FEATURE ARTICLE
Fighting Cancer Through the Study of Sarcomas
Although rare, cancers of the muscle, bone or fat carry the same molecular errors as other tumors, making them ideal subjects for the discovery of new therapies
Igor Matushansky, Robert Maki
Sarcoma Antigens 101
Some tumors produce characteristic proteins. For example, melanomas churn out the pigment melanin and related molecules. Thus, training the patient's immune system to attack such proteins—by using a vaccine, for example—can help the body identify the malignant cells and get rid of the cancer. This process of teaching the immune system to create antibodies against cancer-specific (or in the case of melanin, cancer-enriched) proteins is called immunotherapy.
Sarcomas are excellent candidates for immunotherapy because many have chromosomal translocations that generate fusion proteins not seen in any other cell of the body. The immune system can thus attack these specific molecules (and the cancer cells that contain them) without harming healthy tissue. Of course, the body does not automatically recognize the mutant proteins as foreign. If it did, the tumor never would have appeared in the first place. Part of the problem is access: The abnormal proteins may not show up on the surface of the cell at all; they may be present only within, where they are hidden from immune-system surveillance. Fortunately, in some instances, fusion proteins do appear on the cell membrane, albeit in quantities too small to stimulate the immune system. The challenge then is only to generate antibodies to these cancer-specific proteins. A few years ago, investigators led by Akinobu Matsuzaki at the Graduate School of Medical Sciences in Fukuoka, Japan, succeeded in doing so in the treatment of an 11-year-old girl with synovial sarcoma that had spread to other parts of her body.
The Japanese team started by collecting and isolating the patient's own dendritic cells, a part of the immune system whose job it is to engulf invading microbes, chew them up and wear the pieces on their outer membranes. (This dismemberment allows another type of immune cell, the B cell, to make antibodies that recognize each chunk, or antigen.) Matsuzaki and his colleagues already knew that a translocation of one of this patient's X chromosomes and a chromosome 18 had fused two genes together so that they encoded a unique protein. In the lab, the investigators combined the dendritic cells with that protein and then returned the "stimulated" cells to the patient. The girl's immune system began to recognize the sarcoma, and the treatment temporarily suppressed the growth of the cancer that had spread to her lung. Although such outcomes have not yet been tested systematically, the strong scientific rationale and individual successes like that of Matsuzaki's patient have sparked dozens of clinical trials that use a person's own dendritic cells as a form of therapy for advanced cancers of the kidney, prostate, bre st, colon and lung.
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