Ask a cross-section of scientists how they got into cancer research, and you'll hear about a dizzying variety of routes from fields as diverse as biology, pharmacology, mathematics, and medicine. And with certain attributes—an inquiring mind, self-discipline, and a dash of ambition—it seems that there's no limit to what can be achieved.
Cancer research has moved with the times, embracing new technologies enabling scientists to pursue more varied research goals than ever. Cancer researchers can find themselves in various settings linked to either academia or industry, working in many areas, from tackling basic questions in the laboratory to testing new drugs and vaccines in the clinic.
Many young scientists at the basic research end of the spectrum will admit that they were initially attracted more by the desire to investigate fundamental questions in biology than to work specifically on cancer. But they often then realize the importance and applicability of their work to understanding the underlying biological processes leading to cancer. From such understanding, new treatments can arise.
Laura Buttitta, for example, is a postdoctoral fellow at the Fred Hutchinson Cancer Research Center in Seattle. Armed with a Ph.D. in mouse embryology she was drawn by the center's top-class reputation for basic research. She is investigating the molecular switches that govern cell division — using fruit flies as a model system.
"I have to confess that I was more interested in how our cells work at the molecular level than in cancer research. But since coming to the Hutch, I've been able to attend [clinical research] seminars and have become more interested in that."
"The Hutch" is one of 39 comprehensive cancer centers across the United States designated as such by the National Cancer Institute at the National Institutes of Health (NIH). It brings together, under one roof, basic research into cancer at the cellular level, clinical research, and epidemiology — for studying the cause and prevention of cancer at the population level. It offers various research training and support initiatives, including internal postdoctoral awards, interdisciplinary training programs, and pilot startup initiatives that enable researchers to embark upon new projects that are too speculative initially to win short-term awards.
Cancer research competition increases
In fiscal year 2005, The Hutch received more than $10 million in funding from the National Institutes of Health - the world's largest cancer research funder. This is typical of the favorable status of cancer centers; their portion of NIH funds has risen by around 30 per cent in the past five years. On the surface, NIH spending appears to have increased significantly all-round over the past decade. The agency's total spending on cancer research rose from just over $2 billion in fiscal year 1995 to almost $5 billion in FY 2005. But taking inflation into account, actual spending by NIH on research has flattened over the past five years, including on cancer research. "Obviously, this has negatively impacted cancer research," comments The Hutch's chief financial officer Randy Main.
At the same time, competition has intensified: Since 1996, the number of grant applicants to the NIH has more than doubled, leading to a fall in the proportion of grants awarded, from 27 percent in 1996 to 19 percent in 2005. Researchers are turning instead to smaller funders. The Susan G. Komen Breast Cancer Foundation, for example, received more than four times its usual number of applications owing to cuts in NIH spending on breast cancer research, according to Paula Witt-Enderby, a researcher at Duquesne University in Pittsburgh and a member of the charity's grant review panel.
In Europe, spending on cancer research is highly variable from one country to another. The UK spends the most, and has seen around a 9 percent growth in cancer research funding over the past five years — supported mainly by charities — with £343 million spent in 2005 by the partners of the UK's National Cancer Research Institute. According to Michael Stratton, director of the Cancer Genome Project at the Wellcome Trust Sanger Institute in Cambridge, UK, Europe has a lot to offer, and it is "to be expected" that postdoctoral researchers will move from one country to another to gain experience. Stratton arrived at his position originally from a clinical background. He made such a leap after specializing in pathology at the Hammersmith Hospital in London. "It brought me closer to the scientific basis of disease — you look down the microscope at the diversity of cancer and it makes you want to understand more. I always wanted to do research, but it was a rude shock not to go back to medicine."
Top-level cancer research institutes around Europe are now thriving, including The Netherlands Cancer Institute (NKI), Amsterdam; CNIO in Madrid; the Radium Institute, Oslo; The Karolinska Institute, Stockholm; the Marie Curie and Gustav Russie Institutes in Paris; the World Health Organization-funded IARC in Lyon; and the German National Cancer Institute (DKFZ) in Heidelberg. Each of these institutes has something unique to offer, drawing excellent local researchers as well as exceptional international scientists.
Rather than focus on basic cancer research, many investigators are moving into the burgeoning area of translational research, taking basic developments toward the clinic. Witt-Enderby at Duquesne is using her expertise in molecular pharmacology to study the effects of melatonin on a mouse breast cancer model. She is now in discussions with the University of Pittsburgh about starting a small clinical trial. "It's a very big therapeutic strategy, and I just love it that all this research on signaling and how a cell works is finally paying off," she says.
Witt-Enderby enjoys the academic setting as well as her mentoring role toward graduate students. She notices, too, that increasing numbers of graduate students show a specific interest in cancer research. "They read about it or they know someone who has had cancer. They want to know how drugs work and how to apply that to cancer."
Witt-Enderby is on the grant review panel for the Susan G. Komen Breast Cancer charity, which is placing greater emphasis on translational research, and a corresponding increase in suitable bids. "We're starting to see that bridging. I've read so many grants where you see M.D.s teamed up with Ph.D.s." Other fund-holders are also encouraging the trend, including the biggest of them all, the U.S. National Cancer Institute.
In Europe, a similar boon is occurring, with increasing numbers of scientists becoming involved in running clinical trials. Fran Balkwill, head of the London-based Translational Oncology Laboratory of Cancer Research-UK, sums up the mood: "We've learned so much in the past 25 years but we can't just spend the next 25 years finding out more. We can and should tackle the big divide between what we know and what we can do for those patients on the ward."
Balkwill's first clinical trial starts later this year, based on developments in her laboratory. She will be using therapeutic antibodies to dampen the inflammation around ovarian tumors. This, she hopes, will enable "the good guys" - cells of the immune system - to specifically attack and destroy tumors.
Her lab is embedded within a cancer center, which allows closer contact between scientists and clinicians, and which offers several advantages, including an improved flow and quality of tissue samples from clinic to laboratory and greater commitment from doctors. "It's the only way forward - to have tight collaboration and mutual respect between clinicians and scientists," she says.
Back in the US, and further along the translational pipeline is Doug Lowy, of the NIH in Bethesda, Maryland, who has already experienced the potential of harnessing basic research for clinical use. He has devoted the past 20 years to studying human papilloma viruses (HPV), including their ability to cause cancer of the cervix. This includes the development of the HPV-based vaccines now licensed to GlaxoSmithKline and Merck for the protection of women against this disease. Lowy's next goal is to develop a second generation of vaccines that can be produced more easily and cheaply, making them more available for use in developing countries, and active against a broader range of HPV strains than the currently approved versions.
Many of Lowy's former graduate students, postdocs, and clinical fellows have moved on to prominent cancer research positions in academia and industry. He attributes their success to a combination of skills and qualities, including initiative, curiosity, technical and intellectual abilities, and last but not least, self-discipline. "There are many brilliant people who are not successful as scientists because they don't focus, or are not innovative, or do not have sufficient technical skills. And you need patience, because it takes a long time to achieve anything meaningful."
Biotechnology companies are eagerly promoting translational cancer research. Two years ago, Keith Luhrs moved to Peregrine Pharmaceuticals after completing his first postdoc at nearby University of California, Irvine. He is now developing antibody-based therapeutics for cancer and other diseases. "I was looking for something a bit more applied. Having that goal of something that is useful for human disease is definitely a driving force. I wanted to get things done at a faster pace, and make something beneficial."
What also attracted Luhrs was the prospect of honing many skills. "In a given week I'll do cell culture, protein chemistry, molecular biology, microscopy, and structural biology on the computer," adds Luhrs.
"If you step into the right small company you will end up having to sharpen your skills in a wide variety of the life sciences," adds Missag Parsaghian, Peregrine's director of research and development.
New technologies have enabled a whole slew of biotech companies to form in recent years. Lexicon Genetics of Houston, Texas, for example, grew from the use of mouse embryonic stem cell technology to create mouse models of disease. Its founder, Allan Bradley, was at the time based at the M.D. Anderson Cancer Research Center in Houston, Texas, and now heads the world's largest mouse genetics program at the Wellcome Trust Sanger Institute, which has a strong cancer component. Many of his original team took up positions with Lexicon Genetics.
"There has been a significant trickle of people who've gone to industry from my lab," Bradley said. "They had unique skills that industry did not have and they could get very lucrative salaries. I've had people who've gone to Merck, Pfizer, either into the laboratory or into management and business."
Bradley himself resisted the lure of industry, preferring instead the academic freedom of his current position. This enables him to make his resources — embryonic stem cell lines and mouse models — freely available to researchers outside the institute. He also prefers the idea of having greater control of his research. "In a company you're not in charge of your own destiny. Projects come and go. If the company decides it, a project ends," he says.
Such sudden changes of direction in industry are something that Steve Gendreau, a cell biologist and project leader at Exelixis in South San Francisco, has experienced five times in the past nine years. But rather than give up, he supports the change as necessary for keeping his company's R&D portfolio moving toward a successful product. "These projects can feel like your own children. It's sometimes difficult to say goodbye. But the pragmatic view is that the ability to remain flexible is absolutely key — we have to move people from one project to another," he says.
One of the trade-offs, he adds, is avoiding what some see as the hang-ups of academia. "I am not required to teach classes, write grants, or oversee graduate committees. I am paid to do what I love: discover life-changing cancer therapeutics."
Part of this involves developing assays for assessing the activity of new anticancer compounds. These are aimed specifically at pathways involved in either the initiation and progression of cancer or its resistance to conventional drugs. One successful compound, named Exel 647, that targets nonsmall-cell lung cancer in previously untreated patients is now in a phase 2 clinical trial.
Right person for the job?
As for personal qualities, it is perhaps no surprise that cancer researchers have much in common with other scientists. Bradley emphasizes the importance of academic knowledge. "You need a deep and broad knowledge, very good molecular biology skills, and the ability to generate ideas." He also emphasizes the need for speed in translating ideas into results by being technically competent so as to be able to perform experiments "quickly and efficiently ahead of someone else who's going to compete with you on that idea."
Witt-Enderby prizes students and postdocs with an open mind and a willingness to read about topics as diverse as molecular biology, endocrinology, drug mechanisms, pharmacology, and biostatistics. "Because mine is a very interdisciplinary lab you have to learn so much. You have to know a lot because out of that will come a very good answer to a research question."
Stratton often recruits graduate students and postdocs with an inclination toward bioinformatics, who can organize and process data from genomewide screens, and improve high throughput DNA sequencing and analysis. On top of this, he values the involvement of trained bioinformaticians to be "roaming wild and free through all our data to find something interesting, not constrained by goals and targets."
The future of cancer research
Looking ahead, cancer research looks set to thrive — particularly in the translational research arena and the development of new therapeutics.
"This is one of the most exciting times in cancer research. I believe that the next 10 years is going to be a golden age," says Gendreau. This is partly due to what he describes as "a more sophisticated view that these cancers are similar in their molecular footprint — in the pathways that have caused them to become tumorigenic." New drugs targeting these pathways may be useful against a variety of different cancers.
In turn, Parsaghian of Peregrine Pharmaceuticals predicts that antibody-based therapeutics — and diagnostics — will continue to be a growth area in cancer research, together with other protein-based biological agents and stem cell technology.
The excitement over translational research is tempered, however, by the need to maintain "a balanced portfolio" between blue skies research and clinical studies, according to Balkwill. "You still need the basic research, because there's still a lot to learn, and you need clinical trials. But you also need this not-so-well-developed in-between world," says Balkwill.
"It's just as important that people do basic science," agrees Witt-Enderby. "If you have to show that everything has translational potential within a short space of time, then you would lose out."