 150 other drugs targeting kinases are undergoing clinical trials
of which about 25 are in Phase III
• Kinase inhibitors are being developed for the treatment of other
diseases. e.g. Tofacitinib approved in 2012 for the treatment of
rheumatoid arthritis.
Clinically approved protein kinase inhibitors
The DSTT, a model collaboration between
academia and industry
History of the Division of Signal
Transduction Therapy (DSTT)
• Started in July 1998 as a collaboration in the
field of “mammalian kinases and phosphatases”
with Astra, NovoNordisk, Pfizer,
SmithKlineBeecham and Zeneca, who were
joined by Boehringer Ingelheim in 2001
• Renewed for a further five years in July 2003 at
a greatly expanded level with AstraZeneca,
Boehringer Ingelheim, GlaxoSmithKline, Merck
& Co, Merck KGaA and Pfizer
The Financial Times – 18 March 2003
History of the Division of Signal
Transduction Therapy (DSTT)
• Renewed for a further four years from July 2008 with
AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline,
Merck-Serono and Pfizer
• Renewed for a further four years from July 2012 with the
same five companies plus Janssen Pharmaceutica. Field
changed from “kinases and phosphatases” to “kinases
and the ubiquitin system.”
• Europe’s largest and longest running collaboration
between academia and the pharmaceutical industry
How can so many companies
collaborate under a single agreement?
• The companies supporting the DSTT share all
the unpublished research, reagents, technology
and know-how generated by the participating
Dundee laboratories and have the first right to
licence the intellectual property that is generated
• In contrast, information obtained using a
compound or technology that a company has
introduced into the DSTT is not shared, and only
sent to that one company
How is DSTT support used?
75% of the funding is used for fundamental
research on “mammalian kinases and
phosphatases” (1998-2012) or “kinases and
the ubiquitin system” (2012-2016)
The projects chosen and driven by the
academic researchers in areas of relevance
to human disease in consultation with the
pharmaceutical partners
How is DSTT support used?
25% of the funding is used to support a service
facility, of which the major components are a DNA
cloning team, a protein production and assay
development team, an antibody production team
and a kinase profiling service.
The service facility cloned, expressed and purified
gram quantities of the B-Raf[V600E] mutant,
which was used by GSK for the high-throughput
screens that identified the compound that led to the
development of Dabrafenib for the treatment of
malignant melanoma.
Reagents delivered by the DSTT to the
participating companies 1998-2015
• The DSTT has delivered the huge amounts of kinases needed to launch new drug discovery programmes on 267 occasions
• The DSTT has also delivered pilot amounts of kinases, phosphatases and ubiquitin system components (sufficient for up to 5000 measurements) on 2135 occasions
• 1104 antibodies and 1173 DNA constructs have been delivered to the companies
Unexpected commercial benefits of the DSTT
• The DSTT set up the world’s first protein kinase profiling service in
1998 to enable the collaborating pharmaceutical companies to assess
the specificities of the kinase inhibitors they were generating. A
similar lipid kinase profiling service was developed subsequently
• Led to the creation of the European Division of Upstate Inc in
Dundee which commercialized kinase profiling. Upstate Dundee
employed 125 people in 2004 when it was sold to Serologicals.The
MRC-PPU and College of Life sciences at Dundee received £10
million in royalties from Upstate/Serologicals
• Protein kinase profiling has been commercialized by many
companies and become a $US200 million per annum industry
• The DSTT has more recently set up analogous profiling services for
xomponents of the ubiquitin system, such as E2 conjugating
enzymes and deubiquitylases.
Why has the collaboration continued for so long?
• The MRC-PPU and College of Life Sciences at Dundee, is the world’s largest
centre for the study of protein phosphorylation and ubiquitylation; Over 20
Programme Leaders and 200 scientific and support staff
• The companies can therefore obtain much of what they need in this area from a
single research centre
• The DSTT is considered to be good value for money. By contributing 6
positions, each company obtains the output of 200 scientific and support staff.
The reagents and services provided by the DSTT would be far more expensive to
purchase from commercial sources and many are not available commercially
• The DSTT works to industrial standards, nearly always deliver what they say
they can and on time, and the Dundee scientists have proved they can maintain
confidentiality
• Trust is created in a long collaboration, which increases its value to both parties
• The participating labs wish it to continue since it has greatly benefitted their
research (over Euro100 million of research funding so far). Proprietary
compounds from the companies have advanced our research projects. Our
students and postdocs have learned how the pharmaceutical industry works
The DSTT model should be widely applicable
The key ingredients needed to make it work are a critical
mass of leading researchers operating under a single
agreement in an area of interest to industry
How could pharmaceutical companies enhance
the value of the collaboration?
• The pharmaceutical companies need to ensure that the person they
appoint to coordinate the collaboration is of sufficient seniority to
see an important opportunity when it arises, and ensure that the
new information is relayed to the appropriate scientist(s) in every
division of the company worldwide.
• The companies need to send more scientists to the academic labs to
make sure that opportunities are not being lost, and especially to
senior scientists who are able to take decisions quickly. In recent
years some companies have cut travel budgets drastically, which has
resulted in fewer staff coming to the acdemic labs which has
resulted in lost opportunities.
How could pharmaceutical companies enhance
the value of the collaboration?
• The companies should invite the Principal Investigators to visit their
research Divisions more frequently and take advantage of the free
consultancies that are offered as part of the collaboration.
• The companies should act on the advice of their Academic
collaborators when the latter have, for example, cast iron evidence
that the information on which a drug discovery programme is based
is seriously flawed. The pharmaceutical companies have admitted
on a number of occasions that they have lost a lot of time and money
by not acting for years on such advice.
MRC-PPU
MRC-PPU
The College of Life Sciences at the University of Dundee
DRUG KINASE TARGETS COMPANY APPROVED FOR CLINICAL USE
Imatinib
(Gleevec)
Bcr-Abl, c-Kit receptor, PDGFR Novartis 2001 chronic myelogenous leukaemia
Gefitinib EGFR AstraZeneca 2005 lung cancer
Erlotinib ErbB1 Genentech/Roche 2005 lung, pancreatic and other cancers
Sorafenib Multiple tyrosine kinases targeted Onyx/Bayer 2005 renal cancer
Dasatinib Multiple tyrosine kinases targeted BristolMyersSquibb 2006 chronic myeloenous leukaemia,
acute lymphoblastic leukaemia
Sunitinib Multiple tyrosine kinases targeted SUGEN/Pfizer 2006 renal cancer and GIST
Nilotinib Bcr-Abl Novartis 2007 chronic myelogenous leukaemia
Lapatinib Her2/EGFR GlaxoSmithKline 2007 HER2-positive breast cancer
Temsirolimus mTOR Wyeth/Pfizer 2007 advanced renal cell carcinoma
Everolimus mTOR Novartis 2009 several cancers
Pazopanib VEGFR2/PDGFR/c-kit GlaxoSmithKline 2009 renal cancer
Toceranib Multiple Tyrosine kinases targeted Pfizer 2009 canine mastocytoma
Masivet/Kinav
et
cKIT/PDGFR AB Science 2010 canine mastocytoma
Ruxolitinib JAKs Incyte 2011 myelofibrosis
Crizotinib ALK/Met Pfizer 2011 NSCLC with Alk mutation
Vemurafenib BRAF Roche 2011 melanoma
Vandetanib Multiple tyrosine kinases targeted IPR Pharms 2011 medullary thyroid cancer
Axitinib VEGFR1/VEGFR2/VEGFR3/PDGFRB/c-
KIT
Pfizer 2012 renal cell carcinoma
Bosutinib BcrAbi/SRC Pfizer 2012 chronic myelogenous leukaemia
Tofacitinib JAKs Pfizer 2012 rheumatoid arthritis
Regorafenib VEGFR2, TIE2 and other PTKs Bayer 2012 colorectal cancer, GIST
Cabozantinib VEGFR2, RET, MET Exelixis Inc 2012 medullary thyroid cancer
Ponatinib Src and Abl Ariad Pharma 2012 CML and ALL
Lenvatinib VEGFR2/VEGFR2 Eisai 2013 thyroid cancer
Trametinib MEK1/2 GlaxoSmithKline 2013 skin cancer
Dabrafenib BRaf GlaxoSmithKline 2013 skin cancer
Afatinib Her2/EGFR Boehringer Ingelheim 2013 NSCLC
Ibrutinib BTK Pharmacyclics, J&J 2013 mantle cell lymphoma and CLL
The kinase inhibitors that have been approved for clinical use
Will kinase inhibitors have an impact on
other global diseases, such as chronic
inflammatory and autoimmune diseases?
DRUG KINASE TARGETS COMPANY APPROVED FOR CLINICAL USE
Imatinib
(Gleevec)
Bcr-Abl, c-Kit receptor, PDGFR Novartis 2001 chronic myelogenous leukaemia
Gefitinib EGFR AstraZeneca 2005 lung cancer
Erlotinib ErbB1 Genentech/Roche 2005 lung, pancreatic and other cancers
Sorafenib Multiple tyrosine kinases targeted Onyx/Bayer 2005 renal cancer
Dasatinib Multiple tyrosine kinases targeted BristolMyersSquibb 2006 chronic myeloenous leukaemia,
acute lymphoblastic leukaemia
Sunitinib Multiple tyrosine kinases targeted SUGEN/Pfizer 2006 renal cancer and GIST
Nilotinib Bcr-Abl Novartis 2007 chronic myelogenous leukaemia
Lapatinib Her2/EGFR GlaxoSmithKline 2007 HER2-positive breast cancer
Temsirolimus mTOR Wyeth/Pfizer 2007 advanced renal cell carcinoma
Everolimus mTOR Novartis 2009 several cancers
Pazopanib VEGFR2/PDGFR/c-kit GlaxoSmithKline 2009 renal cancer
Toceranib Multiple Tyrosine kinases targeted Pfizer 2009 canine mastocytoma
Masivet/Kinavet cKIT/PDGFR AB Science 2010 canine mastocytoma
Ruxolitinib JAKs Incyte 2011 myelofibrosis
Crizotinib ALK/Met Pfizer 2011 NSCLC with Alk mutation
Vemurafenib BRAF Roche 2011 melanoma
Vandetanib Multiple tyrosine kinases targeted IPR Pharms 2011 medullary thyroid cancer
Axitinib VEGFR1/VEGFR2/VEGFR3/PDGFRB/c-
KIT
Pfizer 2012 renal cell carcinoma
Bosutinib BcrAbi/SRC Pfizer 2012 chronic myelogenous leukaemia
Tofacitinib JAKs Pfizer 2012 rheumatoid arthritis
Regorafenib VEGFR2, TIE2 and other PTKs Bayer 2012 colorectal cancer, GIST
Cabozantinib VEGFR2, RET, MET Exelixis Inc 2012 medullary thyroid cancer
Ponatinib Src and Abl Ariad Pharma 2012 CML and ALL
Lenvatinib VEGFR2/VEGFR2 Eisai 2013 thyroid cancer
Trametinib MEK1/2 GlaxoSmithKline 2013 skin cancer
Dabrafenib BRaf GlaxoSmithKline 2013 skin cancer
Afatinib Her2/EGFR Boehringer Ingelheim 2013 NSCLC
Ibrutinib BTK Pharmacyclics, J&J 2013 mantle cell lymphoma and CLL
Ceritinib ALK Novartis 2014 late stage NSCLC
Tofacitinib was approved for the treatment of rheumatoid arthritis in 2012,
the 1st kinase inhibitor approved for the treatment of any inflammatory disease
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