Kimmel Center Breakthrough Discovery of Tumor Vascular Targets Promises Safer Cancer Treatment Without Traditional Chemo Side Effects.

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SAN DIEGO--(BUSINESS WIRE)--June 9, 2004

A breakthrough discovery by researchers at the Sidney Kimmel Cancer Center (SKCC) holds the promise of taking treatment of several types of cancer to a much higher level of safety and effectiveness.

The identification of unique biomarkers in the blood vessels of solid tumors in laboratory rats allowed SKCC researchers, using antibodies, to direct toxic radiation therapy to cancer cells without harming normal tissue. These biomarkers also exist in human tumors.

The results of the cancer research, lead by SKCC Scientific Director Jan E. Schnitzer, M.D., will be published June 10 in the scientific journal Nature.

The paper, titled, "Subtractive Proteomic Mapping of the Endothelial Surface in Lung and Solid Tumors for Tissue-Specific Therapy," describes how the markers were identified and how the research was validated using proprietary technology developed at SKCC. The cancer center has applied for patents on this technology.

"My team identified one single protein out of the million or so proteins in the body that can be used to target a drug to travel freely into a solid cancerous tumor," explained Dr. Schnitzer. "The antibody we developed can attach itself to that protein and deliver traditional radioactive or chemotherapeutic drugs to the tumor blood vessels and then inside the tumor to more effectively kill the cancer. It is as if we identified a zip code for the cancer and can now mail nearly all the drug to that zip code exclusively to increase tumor destruction while eliminating side effects from these powerful toxic agents. We find this zip code in many different human solid tumors including metastatic lesions fatal to patients."

Since being established in 1990, the San Diego-based non-profit Sidney Kimmel Cancer Center has been dedicated to the development of advanced biological cancer treatments and to making those treatments readily available to patients. The center is named for clothing magnate Sidney Kimmel, founder of the Fortune 500 company Jones Apparel Group Inc. Kimmel's initial gift in 1995 helped ensure the future of the San Diego cancer center. A recipient of the American Cancer Society's Humanitarian Award, Kimmel, through his foundations, has committed more than $420 million to various causes, including cancer research, the performing arts, education and Jewish continuity.

As reported in Nature, the SKCC researchers have identified unique markers in solid-tumor blood vessels that allow the use of a targeting antibody to cure lung cancer in rats. In the study, rats with advanced lung cancer and only days away from death had a 90 percent survival rate.

Harold F. Dvorak, M.D., chief of the Department of Pathology at Beth Israel Deaconess Medical Center (BIDMC) and Mallinckrodt Professor of Pathology at Harvard Medical School, characterized Dr. Schnitzer's dicovery as, "a highly innovative, indeed a 'pioneering,' approach toward solving one of the crucial barriers to cancer therapy, that of identifying suitable, specific molecules that are distributed in such a fashion that they can be successfully targeted without injuring normal host tissues. Indeed, it is an approach designed to find the long sought after 'magic bullet' that can destroy cancers without perturbing normal tissues. Dr. Schnitzer's work offers a new approach to cancer research that I think will be followed by many other investigators as it is applied to other organs and other tissues."

In the past, the markers for cancer tissue were acquired one at a time and about one a year. Now, through the science of genomics, hundreds of new markers are acquired for cancer every year.

But until Dr. Schnitzer devised a way to isolate the tumor vasculature from the vast excess of cancer tissue, the differences between the vasculature of normal and cancer tissue were undetectable. Through this discovery, Dr. Schnitzer has identified hundreds of differences between normal and cancerous tissue, explained SKCC President and Chief Executive, Dr. Albert B. Deisseroth, M.D., Ph.D.

"The use of these antibodies will revolutionize cancer imaging and therapy," said Dr. Deisseroth. "The amount of drugs that reach the cancer tissue with these targeting antibodies is 150 times higher than can be achieved by conventional cancer treatments used today."

"Current cancer treatment drugs, which can destroy cancer tissue -- but with life-threatening side effects -- could be transformed into drugs which are totally safe and much more effective," Dr. Deisseroth added.

By focusing on one part of the vascular apparatus, the "caveolae" -- which, like conveyer belts, transport molecules from inside the blood vessels to the tissues -- Dr. Schnitzer found proteins that exist in these structures in the tumor blood vessels but not in blood vessels of normal tissue.

He then made monoclonal antibodies to the target protein. Since these antibodies can deliver the chemotherapy selectively to the tumor vasculature, and because the targets are in the caveolae, the antibodies can be used to deliver chemotherapy to the cancer tissues 150 times more effectively than previously possible. The transport process takes place within minutes of injection -- much faster than ever before.

As a result, more of the drug penetrates into the cancer tissue, resulting in cures of lung cancer in an animal model. And since the drugs no longer affect the normal tissue, this vascular targeting of chemotherapy could make cancer treatment safer, less expensive and less disruptive of daily life than ever before. Targeting a lower dose to the tumor vascular caveolae can be actually more effective than administering larger doses using current methods.

When monoclonal antibodies were discovered in the 1980s, researchers thought they had found the "magic bullet" to cure cancer. But what worked in the Petri dish (in vitro) did not work in the body (in vivo) in the case of solid tumors because the antibodies could not pass through the endothelium that lines the blood vessels to reach the tumor tissue.

"The bull's-eye for the magic bullet, logically, was generally on the surface of the tumor cells, but when they made these antibodies, they couldn't get through the gate in the blood vessel," said Dr. Schnitzer, director of the Vascular Biology and Angiogenesis Program at SKCC.

So what we've done is, we moved the bull's-eye to that cell surface that is in direct contact with the blood, because then there's no question of access," he said. "If I put an antibody or a molecule in the blood, it is inherently going to come in contact with all the surfaces of that particular membrane."

The discovery is not restricted to radiation or chemotherapy. The targeting approach can be adapted to the delivery of genes, vectors or any molecule useful in therapy.

Nor are the findings restricted to lung cancer of rat tumor models. Schnitzer and his colleagues found that their hypothesis -- unique protein expression that exists only in tumor cell vasculature -- was true for all the human solid tumors they examined, including lung, breast, kidney, liver, colon, brain and prostate, as well as metastatic lesions.

"Dr. Schnitzer's work is offering the possibility of a whole new way of targeting new blood vessels that we believe are of importance to tumor growth. As such, I think it represents a very important opportunity, both diagnostic and potentially, therapy," said Dr. Edward A. Sausville, M.D., former director of Experimental Therapeutics at the National Cancer Institute, now associate director for Clinical Research at the University of Maryland Cancer Center.

Moreover, Dr. Dvorak of Harvard indicated that, "Dr. Schnitzer's success depended largely on the use of silica and silico -- his use of a silica-based method to isolate the plasmalemma and associated caveolae at the luminal surface of vascular endothelium and his application of an 'in silico' approach to subtracting out the many, many proteins present in even his purest fractions that would not be suitable targets."

Dr. Schnitzer cautions that while this breakthrough is very promising, it needs to be tested more extensively in humans before its true clinical value will be known. The next phase will be applying this research to humans.

Having shown promising expression of this target in a wide variety of human solid tumors by antibody staining of pathological tissue sections, the logical first step is to perform whole body clinical imaging studies directly on patients to find out how many of these proteins are there and how specific they will be for the solid tumor in any given individual patient. The hope is that the same rapid and specific targeting to solid tumors will be visualized in human patients as has been imaged in the rat tumor models.

"Once we see the targeting profile for each antibody and determine which protein target is most specific in humans, then we can rapidly proceed with confidence to therapy," he said.

These target discoveries were made by developing and optimizing several cutting-edge technologies (for example, mass spectrometry, in silico bioinformatic computation, molecular imaging) that harnessed the analytical power of proteomics in a way that identified the few remaining targets after quickly and accurately eliminating the thousands of potential targets not readily available to antibodies injected into the blood.

One fundamental technology behind these important discoveries is known as "subcellular tissue fractionation," which allows researchers to identify proteins exposed on the inner surface of blood vessels -- the so-called tissue-blood interface, which is directly and immediately in contact with the circulating blood and what is injected or absorbed into the blood. More specifically, the surface of the cells lining all blood vessels called endothelial cells have special "little caves" or indentations called caveolae. "We isolate this endothelial cell surface and its caveolae from normal tissues and solid tumors to reveal key protein targets that are exposed to the blood only in tumor blood vessels and not the blood vessels of normal tissues so far tested," Dr. Schnitzer said.

Through subcellular fractionation, eight proteins never before found in tumor vasculature were identified in this study, and dozens more that can serve as unique biomarkers and therapeutic transport agents are expected to be identified, Dr. Schnitzer said.

For this study, the target protein was AnnexinA1. The human, rat and mouse versions of this protein were cloned and expressed to purify recombinant proteins for each species. Monoclonal antibodies specific for this protein were generated in the laboratory and a radionuclide attached to create the therapeutic 125I-AnnA1 IgG, which was then injected intravenously into lab rats with mammary adenocarcinomas metastatic to the lungs.

The radionuclide served two functions: its radioactive properties allowed the progress and ultimate destination of the antibodies to be traced through imaging, and it served as a well-localized source of damaging radiation to kill the tumor cells. In less than one hour, the antibodies could be seen accumulating in the solid tumors in the lung. Because the tissue-specific targeting concentrated most of the radiation dose in the tumor, the low dose of radioactive material proved to be highly effective in destroying the tumor while not damaging other normal parts of the body.

While the tissue-specific therapy is a major breakthrough in terms of potential cancer treatments in humans, the importance of tissue imaging should not be underestimated, Dr. Schnitzer said. "Tissue imaging can be used by researchers and therapists alike to identify the location of primary solid tumors and perhaps more importantly their metastatic lesions and in a matter of minutes determine the effectiveness of the targeted therapy."

Co-authors of the Nature article include Phil Oh, Yan Li, Jingyi Yu, Eberhard Durr, Karolina M. Krasinska, Lucy A. Carver and Jacqueline E. Testa.

Sidney Kimmel Cancer Center

Founded in 1990, the Sidney Kimmel Cancer Center is a non-profit research institute dedicated to the development of advanced biological cancer treatments, such as gene therapy, angiostatic therapy, vaccine therapy and immunotherapy, and to making those treatments readily available to patients. The National Cancer Institute has ranked SKCC as one of the top three cancer centers in the United States in the application of genomics and proteomics to the treatment of specific cancers. For more information, visit www.skcc.org, or contact Jay Jeffcoat, senior vice president of community, government and public relations, at 858-410-4212 or [e-mail].