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“Why is breast cancer such a different disease in Japan and other Asian countries, as compared to the US? The difference is not just an overall lower rate. Breast cancer occurs more frequently among middle-aged females, as compared to older (60+) women in Japan, unlike the US. Furthermore, Japanese women show a better prognosis than US women, even when controlling for tumor size and lymph node metastasis.”

“Why are so few cancer vaccines made against surface tumor antigens? Surface antigens like HER-2 and MUC1 are better targets than the more popular intracellular antigens. Immune recognition of intracellular antigens depends entirely on antigen processing machinery and major histocompatibility complex (MHC) expression, both frequently defective in tumors. Cancer immunology and immunotherapy could find a wealth of new vaccine targets among tyrosine kinase receptors and other classes of cancer-related surface molecules.”

—Sample questions from the NCI's “Provocative Questions” website

When Harold Varmus, MD, became director of the National Cancer Institute (NCI) in July 2010, he proposed a new approach to defining important areas to explore in cancer research. The effort he envisioned would involve both the scientific community and other interested stakeholders in determining key questions in the field.

The resulting “Provocative Questions Project” included a number of workshops with scientific leaders from across the country and a website enabling scientists and others to offer their own questions and comments. The project's overall goal, according to the NCI, was “to assemble a list of important but non-obvious questions that will stimulate the NCI's research communities to use laboratory, clinical, and population sciences in especially effective and imaginative ways.”

Because science is progressing at such a rapid pace, new observations and technologies are now available to answer some of these questions that have not been adequately answered in the past, Dr. Varmus notes. “They are allowing us to answer questions that have been mysterious, perplexing, forgotten, and not known before in ways that are less evident to the casual observer,” he adds. “It is important to understand the answers to these questions that might not receive the attention they deserve.”

Our job was to probe all the corners, to bring up a richness of perspectives and make sure we didn't leave any stone unturned.—Lynn Matrisian, PhD

At press time, NCI leaders were expected to pare down the list to between 15 and 20 questions by the end of summer 2011 and announce a request for applications (RFA). Investigators were invited to submit grant applications to address one of these questions. The RFA was approved for $15 million for FY 2012. It included funding for 25 standard, 4-year R01 awards as well as 10 exploratory, 2-year R21 awards. Awards are expected to be announced this fall.

“We're particularly interested in soliciting innovative ideas with less emphasis on preliminary data than usual,” says NCI Deputy Director Douglas Lowy, MD, noting that the NCI Board of Scientific Advisors was concerned that grant applications with preliminary data would invariably trump those that did not have such data.

“We want to support people with good ideas, even though those ideas may not have been tested,” he adds.

Question Criteria

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  2. Question Criteria
  3. Focusing on Specific Questions

At the time Dr. Varmus first conceived of the project, he and others did not envision the fiscal constraints with which the NCI would be faced—and in such times, grant review committees tend to become more conservative and more risk averse, Dr. Lowy notes. Still, the goal of the Provocative Questions Project is to take more risks by asking questions that may not have a great deal of preliminary data attached to them.

Among the criteria for the questions were that they:

  • Build on specific advances in our understanding of cancer and cancer control;

  • Address broad issues in the biology of cancer that have proven difficult to resolve;

  • Take into consideration the likelihood of progress in the foreseeable future (e.g. 5 to 10 years); and

  • Address ways to overcome obstacles to achieving long-term goals.

The NCI sponsored 4 workshops between October 2010 and February 2011 at its headquarters in Bethesda, Maryland, followed by 3 more on the west coast and another at the NCI. Each workshop focused on discussing questions in key scientific areas, including clinical and translational sciences, basic sciences and behavior, population, epidemiology, and prevention.

“We're trying to get a range of questions in different categories,” Dr. Lowy says.

Tyler Jacks, PhD, director of the David H. Koch Institute for Cancer Research at the Massachusetts Institute of Technology in Boston, Massachusetts, was involved in overseeing the process and was also a participant in the basic sciences workshop.

“It was very different than what we tend to do at think tanks and in brainstorming exercises, where we're driven by the science that is taking place around current trends and then building off of those,” Dr. Jacks says. “This exercise was meant to take stock of what we know and don't know and what we thought we knew. It was much more wide-ranging than typical planning exercises.”

Workshop participants were asked to bring provocative questions, which were then organized into related categories and presented by scientists who had proposed them. The presentations were followed by discussion among the groups, which comprised about 20 or more experts in each specific field from the NCI and across the country. Ultimately, the groups prioritized a list of questions that best fit the project's criteria.

Focusing on Specific Questions

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  2. Question Criteria
  3. Focusing on Specific Questions

One example of a highly relevant question, according to Dr. Jacks was, “Why do certain chemotherapeutic regimens work?” Cisplatin, for example, is extremely effective in testicular cancer, including metastatic disease, yet no one knows why it works so well. “This longstanding observation could be very important,” he notes. “If you could understand why it works in that context, maybe you could understand how it might work in other contexts.”

Other questions, such as cataloging changes that occur as tumors evolve, did not make the cut because they already were considered part of mainstream cancer research, Dr. Jacks adds. Lynn Matrisian, PhD, chair of the department of cancer biology at Vanderbilt University in Nashville, Tennessee, participated in the clinical and translational sciences workshop. “It's always good when the public and scientific community are asked for their opinions,” she says. “Our job was to probe all the corners, to bring up a richness of perspectives and make sure we didn't leave any stone unturned.”

Her contribution to the list of questions involved looking at the role of inflammation as a cancer precursor and trying to determine specific markers of inflammation and an endpoint that could be used in a prevention trial. Encouraged by recent reports of long-time anti-inflammatory users experiencing a decline in cancer incidence, Dr. Matrisian thought this question would be an interesting one to explore. She drew an analogy between the ability to control heart disease by monitoring blood pressure and cholesterol and the possibility of reducing cancer by monitoring inflammation.

The final list of questions is expected to be a composite of those proposed via the workshops, those proposed on the Provocative Questions website, and those refined via the website “to become even better questions,” Dr. Jacks notes.