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 oday scientists understand at least part of that "why?" A gene that is normally regulated -- turned on then off in response to an external stimulus -- is turned on and remains on all the time, resulting in the unchecked cell growth we call cancer. New tools now enable scientists to look at gene expression so they can penetrate directly to the heart of the problem. This enhanced understanding of how cancer strikes and how it can be treated has resulted in a revolution in cancer care.
The Scripps Cancer Center (SCC), under the direction of Alan Saven, M.D., Head, Division of Hematology and Oncology at Scripps Clinic, was launched in 1999 to respond to the challenges presented by research breakthroughs. The Center aims to facilitate collaboration between TSRI and the five constituent hospitals of the Scripps system. TSRI's Chairman of the Department of Molecular and Experimental Medicine, Ernest Beutler, M.D., heads its Board of Governors with the objective of initiating a fast track from bench to bedside. Achieving this goal will begin with the discovery in TSRI's laboratories of new, potentially effective drugs and therapies, moving through their testing in controlled clinical conditions, and finally putting them into the hands of practicing physicians. Since there will never be a single treatment for a disease as complex and varied as cancer, this process will be repeated over and over again as new discoveries are made and tested.
COMPOUNDS FOR TARGETED THERAPIES
Designer drugs and targeted drug delivery are key to the success of new treatments. A well-publicized recent example is Gleevec, developed by Novartis for the treatment of chronic myeloid leukemia. TSRI has developed many molecules in its laboratories that potentially can be used in targeted therapy. Scientists in the laboratory of K.C. Nicolaou, Ph.D., Chairman, Department of Chemistry, for example, can synthesize the most complicated organic molecules that are selectively toxic to tumors but not to the surrounding tissue. Their development has followed the same principles as were used in the case of Gleevec, and they will hopefully have clinical applications for targeted drug delivery. The health care delivery side of the SCC is ideally placed to take these drugs through clinical trials to implementation, completing the journey from bench to bedside. The SCC hopes to harness the biological and chemical expertise at TSRI, and capture the results in studies at the General Clinical Research Center at Green Hospital en route to full implementation throughout the Scripps system. Scripps physicians have an enormous patient reservoir, treating about one-third of all cancer patients in the San Diego area.
Because it is a not-for-profit organization, Scripps Cancer Center evaluates new therapies based on benefit, not on the number of cases. As a result it will test drugs that treat less common forms of cancer, drugs that would likely not be selected by large pharmaceutical companies whose focus is on blockbuster drugs for common diseases. One of Scripps' great success stories was the development of the drug 2-CdA as a remarkably effective cure for a rare form of cancer, hairy cell leukemia, a disease that strikes only about 600 patients each year in the United States. Dr. Beutler describes 2-CdA development as "a scientifically beautiful story, insightful into the way medical research works." TSRI scientists continue to develop new cancer-fighting molecules that will follow the path blazed by 2-CdA development.
One approach to fighting cancer is being pursued in the laboratory of David Cheresh, Ph.D., Professor, Department of Immunology. The original concept upon which all this work is built is very simple. All solid tumors depend upon the growth of new blood vessels. This process, called angiogenesis, occurs in adults only in a few special circumstances. As tumors begin to grow they secrete chemicals that promote formation of new blood vessels, enabling a tumor to acquire the nutrients necessary for its growth and survival. Importantly, these tumor-associated blood vessels also serve as a conduit for escaping tumor cells that enter the bloodstream and seed in distant organs. If the blood supply to the tumors can be blocked, it might be possible to starve the tumor and reduce its chance of spreading throughout the body.
Numerous attempts have been made over the years to cut crucial supply lines and, in effect, to starve tumors to death. Most efforts failed because of the complicated biology of blood vessel growth. In 1994, Cheresh and his colleagues discovered a single biochemical switch that triggers the growth of blood vessels. More importantly, they found two proteins that were able to turn off the switch, depriving tumors of their blood supply. What is particularly exciting about this treatment is that, unlike more traditional cancer therapies, it does not damage normal tissue. Instead, the proteins interfere with a step that is important only in the creation of new blood vessels. Existing arteries, veins, and capillaries are unaffected. A wide variety of solid tumors are targeted for treatment using these anti-angiogenesis proteins, including malignant melanomas and cancers of the prostate, lung, breast, colon, pancreas, and brain.
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very different approach is taken by Ralph Reisfeld, Ph.D., Professor,
Department of Immunology, and his colleagues, who are developing
vaccines that stimulate the immune system to kill cancer self-antigens
before they become established. Two separate tracks are being
followed in the effort to stimulate the immune system to reject
tumors and to battle metastases successfully. The first, passive
therapy, works indirectly by targeting antibodies to find the
tumor cells and then activating the body's other defenses against
them. In thesecond, active therapy, effector cells are asked to
kill tumor cells directly. T cells, if properly activated, can
be very effective killers. Since the tumors have fooled the immune
system into believing that they are not foreign but part of the
self, the trick is to overcome the T cells' natural tolerance
towards self antigens, to put them on alert status and to prompt
them to attack. Overcoming this natural reluctance of the T cells
to attack could become the basis for a successful vaccine.
TACKLING THE PROBLEM OF DRUG RESISTANCE
New strains of disease resistant to proven treatments are constantly developing, defeating the ability of medical practitioners to deal with them effectively. Thousands of proteins in the outer walls or membranes of cells help the cells interact with the outside world. Some act as defensive pumps, shuttling antibiotics out of bacterial cells or chemotherapy drugs out of cancer cells. With the help of these pumps, also called transporters, many cancers and bacterial infections are becoming invincible. In September 2001, Geoffrey Chang, Ph.D., Assistant Professor, Department of Molecular Biology, produced an x-ray crystal structure that provides the first detailed glimpse of a membrane transporter protein. This discovery will provide the basis for creating drugs to help overcome the threat of drug resistance.
A long-range goal is the development of a new class of drugs that patients would take with chemotherapeutic agents to prevent the latter from being denied access to cancer cells where they can do the work for which they were designed. Effectively plugging the pumps would make many of the diseases more vulnerable to the medications they now brush aside.
IMPROVING TRANSPLANTATION
On the clinical side, James Mason, M.D., Director, Blood and Marrow Transplantation and Associate Director of the Scripps Cancer Center, is working at the cutting edge of research making blood and marrow transplant procedures safer and better. Instead of transplanting bone marrow itself, peripheral blood stem cells derived from bone marrow are used. Autologous transplants use the patient's own peripheral blood stem cells, which are "donated" and frozen or cryo-preserved for future use. Chemotherapy, alone or in conjunction with radiation therapy, is then used to destroy the affected cancer cells. In this process other cells are also damaged. The previously donated cells are now transfused back into the patient in a rescue attempt. When cells from the bone marrow or peripheral blood of a donor are used, as opposed to autologous cells, the procedure is called an allogeneic transplant.
Blood and marrow transplants are appropriate for treating a wide variety of cancers, including acute and chronic leukemia, non-Hodgkins lymphoma, Hodgkins disease, multiple myeloma, and certain solid tumors such as testicular cancer in relapse.
To foster communication and cooperation among TSRI and the five Scripps hospitals, a common Scientific Protocol Research Committee and an Internal Review Board (IRB) have been established. Every major action affecting the cancer programs of the separate units now comes under the scrutiny of the IRB. Its members determine which new protocols for the treatment of cancer are adopted throughout the system. In addition, a clinical research network has been established so that cancer patients in the Scripps system will have immediate access to novel and innovative compounds through their local oncologists.
As Saven says: "The emphasis of the Scripps Cancer Center is to promote bench-to-bedside research, harnessing the basic research accomplishments of TSRI and the excellence in Scripps clinical cancer care."
Fortunately, the U.S. federal government continues to supply important grant funds for defined basic scientific research projects. Private donors have also been found to provide major funding not only for the institutional structures that support the overall research enterprise, but also as a way to fill gaps not covered by government grant funds. Nevertheless, although Scripps has been blessed with generous donors in the past, the demand for funding always outruns the supply.
At the other end of the drug development chain, clinical research is woefully underfunded. Government research funds are available to pay for some trials but the amount is never enough. Who then will fund the trials of drugs to treat rare cancers, the area in which the Scripps Cancer Center has a unique role to play? An enormous need and opportunity exists for private donors to support these clinical trials.
The Center is applying for National Cancer Institute funding through a planning grant, with the long-term hope of the SCC becoming a comprehensive cancer center.
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