The Human Cancer Genome Project—one more misstep in the war on cancer

Abstract

Strap yourself in and get ready for some serious ‘more of the same.’ A recent proposal to sequence cancer genomes holds out the promise of personalized cures for each of 50 different cancers. The cost? A mere $12 billion at today’s prices1. This human cancer genome megaproject is the equivalent of 12,500 human genome projects and already has the backing of several prominent scientists. Harold Varmus believes that the project could “completely change how we view cancer”1; Eric Lander argues that “knowing the defects of the cancer cell points you to the Achilles’ heel of tumors”1; and Francis Collins predicts that he “can confidently tell you that something will happen here”1. More pragmatically, Craig Venter points out that “...it’s not clear what answer we’d get; there might be better ways to move cancer research forward”1. In a nutshell, the megaproject aims to catalog all somatic mutations from primary tumors as the basis for designer drugs to cure most cancers. Success is predicated on the assumption that drugs can be targeted to very specific mutated regions of gene products. However, most patients with a localized primary tumor are cured by surgery and local radiation. It is not the primary tumor, but the metastatic spread of a small population of deadly cells that ultimately compromises a normal tissue or organ, that kills in cancer2 (for an excellent popular account, see ref. 3). Are primary tumors therefore the appropriate focus for such a massive project and are their bulk mutational spectra therapeutically useful? The clinical track record Cancer research has consumed hundreds of billions of dollars to date3 and yet the main killers—breast, prostate, lung and colorectal cancer—are essentially as deadly as ever4 (see Fig. 1). Despite the glacial progress in treatment and the advent of ‘molecularly targeted’ therapy, cancer research continues to focus myopically on individual oncogenes, tumor suppressors and repair genes5, with little effort devoted to alternative mechanisms and targets6–8. Although conventional chemotherapeutic agents remain the first-line treatment of choice, newer molecularly targeted therapies are now reaching the market. Thus far, however, these therapies have had very limited success against solid tumors, which after all make up 90% of all cancers. Success has been largely restricted to rare leukemias; for example, imatinib mesylate (Gleevec; Novartis, Basel) has initially proven effective in patients with chronic myelogenous leukemia (CML). Whereas the initial clinical success of imatinib in CML was spectacular, this has not been repeated in most of the succeeding cancer therapies against solid tumors. Gefitinib (Iressa; AstraZeneca, London)-based treatment shrinks tumors in only about 10% of advanced non-small cell lung cancer patients9. A recent study in one very small (35) patient group indicated that trastuzumab (Herceptin; Genentech, S. San Francisco) induces a partial response in only 23% of individuals with advanced HER2/neu-overexpressing breast cancers10; early indications are that bevacizumab (Avastin; Genentech, S. San Francisco) is not much better in colon cancer. All of these agents have serious associated toxicities11–13, most extend patient survival only by a matter of months and there is a variable period of remission before a resistant form of the cancer returns, even in the case of imatinib14. In the light of these findings, the concept of intervening in cancer networks at a single ‘oncoprotein’ or ‘tumor suppressor protein’ George L. Gabor Miklos is at Secure Genetics Pty Limited, 19 Bungan Head Road, Newport Beach, Sydney, New South Wales, Australia 2106. He was an advisor to the Berkeley Drosophila Genome Project and to the human and mouse genome projects at Celera. e-mail: gmiklos@securegenetics.com Figure 1 Glacial progress. National Cancer Institute data of 5 year relative survival for patients with distant metastases of colorectal, lung, breast and prostate cancer. 0 5 10 15 20 25 30 35 40