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

Beyond Sarcomas

The success of imatinib has led to investigation of a growing number of compounds that interfere with the development of more-common (nonsarcoma) tumors in the lung, colon, breast and prostate. Among the approved drugs are gefitinib (Iressa) and erlotinib (Tarceva), which treat non-small-cell lung cancer (NSCLC) by inhibiting a tyrosine kinase called the epidermal-growth-factor receptor (EGFR). This protein is overactive in many solid tumors and is typically associated with a poor prognosis.

Early clinical trials of gefitinib in the United States and Japan showed that almost half of the patients improved while taking the drug—remarkable considering their tumors had resisted standard chemotherapy. However, a different set of studies showed that adding gefitinib to conventional therapy did not provide an additional benefit. Nevertheless, the FDA quickly approved gefitinib for advanced NSCLC in patients whose condition had worsened under standard therapy.

Erlotinib also works by inhibiting the EGFR. In clinical trials, oncologists saw modest success treating NSCLC and bronchoalveolar carcinoma, another form of lung cancer. Evidently, the people who responded the best to erlotinib were those who carried mutations in their EGFR. In November of 2004, the FDA approved, after priority review, erlotinib for the treatment of patients with advanced non-small-cell lung cancer who did not improve after traditional chemotherapy. Because many of the most common cancers contain EGFR proteins, it makes sense to test all the available inhibitors of this protein to find out which are best for each combination of tumor type and genetic constitution. Such studies are now going on, and they should help improve the treatment of these types of cancer within the next few years.

Over the past decade, scientists have made remarkable discoveries of the molecular mechanisms that cause sarcomas and other cancers and are just now seeing the payoff in the form of treatments that specifically target genes or proteins of those cancer cells. However, investigators have much more to learn about the translocation-specific sarcomas, not to mention the large majority of cancers that do not carry a known genetic abnormality.

It is our hope that the knowledge obtained from the study of the better-understood sarcomas will apply to their uncharacterized relatives and to solid tumors as a whole, as demonstrated by recent advances in therapies for lung cancer. We believe strongly that the systematic analysis of these remarkable tumors will result in an enormous benefit to patients within the next few years.

Bibliography

Albritton, K. H. 2005. Sarcomas in adolescents and young adults. Hematology / Oncology Clinics of North America 19:527- 546.
Cheng, E. Y. 2005. Surgical management of sarcomas. Hematology / Oncology Clinics of North America 19:451- 470.
Chansky, H. A., F. Barahmand-Pour, Q. Mei, W. Kahn-Farooqi, A. Zielinska-Kwiatkowska, M. Blackburn, K. Chansky, E. U. Conrad III, J. D. Bruckner, T. K. Greenlee and L. Yang. 2004. Targeting of EWS/FLI-1 by RNA interference attenuates the tumor phenotype of Ewing's sarcoma cells in vitro. Journal of Orthopaedic Research 22:910-917.
Dagher, R., M. Cohen, G. Williams, M. Rothmann, J. Gobburu, G. Robbie, A. Rahman, G. Chen, A. Staten, D. Griebel and R. Pazdur. 2002. Imatinib mesylate in the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors. Clinical Cancer Research 8:3034-3038.
Joensuu, H., P. J. Roberts, M. Sarlomo-Rikala, L. C. Andersson, P. Tervahartiala, D. Tuveson, S. L. Silberman, R. Capdeville, S. Dimitrijevic, B. Druker and G. D. Demetri. 2001. Effect of the Tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. New England Journal of Medicine 344:1052-1056.
Massuda, E. S., E. J. Dunphy, R. A. Redman, J. J. Schreiber, L. E. Nauta, F. G. Barr, I. H. Maxwell and T. P. Cripe. 1997. Regulated expression of the diphtheria toxin A chain by a tumor-specific chimeric transcription factor results in selective toxicity for alveolar rhabdomyosarcoma cells. Proceedings of the National Academy of the U.S.A. 94:14701-14706.
Matushansky, I., and R. G. Maki. 2005. Mechanisms of sarcomagenesis. Hematology / Oncology Clinics of North America 19:427- 449.
Matsuzaki, A., A. Suminoe, H. Hattori, T. Hoshina and T. Hara. 2002. Immunotherapy with autologous dendritic cells and tumor-specific synthetic peptides for synovial sarcoma. Journal of Pediatric Hematology/Oncology 24:220-223.
Tuveson, D. A., N. A. Willis, T. Jacks, J. D. Griffin, S. Singer, C. D. Fletcher, J. A. Fletcher and G. D. Demetri. 2001. STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: Biological and clinical implications. Oncogene 20:5054-5058.