Tumors' shared pathways may hold key to cancer cures

In a recent public lecture, Harold Varmus, Nobel laureate, former head of the NIH and president of Memorial Sloan-Kettering Cancer Center, admonished the world to be a bit more rational about the near-term prospects for finding a cure for cancer, because there will not be a single cure. The tone of his comments was somewhat reminiscent of former Federal Reserve Bank Chairman Alan Greenspan's “irrational exuberance” speech—a speech that has, as of late, proven prophetic.

Why the wet blanket from a champion of biomedical and cancer research? In part, the comments were probably related to some of the attention given the recent trio of publications describing the comprehensive genetic analysis of a large set of human pancreatic and glioblastoma multiforme tumor samples. (Nature. 2008 Oct 23;455(7216):1061-8. Epub 2008 Sep 4; Science. 2008 Sep 26;321(5897):1801-6. Epub 2008 Sep 4; Science. 2008 Sep 26; 321(5897):1807-12. Epub 2008 Sep 4.)

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The findings presented in these studies are somewhat disheartening from a front-line clinician's perspective due to the newly revealed complexity of cancer. Cancer researchers and geneticists won't be out of work soon: the diversity of genetic alterations present in these panels of carefully selected tumor samples was mind-numbing.

In the case of pancreatic cancer, the average number of mutations in a given sample was reported to be 63. Disappointingly, the overlap between mutations in separate samples was minimal (24 pancreatic cancers held mutations in over 1,000 genes). Much the same was found in glioblastoma samples. Each tumor studied held about 47 mutations on average per tumor, and 22 tumors harbored mutations in more than 750 genes.

However, the analysis did discover several interesting gene associations, including confirmation that the gene associated with neurofibromatosis is associated with sporadic glioblastoma, and that mutations in the isocitrate dehydrogenase 1 (IDH1) gene are associated with disease in younger patients and those individuals with secondary tumors. But, patients with IDH1 gene mutations had a considerably longer survival (3.8 vs. 1.1 years) than those without IDH1 gene mutations. This finding may lead to the ability to provide a clearer prognosis for at least some glioblastoma patients.

One of the brain tumor studies was published as part of the first wave of data from The Cancer Genome Atlas project. The pilot phase of this project is examining the genetic alterations found in brain, lung and ovarian cancers. If all goes well, the project will be scaled up to tackle an even larger variety of malignancies. These studies strongly indicate that working out cures for solid tumors is going to be much more complex than targeting more straightforward cancers, such as the BCR-ABL oncogene in chronic myelogenous leukemia.

Despite the daunting complexity of genetic alterations exhibited by the tumors in these studies, developing effective targeted therapies does not have to occur one patient at a time. As it turns out, relatively few pathways are affected by the bewildering array of mutations, and these affected pathways overlap considerably between individual cancers. This raises the possibility that drugs targeting critical steps in these pathways might have applicability to multiple tumors of any given type, and perhaps even multiple types of tumors.

Much more information certainly will come from in-depth genetic analysis of cancer tissue samples, and with the ever-decreasing cost of sequencing technologies the pace of discovery will accelerate exponentially. Network theory, mathematical modeling of complex biological systems, is steadily improving our ability to work out complex associations between seemingly unrelated pathways of cellular function. High throughput screening assays for drug discovery are becoming more widely employed to speed drug identification for new targeted chemotherapies.

Yes, Dr. Varmus is correct to point out that cancer is an extremely complicated constellation of disorders. And there probably won't be a single cure for most specific types of cancer, much less all types of cancer. However, we finally have the tools to crack the enigma of cancer initiation and progression, and more cause than ever to hope for cures (and perhaps prevention).