There is still a lot we do not understand about cancer cell growth regulation, signaling, and pathogenesis. And we look to investigator-initiated basic research to lead the way to breakthrough findings.
—Douglas R. Lowy, MD
On April 1, 2015, Douglas R. Lowy, MD, became Acting Director of the National Cancer Institute (NCI), succeeding Harold Varmus, MD, who left NCI to join the faculty of Weill Cornell Medical College in New York. (See “The Next Step in a Storied Career,” in the May 25, 2015 issue of The ASCO Post.) Dr. Lowy, who had been serving as Deputy Director of the Institute under Dr. Varmus, is a long-time NCI intramural researcher, with a particular focus on the basic and translational aspects of human papillomavirus (HPV) infection and on cancer genes, especially the DLC1 tumor suppressor gene, a Rho-GTPase–activating protein, which is downregulated in many cancers.
Last fall, Dr. Lowy and John T. Schiller, PhD, Deputy Chief of the Laboratory of Cellular Oncology at the NCI, were recognized for their basic research on papillomaviruses, which led to the development of the HPV vaccine, with the National Medal of Technology and Innovation. Their work in papillomaviruses, which began in the 1980s, has resulted in three U.S. Food and Drug Administration (FDA)-approved vaccines for HPV.
The ASCO Post talked recently with Dr. Lowy about his goals for the Institute, the ramifications of budgetary cuts, and his outlook for cancer research advances over the next 5 years.
Greatest Need and Greatest Opportunity
Great progress is being made in cancer research, but funding for the NCI continues to stagnate. What are your priorities for the Institute based on the current budgetary constraints, and what do you hope to accomplish?
The NCI is going to continue to conduct research that goes from the most basic to the most applied. And we will continue to look for areas of greatest need and greatest opportunity. In terms of highlighting some areas we are focusing on, clearly the oncology portion of President Obama’s proposed Precision Medicine Initiative is a high-priority area for us.
Another area I would like to highlight is the importance of precision medicine in cancer prevention and screening, because there has already been substantial achievement in those two areas, just as there has been in the area of cancer treatment. When people hear the words “precision medicine,” many think first and foremost about treatment, but precision medicine is equally relevant in the areas of cancer prevention and screening.
We are also focusing a lot of attention on cancer health disparities to understand the factors that contribute to them, including biology, lifestyle, health care access, and utilization, as well as the relative importance of those factors and what might be done to mitigate them.
And, finally, NCI remains very interested in supporting basic research, even basic research that may not have immediate translational implications—what people sometimes refer to as basic, basic research. There is still a lot we do not understand about cancer cell growth regulation, signaling, and pathogenesis. And we look to investigator-initiated basic research to lead the way to breakthrough findings. Although those findings might not have immediate implications for today, at least a subset of those findings will have important implications for tomorrow.
Balancing Benefit and Harm
How would precision cancer screening be different from current screening modalities?
There are numerous ways in which one could envision changes, and the changes do not necessarily need to be in the area of precision medicine. One could imagine, for example, the development of improved imaging technology for cancer screening, which might help our ability to provide increased benefit and less harm to patients. The big problem with our current cancer screening methods is not being able to achieve a higher benefit-to-harm ratio, because although screening provides some benefit, it also provides some harm. And the overall goal of screening is to increase that benefit-to-harm ratio.
The opportunities for using molecular approaches for cancer screening are also considerable, but many of them have not yet been fully explored. For example, we understand a bit about the performance of Cologuard, which was recently approved by the FDA for colorectal cancer screening, based on clinical studies. However, we do not yet have a clear notion of how the test will perform in the real world compared with some of the other more traditional approaches, such as colonoscopy.
And last year, the FDA approved the first HPV DNA test for women 25 and older that can be used for primary cervical cancer screening, and it was shown to be more accurate in diagnosing cervical cancer than cytology or Pap smear screening. So, there might be additional forms of molecular screening tests that are developed for many other cancer types in the near future.
Bipartisan Support for NCI
ASCO is calling on Congress to support a 7.5% increase in National Institutes of Health (NIH) funding and a proportional increase for NCI for fiscal year 2016.1 What are you asking for in the NCI’s fiscal year 2016 budget, and does Congress seem receptive to increasing NIH’s budget?
The NCI fiscal year 2016 bypass budget proposed a 15% increase. The President’s budget has proposed a 3.3% increase in the NIH budget, which includes an increase for NCI. Those are the two different numbers: one proposed by the President and one proposed by the NCI in its bypass budget.
As for how much enthusiasm there is in Congress for raising the current appropriation, we had a budget hearing recently with the U.S. Senate Appropriations Subcommittee on Labor, Health and Human Services, Education, and Related Agencies. Both Chairman Roy Blunt (R–MO) as well as several other Republican members expressed their strong support for the NIH and interest in raising its budget, as did Ranking Member of the Committee Senator Patty Murray (D–WA) and several other Democrats. Whether their support will lead to an actual substantial increase in the NIH and NCI budgets remains to be seen, but clearly there is a lot of support for NIH and for increasing the appropriation on both sides of the aisle.
The RAS Initiative
In 2013, the NCI launched the RAS Initiative to improve the treatment of many cancers driven by mutant RAS genes. Please talk about some of the findings of the RAS Initiative so far.
There are several active projects being pursued in the RAS Initiative where we have already seen progress. One is in the development of new assays for RAS inhibition, which can be subjected to high-throughput screening. Another is in the joint effort of the Pancreatic Cancer Action Network and the NCI’s Frederick National Laboratory for Cancer Research to award two postdoctoral fellowships to support research on KRAS mutations in pancreatic cancer. A third project is the development of a number of high-quality reagents, which will be made available to the cancer research community, so investigators can be studying material with a similar origin.
Encouraging Cancer Research
When we talked a year ago, you mentioned that the NIH was experiencing a loss in cancer researchers due to reductions in funding. Has the situation stabilized, and what have been the ramifications of stagnant budgets over the past decade?
Unfortunately, some people have left cancer research because of our inability to support as many investigators as we would like. On the other hand, we are certainly trying to provide strong support for early-stage investigators as well as other kinds of support for transition funding for postdoctoral fellows, for example, and for physician/scientists, so they have a greater likelihood of becoming independent.
Last year, we launched the Outstanding Investigator Award, which is not designed to increase retention among cancer researchers, but rather to provide long-term support for some of our outstanding investigators, so they can work on cancer research that might be more speculative or may take longer to pursue. The Outstanding Investigator Award provides a higher dollar amount for a longer period than our other awards—up to $600,000 per year for 7 years—so the researcher has funding stability.
The first round of applications has been received, but we have not yet awarded grants for those applications. The Outstanding Investigator Award is something we are looking forward to continuing to support. We want investigators to take risks and worry that in some funding environments, that may be more difficult to do, and this is one way in which we are trying to support those efforts.
We also support the R21 Exploratory/Developmental Research Grant Awards, which are shorter-term grants that fund more speculative projects. Fortunately, we have been able to award more of the R21 awards in the past couple of years than we had prior to that.
What advances do you see happening in cancer research over the next 5 years?
In the next 5 years, we will almost certainly see a substantial expansion in the number of FDA-approved drugs for cancer. Effective immunotherapeutic agents, particularly the checkpoint inhibitors, show great promise in a number of cancers. We already have FDA approval on several immunotherapies, and I look forward to more being approved.
Over the next few years, we will have a better understanding of how well these therapies work as single agents and where they are less effective. I also expect that we will be making progress in overcoming cancer resistance and in improving outcomes for patients who develop cancer and that we will see this progress not just in adult cancers, but in pediatric cancers as well.
In addition, I see opportunities for cancer prevention. One area we need to do a better job in is getting people to alter their modifiable risk factors, such as smoking and obesity, which we know cause cancer. If we could get people to modify those risk factors, we would have a substantially greater impact on reducing cancer incidence and mortality.
Finally, by having a better understanding of the causes of cancer and its early pathogenesis, we should be able to use our ever-increasing armamentarium of molecularly targeted approaches to do a better job of treating patients than we do right now. And I would see analogous potential in the area of cancer screening.
I would be neglectful if I didn’t mention that we are looking forward to substantial advances in basic research. And one of the great things about basic research is we do not know exactly where those advances are going to come from or what they will be, but I suspect we will be in a different place in the next 5 years than we are right now in terms of our understanding of cancer and our opportunities to intervene.
Will heading the NCI have an impact on your research in HPV infection and your work on cancer genes, particularly the DLC1 tumor-suppressor gene?
Of necessity, I will be doing less laboratory work. I look forward to remaining engaged in the laboratory, but being Acting Director of the NCI is a very big position, and I must give it my top priority and attention.
What would you say are the greatest challenges you face?
My biggest challenge is the Solomonian problem of deciding what to fund, because we run out of money long before we run out of good ideas to test. That is by far my biggest problem. n
Disclosure: Dr. Lowy has received limited royalties from Merck, GlaxoSmithKline, Indian Immunologicals Ltd., and Shantha Biotech.
1. ASCO to Congress: Get serious about putting biomedical research back on track. Statement by ASCO President Peter Paul Yu, MD, FACP, FASCO. April 29, 2015. Available at www.asco.org/advocacy/asco-congress-get-serious-about-putting-biomedical-research-back-track. Accessed May 19, 2015.