Stalking Leukemia Genes One Whole Genome at a Time

An article by Gina Kolata on the front page of the July 8, Sunday New York Times, “In Leukemia Treatment, Glimpses of the Future,” tells the heartwarming story of a young physician afflicted with acute lymphoblastic leukemia. Diagnosed in medical school, the patient initially achieved a complete remission, only to suffer a recurrence that led him to undergo a bone marrow transplant. When the disease recurred a second time years later, his options were more limited.

As a researcher at Washington University himself, this young physician had access to the most sophisticated genomic analyses in the world. His colleagues and a team of investigators put all 26 of the University’s gene sequencing machines to work around the clock to complete a whole genome sequence, in search of a driver mutation. The results identified FLT3. This mutation had previously been described in acute leukemia and is known to be a target for several available small molecule tyrosine kinase inhibitors. After arranging to procure sunitinib (Sutent, Pfizer Pharmaceuticals), the patient began treatment and had a prompt and complete remission, one that he continues to enjoy to this day.

The story is one of triumph over adversity and exemplifies genomic analysis in the identification of targets for therapy. What it also represents is a labor-intensive, costly, and largely unavailable approach to cancer management. While good outcomes in leukemia have been the subject of many reports, imatinib for CML among them, this does not obtain for most of the common, solid tumors that lack targets for these new silver bullets. Indeed, the article itself describes unsuccessful efforts on the part of Steve Jobs and Christopher Hitchens, to probe their own genomes for effective treatments. More to the point, few patients have access to 26 gene-sequencing machines capable of identifying genomic targets. A professor of bioethics from the University of Washington, Wiley Burke, raised additional ethical questions surrounding the availability of these approaches only to the most connected and wealthiest of individuals.

While brute force sequencing of human genomes are becoming more popular, the approach lacks scientific elegance. Pattern recognition yielding clues, almost by accident, relegates scientists to the role of spectator and removes them from hypothesis-driven investigation that characterized centuries of successful research.

The drug sunitinib is known for its inhibitory effect upon VEGF 1, 2 and 3, PDGFr, c-kit and FLT3. Recognizing the attributes of this drug and being well aware of C-KIT and FLT3’s role in leukemias, we regularly add sunitinib into our leukemia tissue cultures to test for cytotoxic effects in malignantly transformed cells.  The insights gained enable us to simply and quickly gauge the likelihood of efficacy in patients for drugs like sunitinib.

Once again we find that expensive, difficult tests seem preferable to inexpensive, simple ones. While the technocrats at the helm of oncology research promise to drive the price of these tests down to a level of affordability, everyday we wait 1,581 Americans die of cancer. Perhaps, while we await perfect tests that might work tomorrow, we should use good tests that work today.

About Dr. Robert A. Nagourney
Dr. Nagourney received his undergraduate degree in chemistry from Boston University and his doctor of medicine at McGill University in Montreal, where he was a University Scholar. After a residency in internal medicine at the University of California, Irvine, he went on to complete fellowship training in medical oncology at Georgetown University, as well as in hematology at the Scripps Institute in La Jolla. During his fellowship at Georgetown University, Dr. Nagourney confronted aggressive malignancies for which the standard therapies remained mostly ineffective. No matter what he did, all of his patients died. While he found this “standard of care” to be unacceptable, it inspired him to return to the laboratory where he eventually developed “personalized cancer therapy.” In 1986, Dr. Nagourney, along with colleague Larry Weisenthal, MD, PhD, received a Phase I grant from a federally funded program and launched Oncotech, Inc. They began conducting experiments to prove that human tumors resistant to chemotherapeutics could be re-sensitized by pre-incubation with calcium channel blockers, glutathione depletors and protein kinase C inhibitors. The original research was a success. Oncotech grew with financial backing from investors who ultimately changed the direction of the company’s research. The changes proved untenable to Dr. Nagourney and in 1991, he left the company he co-founded. He then returned to the laboratory, and developed the Ex-vivo Analysis - Programmed Cell Death ® (EVA-PCD) test to identify the treatments that would induce programmed cell death, or “apoptosis.” He soon took a position as Director of Experimental Therapeutics at the Cancer Institute of Long Beach Memorial Medical Center. His primary research project during this time was chronic lymphocytic leukemia. He remained in this position until the basic research program funding was cut, at which time he founded Rational Therapeutics in 1995. It is here where the EVA-PCD test is used to identity the drug, combinations of drugs or targeted therapies that will kill a patient's tumor - thus providing patients with truly personalized cancer treatment plans. With the desire to change how cancer care is delivered, he became Medical Director of the Todd Cancer Institute at Long Beach Memorial in 2003. In 2008, he returned to Rational Therapeutics full time to rededicate his time and expertise to expand the research opportunities available through the laboratory. He is a frequently invited lecturer for numerous professional organizations and universities, and has served as a reviewer and on the editorial boards of several journals including Clinical Cancer Research, British Journal of Cancer, Gynecologic Oncology, Cancer Research and the Journal of Medicinal Food.

2 Responses to Stalking Leukemia Genes One Whole Genome at a Time

  1. barbaraH says:

    Thanks for taking the time to address this, Dr. Nagourney. I saw the Times article and found it infuriating, knowing what I know about chemosensitivity testing and also what I know about genomics. I hope you send a letter to the Times, and to the author of the article. Maybe they’ll do another front page article about someone with the same condition as the man in the article, who you helped with the same drug, using the results of your chemosensitivity test. The author makes it seem like it’s a huge eye-opener to find that a drug approved for a different cancer could have an effect on this man’s leukemia. Anyone who has had a chemosensitivity test and has benefited from the results knows what outmoded thinking that is. I guess this is what comes from having reporters, with no background in cancer research, write about cancer research. It all looks impressive to them because they don’t have even a rudimentary understanding of the kinds of things you talk about here – VEGF 1: C-KIT, etc.


  2. A number of the targeted cancer drugs, such as Gleevec, work by blocking the activity of various protein switches that tell the cell to grow. They are known as receptor tyrosine kinases (RTKs). They essentially allow the cell to communicate with the external world to sense growth factors that could maintain the survival of a cancer cell.

    These protein switches are on the surface of all cells and they go haywire in a number of cancers. Drugs that target a single switch have transformed the treatment of some patients with certain cancer, Gleevec and chronic myelogenous leukemia. The tyrosine kinase function is essential for chronic lymphocytic leukemia (CLL) cell survival and proliferation. Tarceva is a tyrosine kinase, and a tyrosine kinase may be able to work not only on a lung cancer but also CLL.

    But it would only work in a small percentage of patients. Certain tumors respond poorly to such drugs. One of the reasons suggested is many growth switches are flipped on at once. There are a multitude of activated receptor tyrosine kinases. When you extinguish one with a specific targeted agent, the other ones can simply step in. However, when combining other drugs, the growth signal can shut down and cancer cells die.

    This is a perfect example that it would be more advantageous to sort out what’s the best “profile” in terms of which patients benefit from this drug or that drug. Can they be combined? What’s the proper way to work with all the new drugs? If a drug works extremely well for a certain percentage of cancer patients, identify which ones and “personalize” their treatment. If one drug or another is working for some patients then obviously there are others who would also benefit.

    Patients would certainly have a better chance of success had their cancer been chemo-sensitive rather than chemo-resistant, where it is more apparent that chemotherapy improves the survival of patients, and where identifying the most effective chemotherapy would be more likely to improve survival above that achieved with “best guess” empiric chemotherapy through clinical trials.

    Gleevec has extended the life of patients with CML, not for months but for years, and most patients who started the drug when it was developed in the 90s are still alive. But here is the kicker: they can’t stop taking the drug or their leukemia will come back.

    Why CML drugs are so effective while the other drugs in other cancers aren’t. It is because there is only one defect in CML, the BCR/ABL molecule. Block this and you have a dead cell.

    This isn’t true of solid cancer cells. They have lots of peculiar molecules that help them survive and grow. Block one pathway and another pathway steps in to take its place. Lots of money is being spent, lots of smart people are working real hard, but they are paddling upstream with a busted oar and not getting far.

    The bottom line is that the cancer cell is very complex and if a drug blocks one pathway/mechanism of its growth, it can find a new route.

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