Why do obese people get cancer more often? How can some turtles live more than a century without ever developing tumors while mice can develop them in a year? Could treatments that hold tumor cells in check without destroying them keep people alive longer?
Answering questions like these may lead to the next big cancer breakthroughs, said Harold Varmus, director of the U.S. National Cancer Institute, in an interview. The Nobel Prize winner said the NCI would spend at least $15 million this year in a new initiative to answer 24 “provocative questions” that researchers have often neglected.
“In an effort to stop people from obsessing over the fact that the budget is not growing, I’ve been trying to engage them in workshops to define the great unanswered questions in cancer research,” Varmus, 72, said in an interview at Bloomberg’s headquarters in New York. “We’re trying to drive science in a novel way.”
Spending for the Bethesda, Maryland-based institute Varmus has led since July 2010 will decline to $5.07 billion in the 2012 fiscal year from $5.1 billion in 2010. The provocative question project will try to create a middle ground between top-down big science projects, and relying on scientists to come up with their own ideas, according to a commentary published in Nature magazine this week by Varmus and Ed Harlow, a cancer researcher at Harvard Medical School in Boston and senior adviser to Varmus.
Varmus and his colleague J. Michael Bishop shook up cancer research in the 1970s with pioneering studies suggesting that cancer genes can arise from the normal genes in our cells. The finding, for which Varmus and Bishop shared the 1989 Nobel Prize in medicine, led to the discovery of numerous mutated genes that cause cancer. It paved the way for the current wave of cancer drugs targeting proteins made by these bad genes, including medicines from Pfizer Inc., Roche Holding AG, and Novartis AG.
Now Varmus, in his latest role, is shaking things up again.
“In a time of financial difficulties where budgets are under pressure, this is a method of trying to make sure smart people are working on projects other than the most obvious ones,” Harlow said in a telephone interview.
Varmus started the provocative questions effort after taking over as NCI director, following a decade as president of the Memorial Sloan-Kettering Cancer Center in New York. Before that, Varmus served as director of the U.S. National Institutes of Health.
In October 2010, Varmus and Harlow held the first of 16 workshops bringing together disparate groups of scientists to come up with important questions not being raised by existing research. That generated the current list of 24 questions. About 750 research teams have submitted proposals to address them that are now being evaluated for funding. The winners will be chosen this summer, Harlow said.
One mystery is explaining the relation between obesity and cancer risk, Varmus said. Obesity is linked to higher chances of incurring cancers of the breast, colon, kidney, pancreas, thyroid, gallbladder, esophagus, and uterine lining, according to the NCI website.
“If we didn’t have any obesity in this country we would probably have 20 percent fewer deaths” from cancer, Varmus said. Yet scientists know little about how obesity causes deadly cancers, he said.
Another puzzle is the relationship between aging and cancer, Varmus said. While cancer is often called a disease of aging, turtles can live more than a century without getting cancer, Varmus said, while many mice die from cancer within a couple of years. What accounts for the differences?
A third question came from an evolutionary biologist who attended one of the brainstorming sessions, said Harlow. While cancer doctors have traditionally used high drug doses to kill tumors, the evolution researcher pointed out that rapid cell-killing may clear the way for drug-resistant cancer cells to emerge and grow, Harlow said.
“It was clear that what he was describing is exactly what we are experiencing” with many new cancer drugs, said Harlow. “You select for resistant cells very quickly.” This led to the question of whether therapy that holds tumors in check without killing them might work better, Harlow said.
Harlow said that Varmus “has dramatically raised the expected level of scientific rigor” at the cancer institute.
“We are so fortunate to have him in the NCI position,” said Ronald DePinho, president of the University of Texas MD Anderson Cancer Center in Houston. Varmus has “significant bandwidth” for understanding how to advance toward a cure.
In the interview, Varmus said that the explosion in gene sequencing technology is transforming how cancer is diagnosed and treated. In five to 10 years, all patients with worrisome tumors will have the genes inside their tumors sequenced to find out what genetic alterations are driving their cancers -- and what therapies may benefit them, he said.
“It may be the biggest change we have ever seen in oncology,” he said. Some patients are already getting matched to new drugs as a result of having their tumor genome sequenced, he said.
The genome will allow researchers to precisely target drugs to subsets of patients, and will also allow researchers to find out how tumors develop resistance and how to combat it with second-generation drugs or drug combinations, he said.
“You are going to hear about a lot of cancers in which a certain gene is mutated 5 percent of the time or 2 percent of the time, and we have a drug that works for it,” he said. “You are going to hear that over and over again.”
Pfizer’s new lung cancer drug Xalkori, approved in the U.S. last August, targets a genetic change found in 3 to 5 percent of lung cancer.
‘Very Small’ Market
This trend won’t always be good for drug companies, he said. The market may “get very small” when doctors target drugs to narrow slices of the population, he said.
Varmus also has created a Center for Global Health at the NCI to stimulate research into how to control cancer in developing countries in South America, Asia, and Africa. This is a complex problem, as the incidence of different cancer types varies widely among countries, he said.
Infections are big contributors to cancer in poor countries, he said. In some countries such as Uganda, infectious diseases may be involved in causing as much as 60 percent of cancers, versus 10 percent to 15 percent of cancers in the developed world. Increased use of vaccines for the human papillomavirus and hepatitis B can prevent some of the cancers, Varmus said.
“We have 100 million people who will lose their lives to cancer worldwide this decade,” said DePinho of MD Anderson. “Harold is putting his laser focus on that. He is brilliant.”