Building on success

Lessons learned from leukemia research lay groundwork for solid-tumor advances

by Barbara Berg

For Fred Hutchinson Cancer Research Center, expanding its 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-a world leader in leukemia research-develops its work on solid tumors, Center scientists look toward leukemia as the bedrock that will support breakthrough science in other cancers.

"We have extraordinary expertise in diagnosis and treatment of hematological (blood) cancers," said Dr. Fred Appelbaum, director of the Hutchinson Center's 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 percent 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."

Two of the most common solid cancers in the United States-those of the breast and prostate-are among the areas of research expansion at the Hutchinson Center. This year, about 198,000 new cases of prostate cancer and about 192,000 new cases of breast cancer will be diagnosed in American men and women.

Turning laboratory results into better patient care

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

The Hutchinson Center's expansion of research was accompanied by the opening of the Seattle Cancer Care Alliance, a patient-care partnership of the Hutchinson Center, the University of Washington Academic Medical Center and Children's Hospital and Regional Medical Center. The Alliance provides care for a variety of cancers and other diseases.

"The whole idea of the Alliance 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 Hutchinson Center 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 conducted at the Center-which resulted in Dr. E. Donnall Thomas' 1990 Nobel prize in medicine-leukemia has been 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.

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

"The first type of stem cells to be identified were hematopoetic stem cells," he said. "And 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."

Leukemia also has been an important model for demonstrating the complexity of cancer, said Dr. Mark Groudine, director of the Hutchinson Center's 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 Hutchinson Center's infrastructure, which consists 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 Hutchinson Center research and which are likely to yield insight into treatment of other cancers, Appelbaum said.

"There are important lessons we're learning 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' tissues are imperfectly matched. The difference in tissue type, Appelbaum said, is enough for the donor cells to recognize residual cancer cells as foreign, targeting them and eliminating 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."

The mini-transplant procedure, a type of stem-cell transplant developed by the Hutchinson Center's Dr. Rainer Storb and colleagues, has been a success story for patients over age 50. The procedure uses lower levels of radiation and chemotherapy than traditional transplants, which can be toxic for older patients or those otherwise medically unfit. (See story on page 4.)

The cancer-fighting immune-cell response demonstrated in the mini-transplant procedure has already been applied to treating renal-cell carcinoma. 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 Hutchinson Center, have promise for treating solid tumors.

Antibody-targeted chemotherapies, including an anti-leukemia agent developed by Dr. Irwin Bernstein and colleagues in conjunction with a pharmaceutical company, is one of a new generation of drugs that are designed to target molecules specific to cancerous cells.

Most chemotherapy causes potent side effects because it destroys healthy cells as well as cancerous ones. Antibody-targeted therapy is selective for malignant cells. These therapeutic agents use antibodies-molecules that seek out and attach to cellular targets much like a key fits a lock-coupled with potent drugs. Because the drugs are delivered directly to cancer cells, normal cells are unaffected and toxic complications are minimized or eliminated. As scientists discover other cancer-specific molecules, the same technology for drug development can be applied to other diseases.

Gleevec, a drug developed specifically to treat chronic myelogenous leukemia undergoing clinical trials at the Hutchinson Center and elsewhere, is an example of another type of targeted therapy. The drug initially was thought to be specific for a protein overproduced by white blood cells in CML. But Gleevec also has shown promise against some gastrointestinal cancers, a therapy that will be tested in a second Hutchinson Center-coordinated trial.

The reason Gleevec may work on this solid tumor, Appelbaum said, is that gastrointestinal cancers overproduce a protein similar to the abnormal CML protein-and perhaps other cancers do, as well.

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

Molecular diagnosis of remission and relapse of many malignancies may be based on leukemia research, said Dr. Jerry Radich of the Hutchinson Center's Clinical Research Division.

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

"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."

Although studies on solid-tumors cancers have been historically underrepresented in clinical and laboratory sciences at the Hutchinson Center, the Public Health Sciences Division has a solid record of research in prevention and epidemiology of many types of cancers.

Appelbaum said that augmenting solid-tumor research in the Clinical Research Division may provide future opportunities for interaction between his division and the Center's public health scientists conducting such prevention and epidemiological studies.

"We've probably missed some opportunities for collaboration by not having much of a presence in this area," he said.

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

Indeed, scientists at the Hutchinson Center and the University of Washington are leading two projects funded by the National Cancer Institute designed to identify biomarkers, molecules that might serve as early warning signals of cancer. As part of a nationwide consortium called the Early Detection Research Network, they will help identify promising molecules that will ultimately to used to screen patients at high risk of developing cancer.

This and many other new studies of solid tumors at the Hutchinson Center are launching a new era that will further advance knowledge of cancer and ultimately save thousands of lives.

Barbara Berg, Ph.D., is a science writer for the Fred Hutchinson Cancer Research Center.

Seattle Cancer Care Alliance offers best treatments, enhanced research

The Seattle Cancer Care Alliance brings together the best of three superb Northwest cancer-care institutions: Fred Hutchinson Cancer Research Center, University of Washington Academic Medical Center and Children's Hospital and Regional Medical Center. While each institution already shines on its own, "I think the Alliance gives us the opportunity to have a greater impact," said Dr. Fred Appelbaum, executive director of the Alliance and clinical research director for the Hutchinson Center.

The founding institutions formed the Alliance in October 1998. Last January, the Alliance opened its outpatient clinic, located on the Hutchinson Center's Day Campus. The Alliance provides state-of-the-art care for a wide range of adult and pediatric cancers, including those affecting the blood, breast, prostate and other organs.

The idea behind the partnership's inception was to develop a joint patient-care system that would expand two critical missions: To offer the latest treatments to more cancer patients and to provide clinical researchers at the parent institutions an enhanced setting in which to pursue their work. Already, these goals are being achieved, with ovarian-cancer research a prime example.

A new clinical trial for ovarian cancer, which began enrolling patients earlier this year, was developed through the collaborative efforts of the Hutchinson Center's Clinical Research Division and the Gynecologic Oncology Department at the UW School of Medicine.

Dr. Leona Holmberg, an investigator in the Hutchinson Center's Clinical Research Division and professor of medicine at UW, and Dr. Pamela Paley, a UW gynecologic oncologist and affiliate investigator at the Hutchinson Center, are directing a nationwide trial to test a drug called IM862. The drug appears to have cancer-fighting properties and is administered by nose drops.

Ovarian cancer patients treated at the Alliance's gynecologic oncology division may participate in the study. The division is headed by Dr. Benjamin Greer, a UW professor of obstetrics and gynecology and affiliate investigator at the Hutchinson Center.

Previous research suggests that IM862 stimulates the body's immune system and inhibits the development of blood vessels needed by tumors to grow and metastasize. IM862 may reduce blood vessels that feed tumor cells and increase the ability of the patient's immune system to kill cancer.

Solid-tumor studies at the Hutchinson Center

Fred Hutchinson Cancer Research Center's Public Health Sciences Division has led or played key roles in numerous projects designed to study the epidemiology and prevention of a variety of solid-tumor cancers, including:

• The Selenium and Vitamin E Cancer Prevention Trial (SELECT), the largest-ever prostate cancer prevention that seeks to determine whether vitamin E and the trace element selenium protect against prostate cancer.
  
  
• The Women's Health Initiative, a 15-year study of 160,000 women, designed to prevent cancer, cardiovascular disease and osteoporosis.
  
  
• Demonstrating the key role of human papilloma virus in cervical cancer.
  
  
• Developing an effective screening method to monitor patients at high risk of esophageal cancer.

How you can support cutting-edge research at the Hutchinson Center

You can support groundbreaking cancer research by donating to the Hutchinson Center. Private gifts provide financial support for new researchers and cutting-edge studies aimed at eliminating cancer.

For more information, contact the Hutchinson Center at (800) 279-1618 or visit our Web site at www.fhcrc.org/donating.