Scientists Unravel the Drama of a Decade of Cancer Research

Reviewing the last 10 years of cancer research much as they might the production of a play complete with cast members, opening acts and an ever-twisting plot, two of the most cited names in science say that one of the most promising roles that newly discovered cancer genes may perform is in early detection, which likely will be as important as new treatments.

In an editorial review that is the centerpiece of Nature Medicine’s 10th anniversary August issue, Johns Hopkins Kimmel Cancer Center scientists Bert Vogelstein, M.D., and Kenneth Kinzler, Ph.D., used a lengthy Broadway metaphor to suggest that the conquest of cancer is a drama that has lots more acts to come, some of them destined to refocus large parts of the national research effort.

“The best chance of managing these diseases in the next few decades relies on taking advantage of the genes we now know lie at the heart of the process,” says Vogelstein, who is the world’s most influential scientist according to citation rankings by the Institute of Scientific Information. “Cancer already is curable when it’s caught early. New methods of detecting cancers, although less dramatic and not as popular, offer very promising approaches for limiting cancer deaths in the future.”

In the past, the Hopkins scientists argue that the lack of better “scripts” including key gene characters hindered drug development and early diagnostic efforts. With a refined cast of characters, more researchers may steer their efforts to better diagnostic and therapeutic strategies, which may have a greater impact on cancer death rates.

In their review, Vogelstein and Kinzler describe the progress in understanding cancer and the roles of nearly 100 genes that have been definitively linked to cancer. The opening act introduces three kinds of genes that regulate cancer growth pathways. Oncogenes, when altered, get stuck in active duty, much as a stuck accelerator in a car. In opposite roles, tumor suppressor genes act as malfunctioning brakes. Finally, faulty stability genes act like bad auto mechanics, failing to repair mistakes made in the DNA code during replication or exposure to mutating agents. Genes that control blood supply to a tumor are cast in important supporting roles.

The central plot involves the cell growth pathways that these genes control–discoveries that demonstrate how each gene affects a cascade of protein production that is necessary for cancer development. Remarkably, the majority of these genes, which vary considerably in different cancers, converge on a relatively small number of similar pathways that direct cancer growth, providing a common story line.

“Researchers know many of the genes involved in cancer development and are learning how to put the entire cast together, and we are beginning to understand the best ways to apply gene discoveries to help patients,” says Kinzler. “The last decade of gene discovery now sets the stage for this sequel which will include new methods for early detection as well as targeted therapeutics.”

In addition to developing more sophisticated tools for early detection of tumors, Vogelstein and Kinzler say other areas of future research should include better models for testing targeted therapies and investigating the functions of novel genes auditioning for leading roles in the cancer process.

Vogelstein and Kinzler have been studying the genetics of cancer for more than 20 years and have made pivotal discoveries of genes and pathways that lead to cancer, including those involving p53, APC, mismatch repair and Gli. Vogelstein is the Clayton Professor of Oncology at the Johns Hopkins Kimmel Cancer Center and Investigator, Howard Hughes Medical Institute. Kinzler is Professor of Oncology and co-directs the Molecular Genetics Laboratory with Vogelstein at the Kimmel Cancer Center. Vogelstein, B. and Kinzler, K. W., Cancer Genes and the Pathways They Control, Nat Med 10(8), August 2004.