NCI Research Agenda Includes Expanded Role of Genomics, Global Health

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BETHESDA, MD—Harold Varmus, MD, former director of NIH, does not think of his new post as director of the National Cancer Institute as a step back, but rather as the perfect place to be for someone who has spent his career researching cancer. “I’ve been working on cancer research for 40 years, and I’ve never seen a more opportune moment to try and run the National Cancer Institute,” he told members of the NCI Advisory Board when they met last month. “The chances of making tremendous advances in the control of cancer are remarkable.”

The Nobel-Prize winning scientist, who ran NIH from 1993 to 1999, described a vision for NCI that has the agency focusing on the most pressing issues in cancer research in the most streamlined manner available, with as little wasted effort and energy as possible. To that effect, he has dismantled the NCI executive committee, which he called “too big and cumbersome,” and replaced it with a Scientific Program Leaders group, which provides advice on scientific initiatives. “It’s a manageable size, everyone can speak up and everyone in the room is relevant,” Varmus explained.

Varmus is seeking to identify the big questions in cancer research and direct NCI’s resources to answer those questions, without losing any of the flexibility that allows for lateral thinking or out-of-the-box ideas.

Balancing Priorities

From his years as NIH director and his career as a researcher, Varmus understands the inherent tension between the individual investigator and the team-driven approach. “Teams, in my view, are often good for science. But individuals provide the greatest leaps of the imagination.”

Team-heavy multidisciplinary science is the current trend, and the approach that frequently moves institutes further towards large goals. However, administrators cannot forget about the achievements of lone scientists.

Another area of tension is balancing of public health needs versus scientific opportunities that might lie in research into rarer diseases. “The problem is that it’s so hard to quantify any of this, but it has to come out at some point in dollars,” Varmus admitted. “And budget numbers do not always accurately describe what’s going on in a health enterprise.”

Research into types of cancer that heavily impact the population, such as breast and lung cancer, should obviously receive major attention from the agency. However, history has shown that research into rare disease can produce results that have wide-ranging effects. We know from cancer research that a big investment in a rare disease like retinal blastoma has taught us about cell cycle control, about tumor suppressor genes, and about the way in which cancer genes can be inherited. And we wouldn’t know that if we didn’t take advantage of a rare disease that provided a window into understanding cancer. Only a few viruses cause cancer, but if we hadn’t studied tumor viruses, both the DNA and RNA versions, we wouldn’t know nearly as much about oncogenes and tumor suppressor genes as we do today.”

However NCI focuses its energies, it will be a balancing act and there will be no one single plan on how to proceed. “It’s easy to articulate our overall goals. Our mission is to control cancer, to diagnose it earlier and more accurately, and prevent it and treat it. But it’s very difficult to come up with a simple plan for how to achieve them,” Varmus declared.

Big Questions, Problem Areas

Beginning in October, Varmus will be meeting with a small group of advisors to discuss what the biggest unanswered questions are in the field of cancer research. He explained that he is taking his cue from the Bill and Melinda Gates Foundation, an organization that he worked with. “Eight years ago we got together to define the grand challenges in global health,” he explained. These are questions that, if answered, will allow scientists to get over a major roadblock.

“The goal is to have a set of questions—10 or 20 or 30—that, when we’re done, can be used as a scorecard. How many have we answered? What are we building on that shows we have made progress?” Varmus said.

He expects one of them to be “What does an oncogene actually do?” Others might be “What is metastasis? What do cells do when they’re metastatic?” The field of obesity and cancer may also provide areas of interest. “What is it about obesity that drives the initiation of cancers?” he asked.

There are also a number of problem areas Varmus intends to focus attention on. The first of those is how NCI goes about conducting clinical trials. An IoM report, done at NCI’s request and released last April, noted that the NCI’s Clinical Trials Cooperative Group Program was falling short of its potential. Inefficiency, lack of innovation, and inadequate support for trials has resulted in the hampering of scientific progress, the report stated.

“This is not just about getting the clinical trials groups properly retrofitted or making things run more quickly. It’s about injecting a new kind of science into how we do clinical trials,” Varmus explained. “We’re going to have to think about therapies in a new way and do trials in a new way. [The] basic science of cancer therapeutics is changing and we need to make this a moment where we adapt the system of doing clinical trials across the country into one that makes better use of genetic information; that tries to draw conclusions even if trials don’t work; and make trials smaller and faster. We need to engage more patients and physicians in these trials and explore a very large universe of potential targets for therapy.”

Another problem area is clinical research in the intramural arena, Varmus said. NCI’s clinical research effort within NIH’s Clinical Center could be much stronger. The institute needs to start thinking about how it can support the Clinical Center, how it can recruit scientists into its clinical research program, and how to build its patient base.

Genomics and Global Health

Varmus admitted that not all of NCI’s challenges will be met by just coming up with great questions. One of the biggest challenges he sees is how to better integrate the field of cancer genomics, notably the work coming out of the Cancer Genome Atlas, into NCI’s research process. “This is an area that seems to dominate our thinking at the moment,” he noted. “I think of it as the signature program at NCI. It’s a very complicated program that consists of a very productive collaboration between NCI and the Genome Institute. It’s an incredible opportunity to study any cancer.”

The implications of understanding the damage that exists in the genomes of cancer cells could have a profound effect on all of NCI’s major goals—prevention, diagnosis, classification, treatment, and monitoring of cancer. With that potential as his justification, Varmus intends to move the TCGA out of Center for Scientific and Strategic Initiatives and create a center specifically for cancer genomics.

Another new center planned for NCI—one that focuses on an area of great interest to Varmus as a scientist—is a center for cancer and global health. For the last 14 years, Varmus has been heavily engaged in the global health movement and feels that NCI can play a very important role.

There is a tendency among global health advocates, he admitted, to reach for the low-hanging fruit, such as TB, malaria, diarrhea, and pneumonia. “But there is a growing interest, especially as populations in poor countries become older, in dealing with chronic disease, including cancer,” Varmus explained.

He admitted that it is unlikely NCI will be able to bring advanced therapies like pancreatic cancer surgery or intensity-modulated radiotherapy to poor countries. But much can be done to reduce cancer risk through things like tobacco control and vaccination against oncogenic viruses. For example, cervical cancer is often the major cause of death from cancer in poor countries, and vaccines now exist to protect against the most highly implicated strains of the human papilloma virus.

“Use of those vaccines has been extremely limited because current recommendations call for three injections, and it’s very expensive,” Varmus explained. However, research being done in Costa Rica has shown that two doses can be as good as three, and one dose might be enough. If those results hold true, it would make vaccinations in poor countries far more viable.

“There are more deaths from cancer these days in poor parts of the world, and that’s a responsibility that I think NCI needs to take on,” Varmus declared.

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