A Case Study of Cancer

CURE, Summer 2011, Volume 10, Issue 2

Letter from the editor: A case study of cancer

This issue's feature on melanoma highlights an interesting phenomenon that is becoming more evident over time. To the casual observer, or even to oncologists a decade or two ago, all malignancies had more commonalities than differences. Cancer cells were essentially rogue counterparts of normal tissue that grew in an uncontrolled fashion. While they had specific characteristics under the microscope, there was not much about them that was conducive to unique or targeted therapies.

However, the molecular revolution has clearly told us differently. Some early clues about melanoma were based on clinical observations and came well before gene profiling and other sophisticated tools were available. One aspect that seemed to separate melanoma from other cancers was the tendency to induce an immune reaction, similar to the body’s reaction to infections. This blossomed into a niche area of experimental approaches using “tumor-infiltrating lymphocytes” and “lymphokine-activated killer cells.” Ultimately, this led to the approval of interleukin-2 as the only curative option (albeit rare) for advanced melanoma.

Why is melanoma more immunogenic than other cancers? The answer is unclear. In some cases, melanoma even triggers autoimmunity—reactions against one’s own cells resulting in thyroiditis and vitiligo (loss of pigment in patches of skin). As the field of immunology advanced and we learned about more details of positive and negative feedback loops, this was capitalized upon with Yervoy (ipilimumab), an antibody that inhibits a natural immune response damper known as CTLA-4. Therefore, this drug stimulates the antitumor immune response and gained approval after a pivotal trial showed an improvement in survival, an important milestone that had been the holy grail in melanoma and previously unattainable.

After decades of cancer immunology research—and no new drugs since the general immune-stimulating drugs interleukin-2 and interferon alpha—this is finally a big score for melanoma.

After decades of cancer immunology research—and no new drugs since the general immune-stimulating drugs interleukin-2 and interferon alpha—this is finally a big score for melanoma. Interestingly, there have been advances in genetic-based approaches for melanoma completely distinct from immunology. As we will probably continue to see with other cancers, mutations may represent targets that cut across cancers. Mutations in the c-kit and BRAF genes can be seen in melanoma and other tumors, and much enthusiasm is being generated by the activity of drugs that specifically inhibit the proteins encoded by these mutant genes. Clinical trials are showing a much higher rate of response compared with older drugs like Gleevec (imatinib) and Sprycel (dasatinib) for c-kit mutations, and the experimental drug vemurafenib for BRAF mutations. It is impressive that these advances in melanoma have come from totally different aspects of science—immunology and genetics. The molecular approaches are also gratifying because they do not always require the development of new drugs, just a discovery of mutations that match the capability of off-the-shelf agents.

So the melanoma story will be told with different twists over and over again. As we enter the next frontier of whole-genome sequencing for every tumor, we should be able to discover old and new drugs and combinations that we otherwise would never have matched for a given cancer type in a given patient.

Melanoma is unique in many ways—from its history as a hard-to-treat cancer to its uncanny ability to respond to immunologic therapy and, most recently, the discovery of genetic vulnerabilities. But it is also emblematic of new directions in all of oncology. What you will read about melanoma in this issue will be eye-opening now, but you will see a recurrence of this theme in other cancers for years to come.

Debu Tripathy, MD

Editor-in-Chief

Professor of Medicine, University of Southern California

Co-Leader, Women's Cancer Program at the USC/Norris Comprehensive Cancer Center