Building upon success

Science Article

Leukemia lessons lay groundwork for solid-tumor research

Expanding an area of excellence in cancer research and treatment is a lot like adding a second story on a house: You need a strong foundation.

So it's not surprising that as the Hutchinson Center expands its research on solid tumors - cancers affecting organs and tissues other than blood - Hutch scientists look toward leukemia research as the bedrock that will support breakthrough science in areas that have been historically underrepresented in the clinical and laboratory divisions.

"We have extraordinary expertise in diagnosis and treatment of hematological (blood) cancers," said Dr. Fred Appelbaum, director of the Clinical Research Division. "We're extremely proud of our accomplishments in that area, and we don't want to walk away from that. But only about 10 to 15 percent of the total cancer burden is due to hematological malignancies. We're confident that lessons learned in treating these cancers will impact treatment of solid tumors."

Translating results

The ultimate goal of enhanced solid-tumor research will be translating lab results into improved patient care.

So it's no coincidence that the expansion of research accompanies the opening of the Seattle Cancer Care Alliance, a jointly governed affiliate of the Hutchinson Center, the University of Washington and Children's Hospital and Medical Center that will provide care for a variety of cancers and other diseases.

"The whole idea of the Allinace is to facilitate the translation of research into patient care," said Appelbaum, who is also the Alliance director. "As ideas flow on our campus, they will funnel directly into cancer treatment."

The reasons Hutch researchers look toward leukemia as a model for studying other malignancies are twofold. In addition to the wealth of research on leukemia and other blood diseases performed at the Hutch, resulting in Dr. E. Donnall Thomas' 1990 Nobel prize in medicine, leukemia has been, in many ways, a more accessible cancer to study than most solid tumors.

"It's much easier to take a blood sample than to perform surgery to obtain a biopsy from a pancreas," Appelbaum said. As well, he said treating solid cancers requires surgical expertise and complex diagnostic equipment - resources that the Hutch has not had.

The ease of sampling blood has made the blood and immune system the best-understood organ system, said Dr. Lee Hartwell, Center president and director.

"The first stem cells to be identified were hemato-poetic stem cells," he said. "Because development of the blood system goes on throughout life, we've identified cell-surface markers to distinguish cell types so that when a blood cancer arises, we know where it's coming from. We don't know that for a lot of other organ systems."

Model of complexity

Leukemia also has been key for demonstrating the complexity of cancer, said Dr. Mark Groudine, director of the Basic Sciences Division.

"Years ago, leukemia was thought to be one disease," he said. "Now we know that there are about 20 types of leukemia. This knowledge has a great impact on patient care. Before, every leukemia was treated the same. Now we have methods for figuring out the specific type of leukemia, and we've developed treatments tailored to that subtype. The same is likely to be true for many types of cancer."

The Hutch's infrastructure - consisting of diverse approaches for studying cancer - has proved fruitful for leukemia research and likely will impact studies of other cancers, Groudine said.

"Much of what we know about the genetic abnormality responsible for chronic myelogenous leukemia is the result of both basic and molecular medicine research done at the Hutchinson Center," he said. "That knowledge has translated directly into clinical research in both the treatment of CML and the ability to predict risk of relapse."

Lessons from breakthroughs

Leukemia's relative ease of study has enabled breakthroughs in diagnosis and treatment, many of which have their roots in Hutch research and which are likely to yield insight into treatment of other cancers, Appelbaum said.

"We're learning important lessons from our studies on leukemia," he said. "Some are expected and some are unexpected."

A key finding revealed by studies on allogeneic bone marrow transplants - in which the donor is a non-twin sibling - is that the human immune system has cancer-fighting properties that can be harnessed for treating a variety of malignancies.

Identical twins have identical tissue types, but non-twin siblings are imperfectly matched. The difference in tissue type, Appelbaum said, is enough for donor cells to recognize residual cancer cells as foreign, targeting them and killing them.

"We know that we get a more powerful therapeutic response when the donor is not an identical twin - the mismatched donor cells fight the cancer, demonstrating the enormous power of the human immune system," he said.

"We're exploiting that in the mini-transplant procedure, in which the patient's immune system is not completely destroyed by radiation and chemotherapy. But it's also been shown in renal-cell carcinoma that donor immune cells can fight the cancer. Future research may show that the principle can be applied to other cancers."

Appelbaum said other leukemia therapies, some of which were developed at the Hutch, have promise for treating solid tumors.

Antibody-targeted chemotherapies like Mylotarg, an anti-leukemia agent developed by Dr. Irv Bernstein and colleagues in conjunction with the pharmaceutical firm Wyeth-Ayerst, likely will prove useful for treating many other cancers.

STI-571 (also known as Gleevec), a drug undergoing clinical trials at the Hutch, initially was thought to be specific for a protein overproduced by white blood cells in chronic myelogenous leukemia. But the drug also has shown promise against some gastrointestinal cancers, a therapy that will be tested in a second Hutch-coordinated trial in the Public Health Sciences Division.

The reason for Gleevec's versatility, Appelbaum said, is that gastrointestinal tumors overproduce a protein similar to the abnormal CML protein - and perhaps other cancers do, too.

"Just as we know that normal cellular processes are conserved in biology, abnormal processes are conserved to cause cancer," he said.

Leukemia research also may serve as a base for molecular diagnosis of remission and relapse of many malignancies, said Dr. Jerry Radich of the Clinical Research Division.

"Using very sensitive PCR techniques, we can detect extremely rare leukemia cells in patients who appear to be cured, and predict patients who have a high risk of relapse," he said.

Head start on detection

"This early detection gives us a potentially large head start to intervene with therapy and head off the relapse. These assays are based on our extensive knowledge of the genetic lesions found in various leukemias. They are the 'fingerprint' of the residual leukemia. These types of genetic markers are bound to be discovered in solid tumors, and similar studies detecting and treating residual disease will become part of the therapeutic strategy."

Appelbaum said that augmenting solid-tumor research in the Clinical Research Division may provide future opportunities for interaction between his division and PHS. "We've probably missed some opportunities for collaboration by not having much of a presence in this area," he said.

Although studies on non-hematological cancers have been historically underrepresented in clinical and laboratory sciences at the Hutch, PHS has a solid record of research in prevention and epidemiology of many types of cancers.

"The aim now is to draw on all that expertise, particularly in the area of early detection," Hartwell said.

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