The David A. Karnofsky Memorial Award and Lecture

Julia Draznin Maltzman, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: May 16, 2005

Since 1970, ASCO has been awarding outstanding individuals who have contributed to the both to the field of oncology and to the way oncologists think about this discipline, with a David A. Karnofsky award. This award is named after one of the true great pioneers in Oncology and is further a tribute to this distinguished physician who himself lost a battle with lung cancer in 1969. Over the past 35 years, ASCO has bestowed this honor on many great doctors including Sydney Farber, Vincent DeVita, Saul Rosenberg, Larry Einhorn, Judah Folkman, and Brian Druker, just to name a few. This year this prestigious honor was presented to Charles L. Sawyers, MD, of the University of California, Los Angeles and the Howard Hughes Medical Institute. The title of his acceptance lecture is "Molecularly Targeted Cancer Therapy: Future Challenges.

In his talk, Dr. Sawyers underlined the importance of tedious, time consuming, and often, repetitive laboratory work in identifying the appropriate medicine for the appropriate patients in the right clinical trials. The best example of this approach is the current therapy for chronic myelogenous leukemia (CML). Dr. Sawyers has spent much of his initial efforts trying to understand the molecular mechanisms that underlie this disease and target any molecular aberrations. Novartis capitalized on this approach and developed a small molecule called Gleevec (imatinib) that inhibits only the mutation that leads to the disease. When given to patients with CML this drug has greatly increased survival and improved the quality of life of many individuals.

More recently it has been observed that ten percent of all patients with CML on gleevec develop resistance to the drug and no longer derive a clinical benefit. Dr. Sawyers has shifted much of his focus on trying to identify the molecular mechanisms behind this resistance and to develop ways to overcome the resistance. Dr. Sawyers claims that this resistance is seen, at least in part, because the malignant cells develop other mutations that alter the structure or three-dimensional shape of crucial proteins such that the drug can no longer bind and interact with the mutation. If there is no drug-protein binding, there is no inhibition of the aberrant mutation and cancer flourishes. Dr. Sawyers postulated that other similar drugs may have less stringent binding requirements to the mutant protein and could potentially be effective when Gleevec is not.

Building on this scientific reasoning, Dr. Sawyers and his team have recently completed early phase work with a new compound made by Bristol-Myers-Squibb known as BMS-354825, or Desantinib. This compound is active in fourteen of the fifteen Gleevec resistant cases of CML. These results were truly impressive with almost 90% of all patients enrolling in the trial achieving some clinical benefit.

Dr. Sawyers attributes the success of this new drug (now under consideration by the US FDA for approval) to the scientifically rigorous and calculated approach to the problem. When Gleevec resistance was apparent, his lab asked why. Once the biochemical reason was understood, the next step was to conceptualize a potential solution. The compound was made and assayed in humans for both safety and efficacy.

Dr. Sawyers claims that this compound carries implications that go far beyond CML. CML serves only as an example of how to apply molecularly based clinical trials to all types of cancer. For example, Dr. Sawyers' lab has already expanded this approach to prostate cancer and brain cancer. These two seemingly disparate tumors have the absence of PTEN in common. PTEN is a protein that codes for inhibition of tumor growth. In its absence, cancers could continue to grow and flourish under the control of another protein by the name of mTOR. Drugs have been made whose function it is to inhibit mTOR and may be successful in inhibiting tumor growth and development while sparing other healthy cells. Dr. Sawyers gave examples of early phase clinical trials where treatments with mTOR inhibitors have created much excitement in the oncology community in difficult to treat diseases such as hormone refractory prostate cancer and glioblastoma multiforme.

Dr. Sawyers noted that this is the "golden age for experimental cancer treatment and careful scientific approaches should be used in the investigation of new drugs. He noted that clinical medicine makes sense when there is a clear and rational scientific reason behind it. His energy, enthusiasm and unfading motivation clearly explains why he was the society's choice for the Karnofsky Award this year.

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