An answer to cancer?
Every day (or so it seems), the media announce another “cure” for the disease that kills an estimated eight million people a year. But the reality is that cancer is many diseases, with many different targets for researchers to aim for. For Dr Martin Drysdale and his team at the Beatson Institute for Cancer Research in Glasgow, the challenge is even more daunting. They are after targets that other researchers have described as “undruggable” – in a series of ground-breaking…
“We are challenging the dogma that some targets are undruggable,” says Dr Martin Drysdale, the head of the Drug Discovery Programme at the Beatson Institute for Cancer Research in Glasgow. “They are only 'undruggable' because of what has happened in the past. And this is where FBDD plays a critical role – pushing the limits to find potential starting points to help validate targets and de-risk future research.”
Finding novel compounds which may become drugs for the treatment of diseases such as cancer is one of the major challenges in drug discovery. FBDD (Fragment-Based Drug Discovery) is a new approach to looking for the molecules which could become new candidates for drugs. Instead of screening relatively large, complex compounds, FBDD focuses on very small, less complex fragments with a very low molecular weight – typically screening about 1,000-1,500 fragments. Because these tiny fragments are not very potent (ii.e. do not bind very strongly), they are hard to find using traditional methods, but using biophysical techniques such as X-ray crystallography or nuclear magnetic resonance (NMR) spectroscopy, combined with the latest computational methods, the fragments are more easily detected and enable researchers to understand better how the fragment binds to the target or relevant protein, so the “hits” are more likely to turn into “leads” – and ultimately drugs. In simple terms, this means discovering a very tiny clue which leads to the arrest of a serial killer – in Drysdale'this case, cancer.
Not every researcher is convinced that FBDD is the “answer to cancer” or other diseases but more researchers are becoming more positive now, says Drysdale. “There are many targets in cancer which are amenable to FBDD and structure-based methods, but FBDD is also therapeutically agnostic,” he adds. “It is capable of targetting any disease, and it is at its most powerful when you combine it with structure-based methods.”
The road to Glasgow
Drysdale, who comes from Edinburgh and studied chemistry at the University of St Andrews, did his PhD in an “esoteric” area of chemistry called FVP (flash vacuum pyrolysis) – subjecting molecules to very high temperatures and low pressure to transform them into new compounds.
At this stage, his career could have led him in several directions – including petrochemicals – but what inspired him to go into drug discovery was a TV documentary on the Scottish pharmacologist Sir James Black, who developed beta blockers and won the Nobel Prize in Medicine in 1988 for the development of the anti-ulcer drugs propranolol and cimetidine. Drysdale was so excited by the programme that he wrote to Sir James to “ask him for a job.” Unfortunately, nothing resulted from this but Drysdale persevered and eventually got a post-doctorate post at the pharmaceutical company Parke-Davis (now part of Pfizer), based in Cambridge, where he worked on the development of anti-anxiety agents. This experience also exposed him to a multi-disciplinary environment and a relatively small team of about 25 chemists and 50 biologists who worked and played together and exchanged expertise. “It was a good working model,” says Drysdale. “I have always been a keen sportsman, and Parke-Davis was not unlike being part of a sports team.”
Two years later, Drysdale moved on to Wellcome in Beckenham, joining a medicinal chemistry team led by Dr Allen Miller, formerly of the University of Dundee. At that time, says Drysdale, Wellcome was the “ivory tower of pharma,” famous for the work of luminaries like Sir John Vane, its former R&D Director, who shared the Nobel Prize in medicine in 1982 for his work on prostaglandins. At Wellcome, Drysdale also learned researchers cannot work in isolation – it is better to share a small percentage of something important than have 100 per cent of nothing. Drysdale initially continued research in central nervous system (CNS) drugs then shifted his focus to “the science around nitric oxide,” a chemical compund which is an important cellular messenger involved in many physiological and pathological processes in the CNS as well as anti-inflammatory and cardiovascular areas – and Science journal's “molecule of the year” in 1992. Drysdale then became a project leader and also coordinated the chemistry across two teams developing synthase inhibitors – one of the company's most valuable assets. It was an enjoyable time for Drysdale which also led to practical results by delivering candidates for clinical trials – and exposed him to the commercial pressures of the pharmaceutical industry.
Two years after Glaxo merged with Wellcome in 1995, an opportunity arrived to join a new biotechnology company in Cambridge called Ribo Targets, which later merged with Vernalis. Drysdale's work involved building up the research group from scratch, including designing and building the lab, and after focusing on anti-infectives, he moved into cancer research, using FBDD, and became the company's deputy research director.
His experience in Cambridge was a good preparation for his current position at the Beatson Institute, not just in technical terms but also in collaborative methods of working. “It was very dynamic,” says Drysdale. “People talked to each other and got things done.”
FBDD was pioneered in the US by the pharmaceutical company Abbott. It was “a great idea” but Drysdale and others at Vernalis wanted to take FBDD in a different direction, focusing on ligands rather than proteins, to identify where the binding to atoms takes place, using X-ray crystallography and NMR.
Drysdale also started to focus on cancer. “In recent years, there have been remarkable advances in our understanding of what cancer is and how to treat it, but I became increasingly aware of the unmet needs in cancer research,” he explains. “When I started working in oncology, I quickly realised that was what I wanted to do.”
We now know that cancer is many diseases and the old way of thinking of cancer as organ-based (e.g. lung or liver) is no longer the best way to describe it, says Drysdale. “We also have the potential to target cancer more specifically than ever before,” he adds. And the Drug Discovery programme at the Beatson Institute, where Drysdale has gathered together a team of about 20 people, is a great opportunity not just to prove the scientific worth of FBDD but also make significant breakthroughs in cancer research.
Focus on FBDD
FBDD is beginning to produce practical results, says Drysdale. Thanks to FBDD, there are 18 compounds now in clinical trials, including one discovered by a company called Plexxikon and developed by Roche for the treatment of melanoma which is close to reaching market registration.
Reaching this stage can be an extremely slow process, says Drysdale – and may lead nowhere. “Drug discovery is no good if you choose the wrong target,” he says. “The target may be promising but after years of research, you may find out it is not involved in the etiology of the disease. The biggest challenge is to identify targets, and in cancer there are many, many targets, as well as many types and classes of proteins to deal with.”
FBDD, says Drysdale, has a key role to play. “Many targets are regarded by the industry as 'undruggable' because they've failed to reach the start point, and FBDD helps us find more start points to validate.”
Drysdale also explains that although the work done by his Drug Discovery Programme may not lead to instant results, it does de-risk the process of developing new therapies by industry and also helps to increase understanding by “proving we can target a particular molecule.”
Drysdale has applied the same rigour to his work at the Beatson as he used to do in industry. “It's an industry-standard programme,” he says. Academia is good at coming up with ideas but when it comes to drug discovery, industry simply does the job better – and Drysdale wants the Beatson to reproduce those same high standards, using basic biology to identify and validate targets.
“We have an opportunity to move into the drug discovery paradigm,” Drysdale explains. “My programme acts as a bridge between the basic research and the clinicians. You can't do translational research without this – it's an interesting collaborative environment.”
In Drysdale's new lab, chemists and biologists work side by side. The chemists make a compound and deliver it to the biologists only a few yards away, then watch it being tested. This is not just highly unusual in research of this nature but symbolic of the way the Beatson operates.
The gap between academia and industry is also beginning to close, according to Drysdale, blurring the edges between them. “The industry model has changed,” he continues. “As more facilities close down, commercial companies consider new options for doing research like not-for-profit institutes and universities. There are also more people available with industry experience.”
Five years from now, says Drysdale, the objective is to build up a portfolio of drug discovery programmes at various stages – hit validation, hits-to-lead and optimisation of leads. And over the next five years, he wants to see evidence of de-risked high-profile targets and collaborations leading to the development of clinical products.
He also sees an opportunity to use FBDD to investigate targets in difficult areas such as invasion and metastasis (when a disease spreads from organ to organ), and move into entirely new areas like 3D fragment libraries . “This is a challenging space,” he explains. “It is an area of research outwith industry timescales, and if we can de-risk it, then pharma can take up the challenge from there. In the commercial arena, researchers can't always go after the most important targets. We have the opportunity to lay down the infrastructure for future research and prove we're adding value.”
Cancer research isn't just all about science – it's also about human beings. “Patient benefit is key,” says Drysdale. And like it or not, it's also all about money“a numbers game” – as costly and as time-consuming as putting a man on the moon.
Drysdale relishes the challenge, however: “There is nothing more exciting than drug discovery. It is almost a privilege to be in a position to make a real difference. With FBDD, we are pushing the limits. Not every start point will lead to a clinical trial, but we have to start somewhere.”