I will also ask for an appropriation of an extra $100 million to launch an intensive campaign to find a cure for cancer, and I will ask later for whatever additional funds can effectively be used. The time has come in America when the same kind of concentrated effort that split the atom and took man to the moon should be turned toward conquering this dread disease. Let us make a total national commitment to achieve this goal. America has long been the wealthiest nation in the world. Now it is time we became the healthiest nation in the world.–-President Richard M. Nixon in his 1971 State of the Union address.
I. THE SITUATION AT PRESENT
The famous Greek doctor and the author of the Hippocratic oath defined cancer as a disease which spreads out to grab parts of the body like “the arms of a crab”. What proves fatal for the victim is the spread of the cancer cells beyond the site of origin, and in this sense, it was a thousand years later that Avicenna of Baghdad, noticed that “a tumor grows slowly and invades and destroys neighboring tissues”. Faithful to its name in more ways than could possibly have been anticipated by Hippocrates, the disease which has launched the $200 billion “War on Cancer” in America continues to spread, invading the lives of almost every family. Based on available data, there were 10.9 million new cases of cancer worldwide, 6.7 million deaths, and 24.6 million persons who had been diagnosed with cancer in the previous five years. Like in many other areas, unfortunately the USA is leading this one as well. More than 1.5 million Americans develop cancer each year claiming some 563,700 lives, killing more Americans in 14 months than the combined toll of all wars the nation has ever fought (a new cancer is diagnosed every 30 seconds in the United States, about 1,540 dying each day from their disease). A look at the worldwide incidence of cancer raises some puzzling issues, especially related to the unexpectedly high incidence of cancers in the USA:
If we ascribe the increased incidence solely to the aging of the population, then why is the incidence so much higher in the USA than in some of the developed countries where life expectancy is comparable? On the other hand, if lifestyle is more important as suggested by the association of smoking and cancers of the lung, then why is this incidence not equally high in countries where people smoke at least as much as in the USA? One answer could be that the smokers in countries such as South America or India do not live long enough to develop cancer. However, the incidence of lung cancer in Sweden with an average life expectancy of 80.3 years is less than half of that in the USA which has a life expectancy of 77.4 years ((22 versus 55.7 per 100,000 respectively) even though 22% adults smoke in both countries. This suggests that lifestyles may be important, but that smoking may not be the only important factor.
Table 1. Approximate incidences of daily smoking among adults in different geographic areas.
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Källa: Tobacco Alert. Geneva: World Health Organization, Programme on Substance, 1996
The idea that genetic predisposition to cancer may have something to do with these high American numbers has been largely laid to rest by the experience of the Japanese who immigrated to America. Both the incidence of cancer, as well as the types of cancer, were quite different between the fresh immigrants and their American counterparts, however these differences disappeared in the second generation Japanese Americans who adopted the local lifestyle.
II. PROBLEMS IN THE FIGHT AGAINST CANCER
President Nixon declared the War on Cancer 34 years ago using the 100 words which stand as an epigraph for this essay. Acknowledging the fact that the tools necessary to accomplish the task were missing, the mandate was to invest money in research and apply the results to reduce the incidence, morbidity and mortality from cancer. After spending approximately $200 billion (if we add up the taxes, industry support etc) since 1971 on this war, 150,855 experimental studies on mice and publication of 1.56 million papers, the results can best be summarized in this one graph:
While deaths from heart disease have declined significantly in the last 30 years, the percentage of Americans dying from cancer, save for those with Hodgkin’s, some leukemias, carcinomas of the thyroid and testes, and some childhood cancers, is about the same as in 1950. For the last twelve years, there is a 1% decline annually in cancer mortality. Early detection has had some significant impact, but once the cancer has spread, the outcome has generally not changed for the last half a century.
As someone who has been directly involved in cancer research since 1977, and obsessed by it for longer, I am a first hand witness to the by now familiar cycles of high expectation and deflating disappointments which have been its hallmark for the last three decades. Because the stakes are so high, both in terms of life-death issues as well as the staggering nature of the finances involved, emotions tend to run high on all sides. In this, and a series of subsequent essays, I would like to summarize some of the rather obvious reasons why this war on cancer has not manifested the anticipated, tangible signs of victory so far, as well as the dramatic gains that have been achieved at the scientific level as a result of this unprecedented investment in basic science. I hope that at the end of it all, you will be able to view the score-card dispassionately and declare a winner.
- Even though President Nixon, and subsequent administrations have continued to invest heavily in cancer research, the dedicated budget for the National Cancer Institute alone rocketing up to more than seven billion this year, the monies are not being spent as wisely as they could be. For example, the funding agencies tend to reward basic research being performed in Petri dishes and mouse models that bear little relevance for humans, 99% investigators using xenografts. Imagine the exceedingly contrived scenario of achieving a “cure” in a severely immune-compromised animal injected locally with human tumor cells and then treated with a strategy being tested. Is it a surprise when the results cannot be reproduced in humans? Basic cancer research may one day be successful at identifying the signaling pathways that determine malignant transformation, however, it will be a long time before the entire process of cancer initiation, clonal expansion, invasion, and metastases is understood, especially in the context of the highly complex, poorly understood micro-environment in which the seed-soil interaction is occurring. Using this approach, an effective therapy for cancer can only be developed essentially after we understand how life works. Can our cancer patients afford to wait that long? Isn’t the history of medicine replete with examples of cures obtained years, decades, and even centuries before the mechanism of action was fully understood for these cures? What about digitalis, aspirin, cinchona, vaccination?
- There is an odd love-hate relationship that has developed between Academia and the Pharmaceutical industry. On the one hand, major research and development (R&D) efforts by industry, conducted under great secrecy, result in the identification of potentially useful novel agents which nonetheless must ultimately be tested in humans. Credible clinical trials in human subjects are conducted by academic oncologists. On the other hand, advances being made in the laboratories of academic researchers need the partnership of industry for commercial and widespread application. This forces the Industry and Academia to become reluctant bedfellows. Roughly 350 cancer drugs are in clinical trials now.
- In order for a drug to show efficacy, FDA demands that it be tested first in animal models that are not relevant to humans. To make matters worse, when the drugs are approved for human trials, they can only be tested in terminally ill patients. Many agents that would be effective in earlier stages of the disease are therefore thrown out like the baby with the bathwater. Finally, the end point sought in most drug trials even in end stage patients, continues to be a significant clinical response. Very few, if any, surrogate markers are used to gauge the biologic effects of the drugs. The surrogate or bio-markers include proteins being produced by the abnormal genes, as well as processes and pathways that distinguish cancer cells from normal cells such as formation of new blood vessels or angiogenesis. If a drug does not produce the desired clinical end point, it is then likely to be abandoned completely, even though its biologic activity could be harnessed for more effective use in combination with other agents.
- As the internet dotcom bubble burst in the 90s, the bi-technology industry was the big winner since some of the best minds in the country made lateral moves and began to invest their talents in this area. The striking change over the last decade in the pharmaceutical industry has been its ability to attract and retain high caliber academic scientists and clinical investigators. Even with this vital infusion, it takes 12-14 years and a prohibitive ~800 million dollars for a pharmaceutical company to get a new drug approved, most of the money having been raised from the private sector which is clamoring for a profit. Following the arduous R&D process and the tedious, time consuming and labor intensive animal studies, by the time a clinical trial is undertaken in human subjects, the stakes are already too high and companies may have to be struggling to demonstrate the tiniest statistical benefits over each other’s products.
- The catch phrase today is “Trageted Therapies”; the concept that a convergence of science and advanced technologies will illuminate the cumulative molecular mechanisms that ultimately produce cancer, and this will lead to an objective drug design to pre-empt or reverse the cancer process. Except for the drug Gleevec developed against Chronic Myeloid Leukemia (CML), a rare type of leukemia in which single gene mutation underlies the pathology, all other Targeted therapies so far have met with modest successes. For example, the recently approved Erbitux and Avastin for cancer of the colon and rectum improved survival by 4.7 months when given in conjunction with chemotherapy. Even in the area of targeted therapies, the efforts are frequently scattered. Academia, Industry and Institutions such as the NCI, FDA, CDC, EPA, DOD etc are not coordinating their resources efficiently. For example, hundreds of researchers across the nation are performing gene expression and proteomic experiments, diluting the number of specific cancers examined for potential targets instead of developing organized collaborative studies.
- Research on such topics as epidemiology, chemo-prevention, diet, obesity, life-styles, environment, and nutrition is woefully under-funded.
III. WHAT SHOULD BE DONE TO FIGHT THE WAR MORE EFFECTIVELY
“Stomach cancer has disappeared for reasons nobody knows and lung cancer has rocketed upward for reasons everyone knows,” says John Cairns, a microbiologist now retired from the Harvard School of Public Health. To win this war, some steps that need to be taken are rather apparent while others remain to be carefully debated and planned. For the vast majority of cases, no “cause” can be identified, but cancer is presently believed to be triggered by a combination of genetic predisposition and lifestyle factors such as diet and occupation. Consequently, chances of developing cancer can be significantly reduced by not smoking, adopting a healthier lifestyle, and proper nutrition. Focus is needed in improving methods for early detection, on treating precancerous conditions, (the dysplasias, metaplasias), and on understanding the reasons for susceptibility to the malignant process in individuals and families.
Where research is concerned, man must remain the measure of all things. Human tumors rather than mouse models should be studied directly. To harness rapidly evolving fields like nanotechnology, proteomics, immunology, and bioinformatics, and focus them on serving the cause of the cancer patient, we must insist on collaboration between government institutions (NCI, FDA, CDC, DOD etc), academia and industry. In the case of the Human Genome Project, collaboration was the key to the rapid mapping. The same concerted effort needs to be invested now in sequencing mutations in hundreds of freshly obtained human cancers of all types, a venture which has been proposed as the Cancer Genome Project. It is a well known fact that all those machines and robotics developed worldwide for sequencing the human genome are either sitting idle or being used for sequencing the genomes of microorganisms and fruit flies. They would serve a far better purpose by being employed in sequencing several hundred breast, lung, colon and prostate cancers to identify the most common mutations. Identification of specific mutations will lead to the discovery of seminal signaling pathways unique to organ specific malignant cells which can then serve as therapeutic targets. Given that nature is highly parsimonious, it is likely that some of these pathways would be redundant as was the case with Gleevec. This drug was developed specifically to inhibit the tyrosine kinase of the Abl gene, and has proved to be effective in producing remissions in >97% CML patients. However, it has now been discovered that patients with gastro-intestinal stromal tumors or GIST can also respond to this drug as the cells use the same tyrosine kinase blocked by Gleevec. More recently, thyroid papillary cancers, subsets of patients with other bone marrow disorders (for example those showing translocations between chromosomes 5 and 12) and even cases of as different a disease as pulmonary hypertension, have been found to respond to Gleevec. What this proves is that some key pathways are likely to be present in cancers or even diseases across organs, and their identification could deliver unexpected benefits.
Cancer is a multi-step process that involves initiation, expansion, invasion, angiogenesis and metastasis. Each stage of the disease may offer a variegated set of targets, thereby making the one drug, “magic bullet” approach only feasible in a handful of cancers where single mutations underlie the malignant process (as described above for CML and Gleevec). A critical lesson from developing successful therapy for AIDS is that three drugs targeting the same virus had to be used before effective control of its replication was achieved. Similarly, multiple targets must be attacked at the same time in the cancer cell. The “seed and soil” approach where drugs act on both the malignant cells and their microenvironment would be preferred over those targeting either in isolation. For example, a drug that blocks a key deregulated intracellular signaling pathway and checks the malignant cell’s perpetual proliferation can be combined with an anti-angiogenic drug which stops the formation of new blood vessels and arrests the invasion of tissues by the tumor. The objective choice of agents would require the practice of evidence-based medicine, and this is what the government institutions should be rewarding the investigators for. Many effective therapies directed against components of the seed and soil, are already available, but researchers are only allowed to use one investigational agent at a time, and that too in patients with advanced disease. This stilted and almost self-defeating approach needs to be abandoned. Patients who already have a diagnosis of cancer cannot afford to wait.
I am optimistic that in the next few years, given the power and sheer velocity of the evolving bio-technology, the very fundamentals of cancer research and treatment will have undergone cataclysmic changes. It may not be possible to cure cancer within the next decade, but, in the words of the NCI Director, Dr. Andrew von Eschenbach, it may very well be possible to “transform cancer into chronic, manageable diseases that patients live with – not die from”.