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A pioneer of cancer drug discovery – Professor Ken Harrap 1931–2017

15
Feb
2017

Our Chief Executive remembers Professor Ken Harrap, a pioneer of cancer research who was instrumental to the discovery of life saving treatments including carboplatin and raltitrexed, who died last week.

Posted on 15 February, 2017 by Professor Paul Workman

Kenneth Harrap 1.77

Professor Kenneth Harrap at the Witness Seminar 'The Discovery, Use and Impact of Platinum Salts as Chemotherapy Agents for Cancer' held by the History of Biomedicine Research Group. Image courtesy of Wellcome Library, London.
 

The Institute of Cancer Research, London, and the cancer drug discovery and development community in the UK and internationally was shocked and saddened to hear, at the end of last week, the news of the unexpected death of Professor Ken Harrap – a pioneer of cancer discovery and development.

Professor Harrap, always known as Ken to his very many colleagues and friends, had a highly distinguished career in discovering and developing cancer drugs at The Institute of Cancer Research (ICR) – and was my predecessor as Director of what is now the Cancer Research UK (CRUK) Cancer Therapeutics Unit.

I had the honour and privilege to succeed Ken in 1997 and to become the first Harrap Professor of Pharmacology and Therapeutics.

Ken died suddenly in the early hours of 9th February. He was 85.

Outstanding success and impact over 40 years

Professor Ken Harrap CBE, DSc, CChem, FRSC retired from the ICR on 30 Sept 1997, after more than 40 years’ continuous service in which he achieved outstanding research success and huge clinical impact.

Ken was born on 20 November 1931. He joined the ICR in 1956 from Hopkins & Williams, where he had been employed as analytical chemist after completing his BSc in Chemistry.  He started his ICR career at the Chester Beatty Laboratories on the Fulham Road in Chelsea, central London. He was initially appointed as a Lecturer in Chemistry in Professor Franz Bergel’s department, completing his PhD in Chemistry in 1961. 

In 1964 Ken spent a year as a Visiting Fellow at the Children’s Cancer Research Foundation in Boston, Massachusetts USA. Upon his return to the ICR he became Head of the Leukaemia Biochemistry Group.

In 1970 Ken became Head of the (then) newly-established Department of Applied Biochemistry and in 1973 the group moved to ‘E Block’ on the ICR’s Sutton campus.  

Around this time, Ken set up an ICR a training course in Biochemical Pharmacology for Clinical Fellows, leading to MSc/MD/PhD degrees. Many oncology clinicians across the world have benefited from training in Ken’s programme.

In 1997 Ken’s remit was broadened with the formation of the ICR’s Department of Biochemical Pharmacology.  Also in 1977, Ken was awarded the degree of DSc in Pharmacology and Biochemistry by the University of London

In 1982 Ken was appointed Chairman of the ICR’s newly formed Drug Development Section, which incorporated Professor John Roberts’ group of cellular pharmacologists working on DNA damage – following the closure of the ICR’s Pollard’s Wood Research Station – and also the ICR’s Division of Chemistry under Professor Allan Foster.  The title of Professor of Biochemical Pharmacology was conferred on Ken in 1983 by the University of London.

Success built on team science

The approach taken by Ken and his team was distinguished by the multidisciplinary integration of medicinal chemistry and anticancer evaluation in cell and animal models and was characterised by a deep understanding of the mechanism of action and pharmacology of anticancer drugs.

Ken also considered close interaction with expert cancer doctors treating patients to be essential in order to provide insight into clinical need and the limitations of existing agents, as well as ensuring the rapid progression of the team’s new agents into first-in-human trials.

Throughout his distinguished career, Ken’s research interests focused on two main classes of cytotoxic anticancer agents. These were: firstly, DNA damaging agents – ranging from chlorambucil, melamines and latterly platinum complexes; and secondly, antimetabolites – starting with work on methotrexate and culminating in thymidylate synthase inhibitors.

Very much integrated with his team’s academic cancer drug discovery and pharmacological mechanism of action research, Ken was responsible for securing some highly productive sponsored collaborations and partnership deals with industry. 

Discovering platinum and antimetabolite cancer treatments

Most notable among these was a collaboration between Ken and colleagues with the Johnson Matthey Technology Centre (specialising in precious metals) with later involvement of the ICR’s partner hospital the Royal Marsden (for clinical trials) that resulted in the discovery and development of the second generation platinum-based drug carboplatin (Paraplatin) – an advance on the original platinum-based DNA-interacting drug cisplatin with less toxicity to the kidney. This was obtained by introduction of a dicarboxylate ligand that gave greater water solubility and reduced chemical reactivity compared to cisplatin.

Carboplatin was subsequently approved for ovarian and non small cell lung cancer. It is also used to treat other malignancies – such as testicular, stomach and bladder cancers. The first clinical trial of carboplatin was carried out in 1981 and it was subsequently licensed and launched commercially by the (then) Bristol-Myers company in 1986. Since then it has had enormous clinical impact.

In addition, Ken and his colleagues were responsible for two other, third generation platinum drugs that have undergone clinical development – satraplatin (JM216) which was designed to be orally active, and picoplatin (JM473) which was designed to reduce platinum drug resistance by reducing the likelihood of interaction of the complex with sulphur donors, such as glutathione. In recognition of their work on discovering platinum drugs, Ken and colleagues received the Queen’s Award for Technological Achievement in 1991. 

Turning to his antimetabolite work, Ken had a particular research focus on inhibitors of folate metabolism. A collaboration between Ken and his colleagues with the (then) ICR/Zeneca pharmaceutical company (now AstraZeneca) led to the discovery of the thymidylate synthase inhibitor raltitrexed (Tomudex). This quinazoline antifolate thymidylate synthase (TS) inhibitor underwent Phase I clinical trial in the Royal Marsden which was published in 1986. Raltitrexed was subsequently approved in Europe in the mid-1990s as a conveniently administered alternative to 5-fluorouracil for colorectal cancer.  It was also approved in other territories and in addition has been used in other cancers, including malignant mesothelioma.

The team’s follow-up TS inhibitor – the non-polyglutamatable quinazoline thymidylate synthase inhibitor plevitrexed (ZD933) – was an oral agent designed to overcome tumour resistance by that mechanism. This also entered clinical trials.

Ken was highly successful in building a strong collaborative team of high quality principal investigators – too many to mention here by name – and a strong cadre of experienced support staff.  Following a highly successful peer review and site visit of Ken’s broader group, the (then) Cancer Research Campaign (now Cancer Research UK; CRUK) Centre for Cancer Therapeutics was established on 1st April 1994. Ken was appointed as its first Director. 

Seven cancer drugs were in full clinical development at the time of Ken’s retirement.

A lasting legacy to Professor Harrap

Based on these superb foundations, I succeeded Ken as Director of the CRUK Centre in 1997 and aimed to build on his and his team’s successes in the previous era of cytotoxic drugs by focusing on molecularly targeted agents that exploited the new understanding of the genetic drivers of oncogenesis – accelerating a transition that had already begun.

Currently known as the CRUK Cancer Therapeutics Unit and since January 2016 led by Professor Raj Chopra, the ICR enterprise is acknowledged by international peer review as the world’s largest and leading academic cancer drug discovery centre, with more than 160 staff.  This represents a lasting legacy to Ken’s research and leadership.

Ken was made a Life Fellow of the Cancer Research Campaign in 1994. He served on numerous national and international advisory committees, editorial boards and EORTC committees. He was Chairman of the British Association for Cancer Research from 1987–1990. He was also responsible for organising several International scientific congresses. 

In recognition of Ken’s outstanding contributions to cancer drug development, he received a number of awards, including the prestigious Bruce F Cain Memorial Award from the American Association for Cancer Research, the Barnett Rosenberg Award from the International Platinum Drug Society, the Cain Memorial Award from the New Zealand Cancer Society and a Distinguished Lectureship in Pharmacology at St Jude’s Children’s Research Hospital.

On his retirement from the ICR at the end of September 1997 Ken was made Emeritus Professor of Biochemical Pharmacology of the University of London, Distinguished Emeritus Fellow of the Cancer Research Campaign and an Associate and Visiting Scientist at the ICR. 

He was appointed Commander of the British Empire (CBE) in 1998 for services to cancer research.

Subsequently, Ken joined his wife, Beverley Weston, in a pharmaceutical consulting practice offering advice to biotech and venture capital companies on oncology drug development and technology transfer. He also managed to find some time for his major hobby – sailing his yacht around the Channel Isles and the coasts of France and the West Country.

Ken had many other additional interests as well: including his family, the arts, rugby and The Royal British Legion. Also more latterly he was an active campaigner on local issues in the village of Peaslake in the Surrey hills, where he lived.

A giant of UK cancer drug discovery

Overall, Ken Harrap’s career forms a remarkable catalogue of achievements involving highly successful drug discovery and development research, tremendous impact on many hundreds of thousands cancer patients around the world, and commitment to training the next generation of drug hunters and oncology clinicians.

Ken was a larger-than-life character who greatly enjoyed the social as well as scientific side of cancer research. He was outspoken and influential in his views; could be a formidable protagonist for what he believed to be right for excellence in research and for cancer patients; and displayed a zest and enthusiasm for everything he did.

In addition to maintaining and enhancing the ICR’s position as a world leading centre for drug discovery, Ken was important contributor in helping to preserve the independence of the ICR and Royal Marsden following the 1992 Tomlinson Report on reshaping London’s Health Services.  

From a personal perspective, together with Professor Tom Connors, who also spent much of his career at the ICR, Ken was one of two giants of UK cancer drug discovery who I looked up to as icons when I was training as a young scientist in the field during the 1970s and 80s. Ken welcomed me when I took over from him at the ICR in 1997, immediately stood back and let me get on with the job, and was then always supportive and warmly appreciative of our subsequent progress. I hope we do him proud.

I also vividly recall Ken’s enthusiastic participation in scientific and social activities as a member of the European School of Oncology Task Force on ‘New Approaches in Cancer Pharmacology: Drug Design and Development’ which I had the pleasure to chair in the wonderful environment of Venice.

He will be sadly missed and always remembered by countless friends and colleagues around the world.

Ken is survived by his wife Beverley, daughters Kerry and Gwynne and his granddaughters Hannah and Sophie, to whom we express our deepest sympathies.

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