Leading the Fight // Dr. Ned Sharpless, Director of the National Cancer Institute, talks about the quest to stop cancer

By Yedidya Levin

Dr. Norman E. Sharpless was appointed as the 15th head of the NCI by former President Donald J. Trump and sworn in on October 17, 2017. After a seven-month stint as acting commissioner for food and drugs at the FDA in 2019, he returned to the NCI directorship.
Dr. Sharpless has cofounded two clinical-stage biotechnology companies; authored more than 160 scientific papers, reviews and book chapters; and holds ten patents on his inventions. The married father of two lives in Washington, DC.

Dr. Sharpless practiced as an oncologist for many years, treating patients at the Massachusetts General Hospital and at Dana-Farber/Partners Cancer Care, both of which are affiliated with Harvard Medical School in Boston. He has led teams that made groundbreaking discoveries, utilizing genetically engineered mice to study cancer and aging and how normal cells undergo malignant conversion.

Prior to his appointment at the NCI, Dr. Sharpless served as director of the Lineberger Comprehensive Cancer Center at the University of North Carolina. He is therefore the perfect person to speak to about the so-called “war on cancer”—a phrase, incidentally, with which he is somewhat uncomfortable. The term became popular in the 1970s, when it was coined to describe the mass mobilization of legislative effort against the disease.

“You can see why legislators liked it,” Dr. Sharpless points out. “It talked about a sort of national campaign that required everybody to pitch in, make sacrifices and work together to make progress.” But patients don’t like to see themselves as soldiers. “If they end up dying of cancer, they don’t like to have ‘lost’ this war,” he explains. “So as someone who has talked to Congress about more funding and resources for cancer research, I’m comfortable talking about a ‘war on cancer.’ But as a physician who cares for patients, I’m uncomfortable about it as a metaphor.”


How did you get involved in cancer research?

My father was a pathologist. He always told me how interesting cancer was as a science; it’s one of the most interesting areas of medicine. When I went to medical school in the late ’80s and early ’90s cancer was a fascinating biological subject, but it was poorly understood at the time, so it seemed like a terrific research opportunity.

Of course, like all Americans, I have personal experience with cancer in terms of family members and friends who had it—including my father, who died of melanoma a year before all the new treatments and immuno-oncology approaches were starting to be approved. My father was one of the last people to die of melanoma because we had no effective therapy for it. So I think it’s due to appreciating the personal tragedy of cancer, but also the fact that it’s a very interesting scientific problem.

During my training, I really enjoyed caring for my patients. It’s a wonderful specialty, where you get to know your patients really well and you’re able to help some of them tremendously, although not everyone. I found that very rewarding. Both the science and the clinical opportunities around cancer are exciting, so it’s been a great place to spend my entire career.


Are we beating cancer?

We’ve made significant progress. Death from cancer is steadily declining at an accelerated rate from its peak in the 1990s, and it has gone down by about 30%. In 2018, the last year for which we have records, it decreased by 2.4% in a single year. For some cancers, it’s going down even faster than that. We’ve recently seen 6% and 7% declines in mortality year-over-year for lung cancer. Those declines reflect advances in diagnosis, in screening, in treatment and in survivorship. So it’s a broad suite of efforts that have led to those improvements.

But we still have 600,000 Americans dying of cancer every year. Cancer is the leading cause of death from disease in young adults and children, and it is also a tremendously expensive problem for our society. So while we have made really good progress over the last 50 years, we still have a way to go.


Are some cancers more treatable than others?

Yes. One of the major differences in our knowledge about cancer in 2021 and the knowledge we had in 1971 is that we used to think of cancer as a homogeneous single entity, or at least a handful of diseases. What we’ve learned in the last few years is that that isn’t true. Even within diseases that we thought were relatively homogeneous, like lung cancer, there are hundreds of different kinds in terms of the molecular biology of those diseases and what’s driving them. That is why we need different approaches with regard to prevention, screening and treatment.

It is that appreciation of the real heterogeneity of cancer—that cancer is not ten diseases, but hundreds or thousands of diseases—that has really changed how we think about it and how we’ve made progress over the last decade or two. It’s a fundamental advance.

It is therefore only natural that some of these types of cancer are going to be more treatable than others; that’s what the heterogeneity means. We’ve seen really good progress in particular with lung cancer and in melanoma, which were just about the worst cancers imaginable when I was starting out as an oncology fellow. Now we have patients who benefit tremendously from therapy, many of whom are even cured of advanced melanoma and lung cancer. At the same time, there are other cancers like pancreatic cancer and brain cancer where our progress has not been nearly as good and mortality has declined very subtly or not at all. We’ve even seen cancers where mortality has gone up.
At the NCI, we’re trying to figure out how to make progress for all our patients, not just some of them. We are particularly concerned about the difficult-to-treat cancers where we still haven’t seen the kind of success we would have liked.


A patient referral specialist told me that these days you can have five people getting the same cancer diagnosis at the same hospital, but a different treatment will be recommended for each one—immunotherapy, chemotherapy or radiation—due to new research showing that each patient’s genome makeup affects the efficacy of the various treatments.

Yes, that’s exactly what I was talking about. The way we came to understand that cancer is so heterogeneous was by understanding their genomes. When we research the RNA and DNA that drives each case, we find that they differ widely; cancers that look the same under the microscope can be quite different. The greater our biological understanding, the greater our progress.

With non-small cell lung cancer, for example, all of them look the same physically. They all have the same name, and we used to think of them as one disease. Now, however, there are more than 20 different subtypes that are treated with different approaches and therapies. That is why one individual may get immunotherapy, another may get surgery and radiation, and someone else may get a daily kinase inhibitor pill—and even among those there are probably ten or 15 different kinds. The idea is that the therapy is personalized to that particular individual and his or her tumor.

If you’re talking about a disease like pancreatic cancer, we have far fewer options. Most of those patients are treated in a relatively similar fashion, and most do poorly. One of our challenges is to figure out how to make pancreatic cancer and glioblastoma [brain cancer] more like lung cancer, where we have lots of different options for lots of different patients.


Are there any promising treatments for cancer that have not yet been made available to the public, whether from the NCI or otherwise?

Yes. There are many exciting things that are currently in development or in early stages of clinical testing ranging across a variety of areas. Take the idea of cellular immunotherapy, where you use a patient’s cells to activate his own immune system to fight the cancer. That’s really in its infancy. Even though we think of immuno-oncology as having produced great results—and it has—it’s still in its early days, and our understanding of that biology is very new. So there are a lot of new and exciting approaches that are coming into the clinic very soon.

Another new technology that could have a tremendous impact on cancer mortality is the idea of very early novel cancer screenings. Think about it like any other blood test one gets when going to see their doctor once a year or once every other year. And it doesn’t detect just one kind of cancer; it detects ten, 20 or even 50 kinds of cancer.

It almost sounds like science fiction that with a simple tube of blood you can screen people simultaneously and effectively for multiple cancers, identifying it at a very early stage at a time when it can be resected or treated in some way that won’t cause the patient much inconvenience. In my opinion, these things are not yet ready for usage on a large scale, but it’s a really exciting area that could radically change how we diagnose and treat cancer for most patients.

It’s going to take more study and investigation to figure out how blood-based screening could work in healthy individuals, but I think it’s likely to translate into patient benefit with enough time and analysis. There are something like 20 different technologies and approaches at present, and I suspect that some of them will be helpful.


Are all of these different companies working under the aegis of the NCI or independently?

Well, they’re private companies, so they raise capital and work on their own, but we are very interested in what they are doing. We work closely with many in the industry in general, and we try to support companies that have novel approaches either through helping with clinical trials, early-stage funding, or providing reagents and access to samples they can use.

Some of the names in the multicancer early-detection space are Exact Sciences, Grail and Delfi. Those are only three, but there are probably another 30. These companies have technologies for finding signs of cancer in the peripheral blood at an early stage. It’s not a new idea, but most of the tests that have done that in the past haven’t been sufficiently specific. They also found a lot of fake cancers and it caused problems. So there was an issue with overdiagnosis, but we think that the new technologies are sufficiently specific.


Do you think that there will ever be a cancer vaccine?

Well, I think we should first be clear about what that means. We do have some cancer vaccines, like the human papillomavirus vaccine for HPV. It’s a very effective vaccine that prevents five or six different human cancers, and we think that it needs to be used worldwide. If we had a global effort to eradicate HPV, we would make tremendous progress in getting rid of cervical cancer, neck cancer and other kinds of cancer in the United States and around the world. Hepatitis B is another virus that causes cancer, and there’s a good vaccine for that. So we already have “anti-cancer” vaccines that are working and need to be used more broadly.

We also have the idea of using cancer vaccines in the therapeutics: when somebody has cancer, we try to vaccinate him against his tumor and make the therapy work better. That’s an area that needs more thought and examination.

Then there’s a third group, which is the question I think you’re asking, of preventative cancer vaccines. These don’t attack viruses; they’re against new antigens, the things that make cancer cancer. That’s where the NCI has recently begun a few studies to try to help healthy adults at high risk for cancer due to some feature of their biology. That’s a really exciting area.

The pandemic has certainly taught us a lot about how to make vaccines and mRNA platforms and things like that, and we think that some of what we’ve learned from COVID could be useful for these kinds of preventative cancer vaccines that are not against viruses.


I was actually going to ask about COVID. Globally, around ten million people die from cancer-related illnesses every year. Since the start of the pandemic, “only” five million people have died from the coronavirus, but we saw an unprecedented effort to fast-track vaccines and various treatments. My question is, why don’t we see the same sort of massive, coordinated effort to fight cancer with the same urgency?

You raise a good point. I think many people are surprised that cancer kills substantially more people than the coronavirus, and they’re also surprised that its victims are younger; on average, they are a decade or more younger than those who are dying of the coronavirus.

The burden of cancer on American society as well as globally is enormous. In the US alone, it costs on the order of $200 billion a year for care, and then another $100 billion in terms of lost productivity, missed work and things like that.

Then there’s the overwhelming tragedy of cancer; it’s this bolt from the blue that affects otherwise healthy young adults. Even in those patients whom we are able to cure, it sometimes causes dramatic changes in their quality of life due to toxic therapies or long-term side effects. I believe that the fact that we’ve been dealing with it for so long has made us collectively inured to the tremendous burden it places on society.

What you are asking for—a coordinated, urgent effort to make progress in cancer—is something the NCI would love to see. I would also argue that while we have had a lot of success, there are things we could do more of if we had additional resources and national coordination.

The good news in this regard, in my mind, is that President Biden and the First Lady have a strong personal connection to cancer. They are a cancer survivor family and are familiar with its personal tragedy, having lost a son to it. President Biden has said on many occasions that a top domestic priority of this administration is to “end cancer as we know it.” I think this is an administration that really wants to have a strong, vigorous, coordinated national effort to urgently address the problem.

It is also important to acknowledge that in some ways, a virus is a simpler problem than the heterogeneous mess of biology that is cancer. So I don’t think we should expect the same outcome or rapidity of success for a cancer program that we would for a vaccine discovery effort.

Nonetheless, I still agree with the overarching thesis that a nationally-led effort that has new resources and new urgency would be good, because the burden on society is enormous.


If you could add to or amend the existing National Cancer Act that was signed by President Richard Nixon, what would you do?

Well, as a federal official and member of the executive branch, I’m hesitant to recommend specific policy. I think that could get me in trouble with my bosses in Congress. What I will say is that I certainly think there are areas where policy could be effective. There are opportunities for progress where the solution may not be more research but a new way of doing things, either through policy or other approaches.

A good example of that is in the area of tobacco control. I was acting FDA commissioner for a period in 2019, and I saw the impact that policy has on tobacco use. Cigarettes are the leading cause of preventable cancer in the United States: lung, head and neck, bladder and a variety of others. It’s certainly an area where policy has been effective in the past, implementing things like minimum smoking ages, proscriptions on how tobacco products are advertised, and educational campaigns to alert the public to the dangers of tobacco use. There’s also the idea of low nicotine cigarettes so they’re less addicting and bans on things like flavors.


Are there any other simple measures that could prevent cancer but are being ignored?

There’s the obesity epidemic, which is perhaps a little harder from a policy perspective but still concerns me greatly at the public health level. Obesity is strongly associated with certain kinds of cancer, including endometrial cancer and some forms of breast cancer. These cancers are actually increasing in incidence and mortality. This is something that really keeps me up at night, because obesity has significant health consequences for not only cancer but heart disease, high blood pressure and diabetes.


In 1998, on the anniversary of the National Cancer Act, President Bill Clinton declared, “Twenty-five years ago, America declared war on cancer. Twenty-five years from now, I hope we will have won that war.” Unfortunately, we have yet to reach that point. Where do you see us 25 years from now?

I hope we can say we’ve reached President Biden’s goal of ending cancer as we know it. But let’s be clear: I don’t think this means eradicating all cancer. In some ways, it’s just a biological fact of human aging, intimately associated with the aging process. The idea that we would never have cancer diagnoses or no one would ever die of it is unscientific, or at least it would require a transformational understanding of biology that I don’t see happening in the next century.

In my opinion, we will still have some cancer and some cancer deaths. But what we can do is make really great strides to eliminate the tragic and life-disrupting aspects of cancer: the cancer that’s lethal in an otherwise healthy 20-year-old, the cancer that strikes someone who has no other medical problems but receives an incurable diagnosis that leads to his death in short order. We can do this by diagnosing cancer at a stage when it’s only a nuisance so it can be treated through minimal surgery or other approaches. I think we can also have better and less toxic therapies for those who are unlucky enough to develop it in a more advanced stage, therapies that work better with fewer side effects.

I also think we can turn cancer into some type of chronic disease, where maybe one isn’t cured of it, but we have a way of keeping it at bay so that it doesn’t cause a lot of problems and patients die of something else. They die with cancer but not of cancer.

To me, that’s what “ending cancer as we know it” would mean: Making it a manageable—although perhaps inconvenient—problem for some people, but not the terrible diagnosis that it is in some individuals today.


Thank you for your time, and for the important work that you and the NCI are doing on behalf of cancer patients everywhere.

Thank you for the opportunity to speak today, and for your interest in this topic.

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