Advancing Cancer Research in Challenging Times

A Conversation With Norman E. Sharpless, MD

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Norman E. Sharpless, MD

Norman E. Sharpless, MD

ON OCTOBER 17, 2017, Norman E. Sharpless, MD, became the 15th Director of the National Cancer Institute (NCI), succeeding Harold E. Varmus, MD, who stepped down as Director of the agency in March 2015, and replacing Douglas R. Lowy, MD, who had served as Acting Director for 2 years. The appointment marks a return to the NCI for Dr. Sharpless, who first worked there in 1990 as a young researcher, while a member of the Howard Hughes Medical Institute–funded National Institutes of Health (NIH) Scholars Program.

Most recently, Dr. Sharpless was Director of the University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, and he has spent most of his clinical career caring for patients with leukemia. In addition to serving as Director of the NCI, Dr. Sharpless will continue his laboratory research in the biologic relationship between aging and cancer as well as in the preclinical development of novel therapeutics for melanoma, lung and breast cancers, and other solid tumors.

After spending several months meeting with NCI staff and leaders in the cancer community, gathering information on how best to harness the NCI’s formidable resources to accelerate the pace of cancer research, Dr. Sharpless talked with The ASCO Post about his plans for the agency. He also discussed the impact on the NCI of operating under temporary funding measures and the growing need to support young investigators.

Overcoming Impediments to Cancer Research

You became Director of the NCI at a crucial time in the history of cancer research, when advances in novel therapies are happening rapidly. What are some of the challenges you see that could impede this progress, and how can they be overcome?

I agree; research progress is happening at a dizzying pace, and that is a good problem to have. It is a problem because advances are happening so fast that getting your arms around the implications of these advances is complicated. The good news is we are making progress in a lot of areas.

One challenge is that although we get very generous financial support from Congress—about $5.7 billion—the burden of cancer in the United States is such that even that amount is not enough to fund all our scientific proposals. So I think pursuing the best science that is worthy of NCI support remains our number 1 job. We are pursuing so many promising therapies from so many different avenues, discerning what is crazy science fiction and what is good science is difficult.

“Research progress is happening at a dizzying pace, and that is a good problem to have.”
— Norman E. Sharpless, MD

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Another important challenge is that clinical trials in the United States have changed remarkably over the past 2 decades. The traditional structure of a clinical trial that includes hundreds of patients in two randomized arms with slightly differing treatment protocols and a 1% difference in survival, for example, was really invented for cardiology and is no longer applicable to the investigation of cancer, which constitutes thousands of different diseases that require vastly different therapies. Modernizing the clinical trials apparatus to support that new reality is important and a big challenge for us because cancer clinical trials are becoming fragmented, smaller, expensive, and frustrating.

The third challenge that I’m eager to take on is the use of big data. We realize that data aggregation is a powerful tool in cancer research, but there are reasonable concerns about patient privacy and the complex issues of data sharing. So while we are enthusiastic about data aggregation and data sharing, it is just a lot harder to implement than we would have envisioned.

Using Big Data to Personalize Treatment

Do you foresee NCI using a big data tool such as ASCO’s CancerLinQ® to facilitate the gathering of patient data to better guide personalized cancer treatments?

We are still figuring out the best role for NCI to play in terms of big data and data aggregation. We have our own NCI Data Catalog, which includes data from NCI’s National Clinical Trials Network and the Genomic Data Commons, among other data sets available to cancer researchers, but I don’t think our intent is to make that the only set of aggregated data or the de facto best set of data for researchers.

There are other big data efforts, such as CancerLinQ, that we are very interested in learning how we can support and be involved in their development. I can imagine the NCI playing some role in setting standards for the elements that should be included in a successful cancer data set—for example, how to handle unique identifiers so the same patient doesn’t appear in three different data sets.

Identifying NCI’s Main Priorities

What is your vision for the NCI going forward, and what are your main priorities for the agency?

The NCI is such an immense and complicated agency, to come in as an outsider and say here are five things we have to fix by tomorrow would be an unwise decision. I’ve been spending several months talking to various stakeholders both inside and outside of the organization to get a sense of what NCI does particularly well and where we have problems, to understand NCI’s mission in a complete way. I’m still on that “listening-and-learning tour,” and I expect it to go on a bit longer.

Having said that, there are a few obvious activities we need to continue, as well as directions we need to pursue in a more substantive way. I’ve already touched on a couple of them, including data sharing and data aggregation and NCI’s policies related to that technology, as well as the role of the NCI through our clinical trials portfolio. We make a significant contribution to the ongoing clinical trials in the United States, and we have a real opportunity to make that process better for patients and more effective for scientists, so that’s another area we are exploring.

“There are those who ask why we are not solely doing clinical and translational research, but the next major advance in cancer research always begins with basic research.”
— Norman E. Sharpless, MD

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In terms of our internal programs, the NIH Clinical Center is one of our crown jewels for research and a real challenge for us is to make sure it stays cutting-edge and vibrant. In that regard, I’m particularly enthusiastic about the work of Steve Rosenberg, MD, PhD [Chief of the Surgery Branch and Head of the Tumor Immunology Section at the NCI], and his colleagues in cellular immunotherapy and about exporting those technologies to other centers.

And although I’m a treating physician, I am also a passionate believer in the role of strong basic science. We have made amazing progress in cancer research in some areas, but there are other areas of cancer biology and cell biology where our understanding is far from complete. So an important part of NCI’s mission has always been and continues to be the support of very strong basic science.

There are those who ask why we are not solely doing clinical and translational research, but the next major advance in cancer research always begins with basic research. We have to continue to make that argument, even in 2018, about why basic research continues to be important. I very much believe it is.

Progress of NCI Research Initiatives

Please talk about the progress you are seeing in cancer research as a result of the NCI-MATCH study, the RAS Initiative, and the Beau Biden Cancer Moonshot program.

The NCI-MATCH trial started when I was in the extramural community, where I heard much skepticism about it. There was worry that the trial wasn’t designed properly or that patients weren’t going to accrue to the trial, but I have to say the trial is an obvious and stunning success. It has accrued faster than almost any other NCI trial, and enrollment has closed 2 years ahead of schedule. We’ve enrolled over 6,000 patients, and one of the most important statistics to me is that enrollment has occurred in over 1,100 different centers in the United States.


  • The NCI’s MERIT R37 award aims to allow eligible investigators the opportunity to obtain up to 7 years of support in 2 segments—an initial 5-year award and an opportunity for an extension of up to 2 additional years.
  • Investigators may not apply for the award. Early-stage investigators who submit a single–principal investigator R01 application that receives a score within the NCI payline are eligible for consideration for the award.
  • NCI staff will identify eligible candidates and submit them to the National Cancer Advisory Board (NCAB). If recommended by the NCAB and approved by NCI leadership, the R01 will be converted to a MERIT R37 award for the initial 5-year funding.
  • For more information, visit

When I talk about how clinical trials have to be designed in a new way, I am really thinking of NCI-MATCH, where trials are designed to be exportable to community practice and can be done at a cost that is much lower per patient than a classic phase III randomized trial. NCI-MATCH represents a big step in the direction of the future of medical oncology and how we design clinical trials.

Data from NCI-MATCH are starting to be collected and will be published soon. But we are already seeing that some of the arms to which patients were allocated have clear signals of efficacy, so the process of matching patients to therapy based on the somatic mutations in their tumor is working for some patients.

The allocation rate—the number of patients being assigned to a therapy based on their mutation—is higher than I would have predicted. It’s 15% in one analysis and 10% in the intent-to-treat analysis, but still 1 in 7 to 1 in 10 patients is being told what drug to take based on sequencing. And these are patients who had no standard-of-care options left.

Similar studies are underway, including ASCO’s Targeted Agent and Profiling Utilization Registry (TAPUR) Study, and others are being planned. I expect the experiences of these other trials will be consistent with what we’ve seen in NCI-MATCH, which is that the process of allocating patients to therapy based on the molecular details of their tumor is workable in a real-world setting. And if the trial is designed properly—meaning there are enough different drug options for each patient—a large number of patients will benefit.

The RAS Initiative was the vision of Harold Varmus and Doug Lowy, to figure out how to target RAS mutations. That initiative is also shaping up to be a terrific success. We’ve already learned some important lessons from a basic science viewpoint, such as the understanding that there is probably not going to be one mutant RAS drug. We’re going to have drugs for NRAS mutations or KRAS mutations, and even the different codons may have different sensitivities to these different agents.

We’ve realized that our initial vision of RAS therapies was naive; like everything else in cancer, the subsets are much more fragmented than we had envisioned. But that is also helpful to know, because now we can work on specific RAS mutants and try to develop novel therapies for each one.

“NCI-MATCH represents a big step in the direction of the future of medical oncology and how we design clinical trials.”
— Norman E. Sharpless, MD

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By my count, we now have about five different, completely distinct lines of therapy in clinical trials trying to target RAS mutations or immediately downstream RAS proteins based on work or expertise provided by the RAS Initiative. So it is certainly leading to novel clinical trials. The real test will be whether the initiative leads to novel therapies, but it’s too early to tell. Still, I’m very excited about the prospects; so far, so good.

The Beau Biden Cancer Moonshot is just a year old. I’m a big fan of the way the Moonshot was conceived and the research priority areas identified by the Blue Ribbon Panel. A significant initial success of the Cancer Moonshot is that its passage meant an infusion of $300 million of new money into the NCI budget, which had to be spent rather quickly because of the fiscal year issues. Within months, NCI staff identified and awarded grants that were consistent with the Moonshot priorities. We are starting on Year 2 of this program, and we have released a new slate of requests for applications for Moonshot proposals.

We will see over the next few years what impact Moonshot funding has had on clinical research, but I’m highly optimistic that it will accelerate research progress in a meaningful way for patients.

Are you planning any new research initiatives?

Yes, but they are probably not ready to be discussed just yet. I am still on the listening tour.

Budgetary Issues

The NCI is still operating under a continuing resolution that funds the government at fiscal year (FY) 2017 levels. The FY 2017 budget included about $5.4 billion for the NCI and an additional $300 million in FY 2017 for the Cancer Moonshot initiative. When adjusted for inflation, the NCI budget remains below prerecession levels. How is funding impacting the number of grants awarded each year, and do you worry that continuing resolutions and inconsistent funding are hindering research progress and driving away young investigators?

First, it is important to note that the budget for the NCI and the NIH for the past 2 years has been good. The NIH had two $2 billion increases in a row, and the proposed numbers from the Senate and the House for 2018 would also be favorable, although we don’t have a budget yet. [Editor’s Note: On February 9, 2018, President Trump signed into law the Bipartisan Budget Act of 2018, which includes $2 billion in increased funding for the NIH for FY 2018 and FY 2019.] I believe there are people in Congress who are very interested in supporting the NIH, and particularly the NCI. So that is the good news.

“Our grant portfolio is so big, I estimate we probably need more than $100 million of new money not to lose ground on our existing grants. If we have an increase that is smaller than that, we have to start cutting grants in proportion to the awards.”
— Norman E. Sharpless, MD

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The challenging part is that the legislative process is complex, and the NCI and NIH are part of a larger Federal budget. And, of course, the White House has its additional priorities, so the budgeting process is unpredictable.

The way the NCI is set up, if we were to have a full year of continuing resolutions, that would actually entail cuts for us, because many of our grants have cost-of-living increases built into them. Our grant portfolio is so big, I estimate we probably need more than $100 million of new money not to lose ground on our existing grants. If we have an increase that is smaller than that, we have to start cutting grants in proportion to the awards, so instead of the full 100%, we give 98%. That is the reality of the job.

There are also other ongoing year-to-year commitments at the NCI that are quite large, and continuing resolutions limit our ability to be flexible and take on new initiatives. And this problem gets to the question about what these budgetary restrictions mean for young researchers. If they see paylines (the funding cutoff points for grant applications) of less than 10% or grant approval success rates of 12%, will this be demoralizing and cause young investigators to go into other areas of research or leave biology and go work for Google? I’m very sensitive to this worry.

Developing the future scientific workforce, training young scientists, and making young scientists successful are among our top priorities, and we are very interested in supporting early-stage investigators—ie, a program director or principal investigator who has completed his or her research degree or postgraduate clinical training within the past 10 years.

We have a number of training grants for graduate students and postdoctoral students, and I think we are delivering a large number of people who want to do cancer research. But it’s really at the early faculty stage where a significant bottleneck still exists. When you talk to young investigators, they tell you about the stress they are under and the worry they have about tenure promotion and balancing their young families with their passion for scientific research.

So here are some things we can do to help. We have just rolled out the Method to Extend Research in Time (MERIT) R37 award for early-stage investigators. Beginning in FY2018, when early-stage investigators apply for a research grant (R01) and get a score that is within the payline, they will be eligible to have their award converted to an R37, which is a 5-year award that is exactly the same amount of money as the R01, but it also includes the option for 2 additional years of funding with a minimal application process. We also award a number of R01s outside of the payline through a select-payment mechanism.

We also looked at the demographics of our early-stage investigator grant recipients, and the data don’t support keeping the early-stage investigator designation for completion of a research degree or postgraduate clinical training at 10 years. We think people who are 9 years from their graduate degree vs those who are 11 years from their graduate degree don’t differ much in terms of their future success in science, so we are in the process of redefining early-stage investigators using a more liberal definition, extending the date to 15 years instead of 10 years.

We are also committed to finding money to support a few more early-stage investigator awards, so the success rates for early-stage investigators, which now sit at about 16%, should go up, relative to the rest of the R01 pool.

I’d also like to point out, in terms of the training and workforce development mission at the NCI, we are training exactly the right complement of people in some areas of research. However, there are two areas—big data and the clinical application of immunotherapy—where there is a clear-cut need to develop future scientists and future clinical researchers.

In big data, there is a real need for more physicians who can code for billing, enter data in patients’ electronic health records, and work in a Unix environment. In the area of the clinical use of immunotherapy, we have realized there are a limited number of clinicians available at institutions to treat patients in need of immunotherapy or cellular immunotherapy and who understand the toxicities of these therapies. We want to train more scientists and more clinicians in these two areas, and we are thinking about the mechanisms we can put in place to address these specific needs. ■

DISCLOSURE: Dr. Sharpless is Director of the National Cancer Institute.