A commentary by Dario C. Altieri, M.D.
We are in the early days of a revolution in cancer medicine. One that takes us from the broad-based approach of chemotherapy to the selective targeting of cells informed by the genetics of individual tumors. To use the war analogy, we are moving from the indiscriminate use of large-scale carpet-bombing to the pinpoint accuracy of guided missile attacks.
On the occasion of the 40th anniversary of The Wistar Institute Cancer Center designation from the National Cancer Institute, I thought it might be time to reflect on cancer therapy, both in terms of what cancer research has achieved and what the future holds.
I must apologize at the outset for all the war-related imagery. Personally, I hold that our national efforts to end cancer are not part of a “War on Cancer,” exactly, but an extended campaign of exploration. The fact remains that most of us — cancer researchers, doctors, and patients — discuss the struggle against the disease in terms of war. Moreover, it may be appropriate given that the birth of modern cancer medicine began in the bloody trenches of World War I. Before we discuss the battlefields of France, however, let us use history to illustrate what we know about cancer.
Of Chimney Sweeps and Ancient Egypt
Cancer itself is as old as humankind. There is a document we now call the Ebers papyrus, written about 3,500 years ago by ancient Egyptians. It provides detailed accounts of the ancient ill of Egypt and, in particular, the first early accounts — case studies, if you will — of breast cancer. One of these cases describes a condition exactly like inflammatory breast cancer, a very rare and aggressive form of the disease, but one that has apparently been around for quite some time. Cancer is and always has been a consequence of life — accumulated errors in the mechanics of genes and proteins.
Cancer is also the product of our actions. Today, you would be hard pressed to find someone who is not at least aware of the link between smoking and lung cancer, or the dangers of too much sun. The first case of what could be termed “man-made” cancer was described in 1779 in England, the first occupational cancer of the still-nascent industrial revolution. It is the heartbreaking tale of deadly squamous cell carcinomas in chimney sweeps, typically young men in their late teens and early 20s. For these boys, their exposure to the carcinogens in coal soot probably began at an age where kids today would be learning to read.
What we know now about cancer, whether environmental or inherited, is that it is a genetic disease. It arises from cells that make mistakes and those mistakes are then accelerated by environmental factors, be they natural or man-made.
The end point is the formation of cells that harbor enough mistakes to give rise to a much-expanded proliferative clone, which eventually acquires the ability to do many things over time, such as spread and become resistant to drugs. And how much time? Science recently just quantified what these poor chimneysweeps have suggested to us in the18th century: the average life cycle of cancer — from initiation to metastasis— is about 20 years.
In 2002, Bert Vogelstein, M.D., and his colleagues at Johns Hopkins University were the first to report a complete reading of a tumor’s genome, colon cancer specifically. Now in 2012, using protein approaches and solid phase sequencing we can probably sequence the genome — reading each and every gene within the DNA of an individual human being — in two weeks for a cost of about a thousand dollars. Gene sequencing is coming to clinical practice, and it will probably become as routine as a blood test.
In time, as I will explain, this will be a great resource for treating individual cases of cancer.
From Dealing Death to Saving Lives
Across the battlefields of World War I, tens of thousands of soldiers from Germany, France, Italy, the United States, and England died horribly when exposed to chemical weapons. The Germans invented one of these weapons, called nitrogen mustard — or mustard gas — that was particularly effective at killing people, so much so that armies on either side added it to their arsenal as fast as it could be synthesized.
Doctors are a curious bunch, even in wartime, and they collected vast amounts of scientific data on the nature of mustard gas. There are countless autopsy reports of soldiers in the scientific literature, each demonstrating one consistent finding: dead lymph nodes and spleen. These lymphoid organs, which produce cells that fight infections, had been almost wiped out by exposure to mustard gas.
Enter two gentlemen at Yale University; Louis Goodman, M.D., and Alfred Gilman, Ph.D. In the years following the war, the pair had read the scientific literature surrounding nitrogen mustard and reasoned out one very simple question: if whatever was in the chemical weapon really wiped out the normal immune system, could it do the same trick for tumors of the immune system?
It’s a perfectly fair question. So they began treating rats that harbored lymphoid tumors with what was basically a chemical weapon, nitrogen mustard. Confirming Goodman and Gilman’s suspicions, these rats experienced a dramatic remission.
So back then, like today, the only way we can make progress is to bring together the scientists and the clinicians. Goodman and Gilman finally convinced their colleagues at Yale to contemplate treating a patient with a biological weapon. That patient was a young man who had non-Hodgkins lymphoma; a type of lymphoid tumor, and the disease was so advanced that this individual was going to die of massive obstruction of the respiratory airways.
It was a tale of translational medicine that could not be told today. At that time there was no Food and Drug Administration, there was no regulation, and there was no Institutional Review Board to approve research protocols. It was an odd time where you could use a known chemical weapon to treat a patient.
The patient had an extraordinary response: the tumor melted away. They published their results in 1946, and, while it would be another quarter century until President Richard Nixon signed the National Cancer Act of 1971, this would be the first step on a larger journey of exploration. It was revolutionary. For the first time there was hope.
You must realize that, before this paper was published, cancer was considered a local disease where the best chances for survival was to send the patient for surgery to remove the primary mass. The Yale experiment was revolutionary because it introduced the concept that you could inject your patient with something and that agent would travel around the body and somehow kill the tumor cells. Nitrogen mustard became the first cancer chemotherapy and it led to a class of drugs called alkylating agents that we use today.
Of course chemotherapy is an inelegant weapon. Like carpet-bombing, it does not discriminate friend from foe. Chemotherapy kills normal cells, but it also kills tumor cells better. Rapidly dividing cells like cancer cells are the most vulnerable, which is why hair follicles are among the most noticeable collateral damage. The side effects, of course, can be really severe, and while modern regimens minimize these effects, some of them really decrease the quality of life for both patients and their families.
Carpet-bombing, while devastating, is very effective. Indeed, over the last few decades, the combination of early detection, chemotherapy, and surgery together have made tremendous progress. We have seen dramatic decreases in deaths from cancers across the board. Childhood leukemia; down 90 percent. Hodgkins lymphoma once had a 70 percent death rate, now it’s associated with a 90 percent survival rate. Thanks to routine testing, breast and prostate cancers are typically caught in their early stages, where 5-yearsurvival rates reach nearly 100 percent.
This is not true, however, for all cancers. Some, like pancreatic cancer, benefit from neither early detection nor effective therapeutics. So, too, with late-stage metastatic cancers of most types, which generally spread far too invasively so that long-term survival is unlikely.
Smart Drugs On Target
One undeniable result of every tumor gene-sequencing project is that each tumor is different, from breast cancer to leukemia, from patient to patient, and even from tumor to tumor. We have spent the last 20 years learning that each tumor is unique and that this individuality is driven by genetics.
The question now is can we harness what we learn about the genetics and the changes in the genomes of cancer patients to develop new therapies? Can we go to the heart of what drives tumor progression and metastasis and target them? The advances would be extraordinary. It would be tumor specific, it would have few side effects, it would be safe, and far more effective. Could we do that?
Yes, we can. This is the concept of personalized medicine. And this seems intuitive because then we would have a treatment plan that derives from the genetic makeup of the tumor, prepared for the individual patient. But this piece is just as important: we must not treat those who will not respond. We do not want to give a toxic drug to an individual who is unlikely in fact to derive clinical benefit. That alone would be a tremendous boon, saving both money and time.
The first truly targeted cancer therapy came in the year 2000. Chronic myeloid leukemia (CML) is a very rare cancer of white blood cells, occurring in one or two cases per 100,000 individuals. It progresses eventually to acute leukemia, which was invariably fatal within four years.
I say “was” because of the development of Gleevec (imatinib). It targets a single enzyme and works because of the unique genetics responsible for CML, namely the accidental rearrangement of a chromosome that hyper-activates this enzyme. Gleevec affords a survival rate of 90 percent over five years. These patients are not cured, however, as they need to stay on the drug for as long as they can, which has made a rare disease into a big market. Gleevec is close to being a one billion dollar drug today.
So this what we have to do. We have to identify the right target, get our chemists to work, and convince the drug companies that what we are doing makes sense. Right?
No, unfortunately it’s not that simple. Patients relapse and diseases come back. What we have learned is that molecular therapies are possible and are feasible, but clinical responses are particularly short. That is, except for Gleevec, because of the nature of the disease, these patients stay in remission for a few years before they relapse. And then, for CML, we have other drugs that would work on the relapsed tumor.
The challenges are really based on what we do in order to generate new molecular agents. We start with the identification of a target, of a cancer gene, that maybe is mutated or amplified in cancer, and then we screen chemical libraries to identify the lead agent. Then we optimize it, we test it in laboratory animals, and then we begin clinical trials. It sounds simple.
It turns out that there is likely no single targeted drug for every tumor. Tumors are genetically chaotic. They evolve. You cut off one pathway with a targeted drug, and the surviving cancer cells find a new path. You can, however, use two or more targeted therapies. Use one drug to attack and another to block off points of escape. Unfortunately, large-scale trials of combination drug therapies rarely occur. The drug approval system is not designed for it and drug companies rarely work together in a way to make it feasible.
Moreover, the yield for drug discovery is extraordinarily low. In general, it takes one in a million hits to find something that could be developed into a new drug. Yet about 85 percent of the agents that are identified through this process never see the light of day. It’s called the attrition rate, and oncology drugs have the highest attrition rate of any that enter testing. It is what we call the “Valley of Death” — the black hole between discovery and clinical use where potential new drugs often fail.
And because of that there has actually been a drop in new drugs registered with the Food and Drug Administration. Drug companies, by and large, are stepping back from new cancer drug development.
We Are the Bridge Over the Valley Of Death
This is the where academic research centers have the advantage. Like Goodman and Gilman before us, Wistar and our partners in research and medicine can take on more and riskier cancer projects. We can apply the knowledge accumulated over the last40 years — and the expected discoveries to come with basic research — to new and innovative approaches that have been made possible through funding from the National Cancer Institute and other government and private agencies.
It’s not just the scientists and the clinicians; it’s the community and the patients, patient advocacy groups, government, and the pharmaceutical industry. We really all have to come to the table, if we are to transform advances in scientific knowledge into advances in medical practice.
Sometimes you hear that research is a luxury our country cannot afford. Let the drug companies do it, they say. This is wrong. Research is not a luxury, but an essential component of who we are as a nation. Only a sustained national investment can really bring about cures.
This article appears in the Fall 2012 issue of Focus magazine, online soon.