Professor Paul Workman

Professor Paul Workman


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This interview is with Professor Paul Workman, for CANCERactive originally published in icon November- December 2004
Breaking New Ground in Cancer Drug Design

By Melanie Hart

Paul Workman was studying Biochemistry in the mid 70s, when he was "let loose" in a lab at Leicester University. "Doing experiments, with my own hands, that no one had ever done before, was the most fantastic experience," he enthuses. "Thats when I realised I wanted to research disease at what we now call the molecular level - understanding whats responsible for it and developing treatments which are rational, scientific and logical."

Iressa, one of the first three post-genomic "smart" cancer drugs (Gleevec and Herceptin being the other two). Iressa inhibits the Epidermal Growth Factor receptor, and people with non-small-cell lung cancer who have mutations in their kinas component of the EGF receptor have had remarkable responses.

Open quotesWere working towards personalised medicine - tailoring drugs to the individual rather than using drugs on patients who wont benefitClose quotes

His efforts were rewarded in 1985 with the European School of Oncology Award for Excellence in Oncology Research, for his research into detecting and treating hypoxic cells at Cambridge. Hypoxic cells (those with low levels of oxygen, which occur in parts of tumours) are very resistant to treatment, but Paul worked with several drugs - one of which is looking promising in clinical trials - as well as developing the hypoxia detection agent SR4554. He has been involved in taking several new drugs into clinic, including the Hsp90 molecular chaperone inhibitor 17AAG and the cyclin-dependent kinase inhibitor CYC202. And is excited about work to inhibit the PI3 kinase pathway (which could be vital in treating some brain tumours) and drugs that modify gene expression by blocking chromatin modifying enzymes.

Despite his successes, Paul Workman is not one to court publicity. The Harrap Professor of Pharmacology and Therapeutics at the University of London, Fellow of the Academy of Medical Sciences and author of close to 400 research papers is rarely interviewed. He may travel the globe giving 50 lectures a year, but admits to turning down many more to be an effective team leader at the Centre for Cancer Therapeutics that he has headed and modernised, at Suttons Institute of Cancer Research, since taking over from Ken Harrap in 1997.

"Drug development is all about teamwork," he stresses. "There are 170 people here; chemists, biologists, molecular biologists, pharmacologists, doctors and nurses, all with complementary skills. We also work closely with the Xray crystallographers here at ICR. Its fantastic to be able to build up such dedicated teams of people to achieve more than you could dream of as an individual."

Under Pauls direction, his team has established a range of modern technologies to accelerate the drug discovery process including: high throughput screening ("pretty rare in academic circles"), combinatorial chemistry, gene expression microarrays and high throughput pharmacokinetic analysis (cassette dosing). "We have built up a library of more than 100,000 compounds," he informs, "which we can screen at 10 compounds a day against our nominated target ( e.g. the protein from a gene thats wrong in cancer). Then once youve got a hit from the screen, you need chemists to modify those and build them up into a drug thats got the right properties. And biologists and pharmacologists to test them out.

Open quotesHis team has established a range of modern technologies to accelerate the drug discovery processClose quotes

"What was here before was a very successful operation developing platinum drugs like Carboplatin (used in testicular cancer) and Tomudex (in colorectal cancer). I would class those as being in the cytotoxic era - DNA-damaging agents and relatively toxic drugs. What were doing now is building on the knowledge of the molecular causes of the disease, understanding precisely what goes wrong in a cancer cell and then designing a drug that counteracts it.

"Its a privilege to work in this field because theres a real buzz about the likelihood of success in the future," he expands. "Cancer is a tough opponent, but we are finding chinks in its armour now. In some ways cancer is becoming addicted to certain pathways and therefore is living on the edge of life and death. We have to find a way to tilt that balance and, although Im realistic about how much work and funding it will take, Im optimistic about our chances."

Its his determination and, like many involved in the fight against cancer, his personal memories that keep Paul focused. He was a year into his PhD in Cancer Pharmacology at Leeds University when his father was diagnosed with bowel cancer. "That was so poignant..."he recalls quietly. "He was only in his mid-50s, which is an awful thing. Many years later my mother also died of a rather rare cancer, spinal chordoma, so Ive got two strong personal reasons, but I was already bitten before my father got ill. I was fascinated by disease at a molecular level and thought cancer was interesting and challenging - and still do."

Open quotesPauls schedule starts at 8 am most mornings, and he sets off for home at about 7.30pmClose quotes

Another personal challenge Prof. Workman faced, during the first four years of his directorship of the Centre, was living apart from his wife, dietician Liz, and their two children. "We live in the Surrey hills now, but commuting between here and Manchester for those years while the kids were going through A Levels and so on was tough," he admits. "I stayed here during the week and went home at weekends, but its been worth it. Now weve just finished renovating our old Victorian house, Liz and I enjoy long country walks together."

That must be at weekends because, when hes in Sutton, Pauls schedule starts at 8 am most mornings, and he sets off for home at about 7.30pm, unwinding by listening to his favourite Mozart operas. But his work is so vital and exciting that no one could resent the time he spends trying to develop better drugs.

Patient Benefit v Profit

"I hope icon readers will see just how valuable it is in an academic environment to have a drug development centre that isnt primarily commercial. Patient benefit is our sole objective, and my bit of the Institute is funded almost completely by Cancer Research UK," he explains.

"The size of the market and the numbers of patients that will benefit isnt critical for us. Increasingly, as we learn more about cancer, we realise that smaller groups of patients have particular abnormalities, and you tailor the treatment to that particular need. The downside, particularly for the huge pharmaceutical companies that have been formed by the mergers and acquisitions of the last few years, is that they really need blockbuster drugs for the industry to be successful."

The lifestyle drugs used by huge numbers of middle-aged to elderly patients? "Yes, the cholesterol-lowering drugs, the Beta-blockers and the like. Lets not decry them, because theyre valuable in terms of preventing heart disease, but the bigger the companies become the more dependent they are on these for survival. Im not criticising the industry, because Ive seen both sides, and we have to work together on many of our projects to get them beyond Phase II trials, but they have different agendas. (Prof. Workman has founded two biotechnology companies, Chroma Therapeutics and Piramed Limited, in the last few years to speed up his teams new drug development projects. They currently have a combined funding of 18 million to use on research from the private equity market.)

Open quotesThe bigger the companies become the more dependent they are on these for survivalClose quotes

"If you can pinpoint smaller sub-groups within say breast or lung cancer that are caused by different abnormalities in the DNA, then the treatment of these sub-groups will be different and probably different drugs will be used," he continues. "When I think about the way that cancer used to be treated I often use the analogy of a car breaking down. Instead of the mechanic opening up the bonnet and having a look at what the problem is, imagine he just took a sledgehammer to it and said, Well, well just try knocking a few things around and see what happens!" The idea now is that if you take your car in with a problem you want that specific fault solved, not something else done.

So in the same way with patients, you want to find out whats driving Mrs Browns breast tumour or Mr Joness colon tumour. Whats the problem in the engine of this cancer? Whats making it different from the normal cell? We want to tailor a drug that works on that. The problem industry faces is that, for its business model, it would prefer to treat very large numbers of patients all with the same drug. We have to make the business model adapt to the credible scientific opportunities being opened by the genomics of disease, and particularly of cancer, and that may require big changes."

Open quotesInstead of the mechanic opening up the bonnet and having a look at what the problem is, imagine he just took a sledgehammer to it and said, Well, well just try knocking a few things around and see what happens!Close quotes

Prof. Workman thinks that the way to tackle this is to be able to identify the small groups of patients who need the highly-focused drugs that will hit pathways and abnormalities present in their cancers. "Up until the last few years cancer was tending to be classified by its location. Have you got a lump in your breast or a melanoma on your skin? Then a small biopsy sample was taken and put under a microscope to see what the cells look like. What were going to do now is analyse the DNA and describe in detail what the pathology (abnormality) is. We need simple tests that will allow you to take a sample from a patient, and maybe eventually therell be imaging tests so that a biopsy isnt needed. The test will show one, three or four or, possibly in the future, up to 10 abnormalities," he predicts.

"We think that there are five or 10 genes wrong in each cancer, and this is one of the big challenges we face. If the majority of human tumours, particularly the more common solid ones, are driven by several genes it is likely that you will probably have to hit several of these genes to get a full clinical effect. To do this I think well either have to find a drug that can hit more than one of these gene pathways,like our drugs that act on Hsp90 or chromatin enzymes, or use cocktails (mixtures of very specific drugs together) according to the molecular make-up of the patient. Well be treating patients in a much more intelligent way. Its tailored drug therapy - like having a suit made, rather than buying one off the peg!"

Is Gleevec a Magic Bullet?

This is exciting stuff for the future, but whats even better is that some patients - those with chronic myeloid leukaemia - are benefiting now from taking Gleevec. "Its an unusual disease in that its caused predominantly by one gene, the BCR-ABL gene, which is joined by two bits of DNA coming together when they shouldnt because of damage inside the cancer cell," Prof. Workman explains. "These form a new gene that makes a protein thats much more active than it should be, and this is what makes the leukaemic cells become leukaemic. They then proliferate, divide and prove fatal if not treated. The protein this gene makes is a kinase, called the BCR-ABL. Gleevec is a kinase inhibitor. It blocks the BCR-ABL, the protein that drives the cancer, and patients then go into long-term remission."

Open quotesProf. Workman is not comfortable with that
term
Close quotes

Its because of this success that Gleevec has been described as a magic bullet, but Prof. Workman is not comfortable with that term. "Maybe it is close to being a magic bullet, because its almost devoid of side effects and is very, very effective, but when you put a chemical or even a natural product into a patient its never the case that you only perturb one pathway. Because of the complexity of biology, there are always more things going on than you think.

"Patients are already beginning to develop resistance to Gleevec. Its a little like the resistance that develops in AIDS, where some of the success has been had by using drug cocktails that hit the virus in multiple different ways and prevent this type of resistance developing. Even in leukaemia, where we know its predominantly one gene, you can still get this problem with resistance suggesting that more than one drug will still be needed."

The Human Genome Project

Professor Workmans team, along with researchers around the world, have been helped enormously by the ongoing Human Genome Project. This involves big robots working quietly in large empty rooms sequencing their way through the genes of several normal individuals. "My prediction for the future is that instead of talking about drugs that are useful in breast or skin cancer we will talk about those that work on particular genes. Those wont necessarily break down into anatomy, but into molecular biology (or molecular pathology as we call it)," he says.

Open quotesIn the next 10 to 15 years we will be able to sequence the whole of a cancer patients genome and pinpoint exactly which genes are wrong in that patientClose quotes

"My colleague Mike Stratton is doing a follow-on project to the Human Genome, called the Cancer Genome Project at the Sanger Centre in Cambridge. They are taking samples of DNA from cancer patients, and cancer cell lines, and resequencing the genome to look for the differences - the abnormalities. In the past we found cancer genes either by chance, or by low throughput highly-focused long-term projects. In the next 10 to 15 years we will be able to sequence the whole of a cancer patients genome and pinpoint exactly which genes are wrong in that patient. The technology is available and, if you have millions to spare, you can have your genome sequenced by going to a private company that will do it for you. I believe a handful of incredibly rich people have done that in the States."

Such mindboggling advances make most of the cancer treatments currently being meted out in oncology departments seem positively cavemanlike. No wonder Paul Workman (never was a name more suitable) is so enthusiastic about his work. The phones start ringing madly in his office, colleagues are waiting for him to help with the paperwork needed about a new target, but this professor has a few more important revelations for icon readers before he rushes off.

"The first exciting discovery to come from Mike Strattons robotic sequencing was a mutation in a gene called BRAF. He knew the importance of kinases in cancer and sequenced all the kinases in all cancers. That gives you an idea of the scale of this project and the robotics that make it possible," he says, eyes sparkling. "They sequenced BRAF and found activating mutations (mutations that occur in the gene so that when it makes its protein it is hyperactive). This defect is particularly common in melanomas. As soon as that discovery was published in Nature, we established one of our high throughput screens to search for inhibitors of the BRAF, and were now developing those inhibitors. That will be an example of us working on a new drug within months of the discovery. We have the ability to move quickly at this Centre and we hope to have this drug ready within five years."

Latest News on Brain Tumours

Open quotesThere is so little brain tumour research underway that they already have a grant from US charity ABC2 for this projectClose quotes

There are other exciting new drugs in the pipeline in Professor Workmans section, and, desperately needed, but still at the pre-trial stage are the PI3 kinase inhibitors. He thinks these may be particularly effective in treating glioblastomas (the most malignant brain tumours), as well as prostate and other cancers. There is so little brain tumour research underway that they already have a grant from US charity ABC2 (Accelerating Brain Cancer Cures) for this project.

"Some brain tumours have a mutation in their PI3 kinase which activates the protein," Prof. Workman explains. "The other thing that happens a lot is that theres a loss of the tumour suppressor gene that reverses the PI3 pathway - called the PTEN tumour suppressor gene - which acts as a brake on cancer, while the PI3 kinase is the accelerator. In general with cancer you activate the accelerators and lose the brakes, and many many patients with brain cancer have lost the PTEN brake, so what weve done now is develop drugs, inhibitors, that will block the PI3 kinase pathway. Weve shown that these inhibitors work in brain cancer models, but theyre not in trials yet. Were involving the company I helped to set up, Piramed, to do this quickly."

Many peoples lives are riding on Professors Workmans teams efforts to keep on finding and refining this new generation of drugs. The pressure is on and everyone is conscious that speed, effectiveness and far fewer side effects are vital. These drugs were needed yesterday, but many patients will still benefit tomorrow.

As the phone and email messages pile up, Professor Workman prepares to rejoin his colleagues. "Our aspiration here at the Cancer Research UK Centre for Cancer Therapeutics is to develop the drugs that will address every single abnormality in all cancers," he says confidently. "Then in 15 to 20 years time when the patient comes in and has some kind of robotic analysis on their DNA, that pinpoints exactly whats wrong with their cancer, the clinician will have those five or 10 drugs available.

Open quotesOur aspiration here is to develop the drugs that will address every single abnormality in all
cancers
Close quotes

"Cancer medicine will be completely different in the next generation. Its already different from just five years ago. Dramatic things have happened with Iressa, Herceptin, Velcade and Gleevec. They are all dramatic breakthroughs, and I think these will continue in the next 15 years. One of the most difficult things about cancer is its ability to develop resistance and change its mode of attack, and our new treatments have to bear this in mind.

"It will be hard work," he acknowledges, "but you see young and even not-so-young researchers, like me, very passionate, excited and positive about our chances of success. Yes, we have to temper it against awful situations where family, friends and colleagues dont survive from cancer. On the one hand youre doing tremendous things, and making progress, and on the other these tragic things still happen. But that just makes you more resolved to fight on."

Timetable Of A New Drug

1: Find a target (abnormal gene)

2: Start high throughput screening of compounds, at a rate of 10,000 a day against the nominated target until youve got a hit

3: Chemists modify the compounds, ideally with the help of Xray crystal structures, and build into a drug formulation in injectable or tablet form

4: Carry out toxicology tests in a limited way on animals before exposing patients to a "risky" drug

5: Drugs go into Phase I Clinical Trials, for 12 to 18 months, on 20 to 30 patients

6: Drugs go into Phase II Clinical trials, for 12 to 18 months, on about 30 people, all with the same cancer, eg:melanoma, often those who reacted well to the drug in the Phase I trials

7: Drugs go to large Phase III trials(on how many patients? For how long??) before they get regulatory approval and are licensed. (A drug that works well on brain tumours could skip Phase III and get approval for use straight after Phase II, as there are so few good treatments available.)

8: The new drug is ready to be used widely on patients

Gleevec - stages 1-8 took about 40 years (because of the time taken to understand the molecular basis of the abnormality involved in the BCR-ABL translocation).

Taxol - stages 1-8 took about 30 years

Todays new drugs - stages 1-8 should take between 5-7 years

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