Translational Research Speeds the Journey from Lab Results to Clinical Outcomes

by Beth Notzon

While basic science researchers work to unravel the mysteries of the causes of cancer and the cellular and molecular mechanisms involved, clinical researchers study the effects of new drugs and other treatments on patients with cancer. For decades, efforts have been under way to bring the two ends of the research spectrum together to translate the findings in the laboratory into increasingly more effective cancer treatments. In recent years, this collaborative spirit has become so much a part of the cancer research climate that translational research is now a byword of cancer research.

“Translational research is really about trying to bring together the progress we’re making in the laboratory with the progress we’re making in the clinic.” This is how Robert C. Bast, Jr., M.D., vice president of the Office of Translational Research at The University of Texas M. D. Anderson Cancer Center, sums up the current situation in cancer research. “If you look at the progress that has occurred in the laboratory in the past 10 to 20 years, our knowledge has increased exponentially. Our progress in the clinic—in detecting, preventing, and curing cancer—has increased steadily but is more linear, more incremental.”

M. D. Anderson’s Office of Translational Research was created in 2000, with Dr. Bast as its first head. This office has as its chief responsibility coordinating and facilitating translational research conducted at M. D. Anderson and collaborating institutions—in effect making sure that the right hand always knows what the left hand is doing.

Dr. Bast is a veritable directory of the translational research being done at M. D. Anderson, and he can provide a litany of names and research areas. In some cases, very basic research can have an impact on important clinical problems. For example, Benoit deCrombrugghe, M.D., identifies
genes that control bone formation and destruction, which are especially relevant to breast and prostate cancers that metastasize to bone. Studies of basic tumor immunology also are leading to new treatments for cancer. Several years ago, Eugenie Kleinerman, M.D., translated observations of immunostimulants in a mouse model into a novel and effective treatment for osteosarcoma in children. Yong Jun Liu, M.D., Ph.D., an authority on antigen-presenting cells, recently arrived at
M. D. Anderson and is working to develop vaccines for cancer. Jeffrey J. Molldrem, M.D., has already developed some of the first effective vaccines for leukemia, and cancer vaccines are also the focus of Patrick Hwu, M.D., and Larry Kwak, M.D., Ph.D., who are building a remarkable community of researchers whose goal is to translate immunologic insights into clinical results.

Antiangiogenesis is a primary research interest of Isaiah J. Fidler, Ph.D., D.V.M. The aim of antiangiogenic research is to block tumor growth by starving it of blood-borne nutrients. Michael O’Reilly, M.D., and Lee M. Ellis, M.D., also work with laboratory models to understand angiogenesis and to develop novel methods for inhibiting tumor growth. James L. Abbruzzese, M.D., Roy Herbst, M.D., Ph.D., and Christopher Logothetis, M.D., have translated laboratory observations into novel clinical trials of angiogenesis inhibitors, alone and in combination with cytotoxic drugs. Renata Pasqualini, Ph.D., and Wadih Arap, M.D., Ph.D., are studying molecular “zip codes” on the inner surface of tumor-associated blood vessels that might be used to deliver drugs and other agents selectively to cancers. At the same time, researchers such as Edward F. Jackson, Ph.D., and John D. Hazle, Ph.D., are working out ways to measure angiogenesis using diagnostic imaging methods, initially in animal models and subsequently in patients. A recent addition, Juri Gelovani, M.D., Ph.D., is developing a molecular imaging method that can identify biochemical changes in cancers before and after treatment.

Gene therapy is the focus of research for a large group at M. D. Anderson that includes Michael Andreeff, M.D., Ph.D., Jack A. Roth, M.D., Gary Clayman, M.D., and Mien-Chie Hung, Ph.D. Other investigators, such as Jean-Pierre Issa, M.D., are devising ways to reawaken the expression of silenced genes that can inhibit cancer growth. In cancer prevention, Scott M. Lippman, M.D., and his colleagues are testing several different drugs to protect people against prostate, breast, and colon cancer. Over the years, Waun Ki Hong, M.D., and Reuben Lotan, Ph.D., have been at the forefront internationally in the study of retinoids to prevent tobacco-initiated cancers. Molecular epidemiologists, led by Margaret Spitz, M.D., are identifying methods to assess the risk of developing cancer, and researchers such as Xifeng Wu, M.D., Ph.D., are making exciting discoveries in the area of single-nucleotide polymorphisms, which offer promise as a way to identify people in large populations at risk for certain cancers who would benefit from cancer screening and chemoprevention.

As these research interests illustrate, translational research occurs at each organ site. Dr. Bast himself heads up the ovarian cancer Specialized Programs of Research Excellence (SPORE) grant, and he noted that SPORE grants are “specifically translational research grants.” Or, as the National Cancer Institute Web site explains, the main purpose of these grants is “to promote interdisciplinary research and to speed the bi-directional exchange between basic and clinical science to move basic research findings from the laboratory to applied settings involving patients and populations.” Eight other SPORE grants awarded to M. D. Anderson are in the areas of lung, head and neck, endometrial, bladder, pancreatic, and prostate cancer; melanoma; and leukemia.

Another byword in cancer research is targeted therapy. Translational research is particularly feasible now because of, as Dr. Bast explained, “the new understanding of what causes cancer in different individuals, which relates to different combinations of genetic events.” This understanding has come primarily from the work of basic research scientists. Until fairly recently, the only effective way to treat cancer was to destroy or eliminate the cancerous cell using surgery, radiation therapy, and chemotherapy. These treatments destroy not only cancerous cells but also healthy cells, leading to the often serious side effects that are a hallmark of most traditional cancer treatments. While these standard therapies will continue to play an important role in the treatment of patients with cancer, they can be vastly aided in this process by targeted therapy, which literally targets the aberrant biochemical pathways that actually cause the cancer. Malignant cells become dependent on only a few abnormal chemical signals for their survival. Normal cells have many different biochemical pathways that ensure their survival. Therefore, targeting only one pathway in malignant cells leaves normal cells unharmed. Gordon Mills, M.D., Ph.D., has found that inhibition of the PI3 kinase enzyme can selectively kill ovarian cancer cells, with tolerable toxicity to normal cells, particularly when the inhibitor is used in combination with a standard cytotoxic drug such as paclitaxel. This approach promises to open up an entirely new vista in cancer treatment. As Dr. Bast explained with some excitement, “It is now possible to imagine designing a specific prescription for each patient wherein you would treat just exactly those abnormalities that occurred in their cancer.”

It may take a while for this particular dream to become a reality, but in the meantime, translational research is already making an important difference in the lives of cancer patients. A prime example of this is imatinib mesylate (Gleevec), a drug that has shown amazing promise in the treatment of patients with chronic myelogenous leukemia (CML). “This is the poster child of translational research,” Dr. Bast noted. The development of the drug began with the finding that 99% of patients with CML have a single type of molecular abnormality in their white blood cells—a chromosomal translocation that results in the formation of an aberrant Bcr-Abl fusion protein that constantly activates Abl kinase, which is ordinarily only intermittently activated. The continuous activation of the enzyme causes CML cells to proliferate and survive.

“Ninety-eight percent of patients in the chronic phase of CML respond initially to Gleevec. About a third of the patients will show a resolution in molecular abnormalities. And it is even possible to effectively treat patients who lapse into blast crisis,” Dr. Bast said. These results improve dramatically the outlook for most patients with CML.

According to Dr. Bast, translational research is focusing on “identifying new drugs, antibodies, or genes that would either neutralize the oncogenes, the ‘accelerators’ that turn on tumor growth, or that would replace the ‘brakes’ on cell growth, the dysfunctional tumor suppressor genes. Targeted therapy can also intervene in the signaling pathways of cancer cells so that the cancer cells would be stimulated to self-destruct, whereas normal tissues would be spared.”

He went on to explain that translational research is not just a single process. “You are talking about the whole spectrum of cancer research,” Dr. Bast said. “There is translational research at all different sites—breast cancer, gastrointestinal cancer, lung cancer, and prostate cancer. There is also translational research in early detection, diagnosis, prevention, and treatment.”

Moreover, the process of translational research is not a one-way street. Discoveries also travel from the clinic to the laboratory in the form of clinical observations, human tissue, diagnostic images, and blood samples, which researchers use to further unlock the secrets of cancer. Prime examples of this are studies of the cells from patients with CML who have become resistant to Gleevec, such as those being led at M. D. Anderson by Moshe Talpaz, M.D. Stanley Hamilton, M.D., has developed a molecular monitoring laboratory to study changes in signaling within tissues from patients who have received targeted therapies. A phase I working group headed by Razelle Kurzrock, M.D., Dr. Herbst, and Frank Giles, M.D., is developing hypothesis-driven trials of new agents, and Dan Karp, M.D., has established a 17-bed Clinical and Translational Research Unit to facilitate close observation and frequent sampling of blood and tissue.

Regardless of whether the patient is on the giving or receiving end, participation in translational research benefits everyone.

For more information on this topic or for questions about M. D. Anderson’s treatments, programs, or services, call askMDAnderson at (877) MDA-6789.

Other articles in OncoLog, March 2004 issue:

• New Tests Could One Day Predict Response to Chemotherapy and Presence of Metastatic Disease in Patients with Breast Cancer
• House Call: Mind-Body Approaches for Patients with Cancer

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