by Brian J. Druker, M.D.
Source: Spring 2002 CCCF Newsletter
Cancer: one of the most feared words in our vocabulary, with the prospect of cancer treatment – commonly chemotherapy, often heightening our anxiety.
Now, imagine a future where cancer has been relegated to something as trivial as an infection. It’s not unfathomable. But, to reach this goal, we need to understand the critical abnormalities that distinguish cancer cells from normal cells, and then figure out how to target those cancer cells. Under normal circumstances, cells grow and divide just enough to replace daily losses. Think of this as a thermostat with perfect climate control. In the case of cancer however, the thermostat is broken. The temperature continues to climb — or in the case of cancer, the cells keep growing and growing, forming a tumor. The problem for scientists is figuring out which part of ‘the thermostat’ has broken. Sure, we could replace the thermostat, or in the case of chemotherapy, we could hit the thermostat with a hammer and hope that this fixes the problem. But imagine if we could take the thermostat apart, piece by piece and figure out how each part works and just replace the broken part.
That is where we are in the year 2002. The human genome project has been completed and it now gives scientists a list of all the parts. Now we need to figure out how they all fit together and then determine which parts are broken in different cancers.
Gleevec (formerly STI-571) shows how this knowledge can be translated into an effective and non-toxic therapy for a particular type of cancer called chronic myeloid leukemia (CML). This leukemia accounts for 15-20 percent of all leukemias, primarily affecting adults. The only curative therapy for this disease is a bone marrow transplant, but that treatment carries numerous risks and is currently available only for those patients who find a matching donor.
Over the past three decades, cancer researchers have identified the precise abnormality that causes the white blood cells to grow uncontrollably in this leukemia. This abnormality is an enzyme, called a tyrosine kinase, that normally regulates cell growth. In CML, due to an exchange of genetic material between two chromosomes (known as a translocation), a mutated enzyme is produced. Instead of regulating cell growth, this enzyme now signals the cells to grow continuously, thus leading to leukemia. In collaboration with Novartis Pharmaceuticals, my laboratory developed Gleevec - a drug that works by completely shutting down this specific abnormality at the molecular level. In clinical trials, virtually all of our patients have had their blood counts return to normal, and in up to one-third of our patients we can no longer detect leukemia cells in their bone marrow. Remarkably, the once-a-day pill treatment has been well tolerated, with minimal side effects. In short, it is a simple, effective treatment that disables the cancer without disabling the patient. In May 2001, the FDA approved Gleevec for the treatment of CML in record time.
Patients often ask me if Gleevec will work in other cancers. As we enter this new era of targeted cancer therapies, it is likely that new treatments will have narrow spectra of activity. This is because each cancer is driven by unique abnormalities, or a combination of multiple abnormalities. Again, remember our thermostat. There are many parts that can break and if we replace the wrong part we may make things work a little better, but we haven’t fixed the problem. Thus, we need to first identify the precise abnormality that drives the growth of each cancer so that it can be targeted with a drug like Gleevec.
However, there are a few other cancers whose abnormalities are shut down by Gleevec, including an intestinal cancer called gastrointestinal stromal tumor and a rare, but usually lethal form of brain cancer, glioblastoma. Clinical trials for gastrointestinal stromal tumors have already shown remarkable results and studies in glioblastoma are just getting underway.
For the future, we need to learn how long the responses to Gleevec will last, whether we can improve responses by adding other agents, and if we can predict in advance how certain patients will respond to treatment. The goal of these studies will be to tailor therapy to individual patients.
As we look back on the 1900’s, infections went from being the most common cause of death of individuals to being easily treatable. Meanwhile, cancer went from being the eighth most common cause of death to the second most common. The eradication of infections has resulted from improved sanitation methods (prevention), specific therapies (antibiotics), and vaccines. Our task to successfully treat cancer in the 21st century is to follow this same approach: prevention, specific therapies such as Gleevec, and vaccines.
We are at a dramatic juncture for cancer research. As we attempt to cure cancer, there are several factors which will accelerate our progress as researchers. The first is the need for an on-going increase in cancer research funding so that we can identify the molecular fingerprinting of specific cancers, and translate such knowledge into effective targets for therapy. The second is the need to improve the climate for collaborations between university researchers and the pharmaceutical industry, in order to speed up drug discovery. The third is the need for both public and private health insurance coverage, to include payment for routine care costs of patients enrolled on clinical trials. Currently, most oncologists lose money when enrolling their patients on a clinical trial.
There is currently an enormous amount of momentum and optimism in cancer research . Although there is much work to be done, there is much reason for hope.
Brian J. Druker, M.D., is a professor of medicine at the OHSU School of Medicine and director of the Leukemia Center at Oregon Health & Science University, Portland Oregon.