NCI Cancer Bulletin: A Trusted Source for Cancer Research NewsNCI Cancer Bulletin: A Trusted Source for Cancer Research News
July 27, 2004 • Volume 1 / Number 30 E-Mail This Document  |  Download PDF  |  Bulletin Archive/Search  |  Subscribe

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Director's Update

In Cancer Research Today, Success Breeds Success

Advances in cancer research and treatment are truly gratifying things to witness, which is why I'm extremely excited about the prospects for important new advances heralded by a study published recently in Science. The study gets to the heart of a problem that has vexed many cancer researchers: drug resistance. In the past, when drugs, especially chemotherapy drugs, did not work in some patients, we had limited success in quickly determining why. But today, we have the tools and knowledge at our disposal to "reverse engineer" developmental therapeutics and determine the genetic or molecular basis for success or failure of a targeted therapy. And that is exactly what has now been done for the targeted therapy imatinib (Gleevec), and in a staggeringly short amount of time.

Imatinib has been one of the most dramatic success stories in cancer therapy over the past few years. This targeted agent has produced impressive results in patients with chronic myeloid leukemia (CML), achieving remission in many patients. Unfortunately, imatinib has its shortcomings: 15-20 percent of CML patients are either resistant to it or develop resistance to it. But insights from research conducted over just the past few years have laid the groundwork for efforts to test agents that could overcome imatinib resistance. The results of the first such studies were published in the July 16 issue of Science, by researchers from the UCLA School of Medicine and the Howard Hughes Medical Institute. The research team, led by Dr. Charles Sawyer, showed that an "off-the-shelf" oral agent initially developed for use against solid tumors could significantly prolong survival in a CML mouse model and demonstrated promising activity in laboratory tests on bone marrow cells from CML patients. Based on these results, the drug, BMS-354825, is now being tested in phase I human trials.

This seminal study followed from earlier structural biology research that made several important findings about how imatinib binds to its target enzyme and the mutations that lead to imatinib resistance. Those findings led the researchers to investigate an agent that was less selective and could bind to these mutated targets. Relying on technologies such as small molecule screens, crystallography, and bioluminescence imaging, the team was able to show that BMS-354825 was effective against 14 of the 15 imatinib-resistant CML mutations they tested. They suggest in their paper that other such kinase inhibitors might also be effective at combating imatinib resistance.

The excellent work of these investigators provides tremendous promise. Based on these results, similar agents are now being further investigated and there is great potential to use them alone or as part of a treatment cocktail, as is typically done with HIV. It's often said that it takes 10-15 years to bring a new drug to market, but we have entered a remarkable era where this is no longer the case. We are reaping the fruits of the knowledge that we have amassed about the genetic, biochemical, and structural underpinnings of cancer and are refining our ability to apply that knowledge with the use of advanced technologies. And, most importantly, we can do this quickly and more accurately. In a short time, researchers were able to identify the cause of clinical resistance to imatinib and identify drugs that can overcome that resistance. This is just another example of the exponential progress that we will see over the next few years, with rapid development of first- and second-generation therapies that are swiftly moved through the appropriate clinical trials and into clinicians' treatment arsenals.

Today, the process of cancer discovery, development, and delivery is drastically different than it was yesterday. We are witnessing success that was unimaginable 5 to 10 years ago and, as a result, we are a step closer to our goal of ending suffering and death from cancer.

Dr. Andrew C. von Eschenbach
Director, National Cancer Institute