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Research Articles: Targets

Targeting changes in cancer: assessing pathway stability by comparing pathway gene expression coherence levels in tumor and normal tissues

¹ Developmental Therapeutics Program, Screening Technologies Branch, Laboratory of Computational Technologies, National Cancer Institute-Frederick and ² Science Applications International Corporation-Frederick, Inc., National Cancer Institute-Frederick, Frederick, Maryland

Requests for reprints: David G. Covell, Developmental Therapeutics Program, Screening Technologies Branch, Laboratory of Computational Technologies, National Cancer Institute-Frederick, Frederick, MD 21702. Phone: 301-846-5785; Fax: 301-846-6978. E-mail: covell{at}ncifcrf.gov

The purpose of this study is to examine gene expression changes occurring in cancer from a pathway perspective by analyzing the level of pathway coherence in tumor tissues in comparison with their normal counterparts. Instability in pathway regulation patterns can be considered either as a result of or as a contributing factor to genetic instability and possibly cancer. Our analysis has identified pathways that show a significant change in their coherence level in tumor tissues, some of which are tumor type specific, indicating novel targets for cancer type–specific therapies. Pathways are found to have a general tendency to lose their gene expression coherence in tumor tissues when compared with normal tissues, especially for signaling pathways. The selective growth advantage of cancer cells over normal cells seems to originate from their preserved control over vital pathways to ensure survival and altered signaling, allowing excessive proliferation. We have additionally investigated the tissue-related instability of pathways, providing valuable clues to the cellular processes underlying the tumorigenesis and/or growth of specific cancer types. Pathways that contain known cancer genes (i.e., "cancer pathways") show significantly greater instability and are more likely to become incoherent in tumor tissues. Finally, we have proposed strategies to target instability (i.e., pathways that are prone to changes) by identifying compound groups that show selective activity against pathways with a detectable coherence change in cancer. These results can serve as guidelines for selecting novel agents that have the potential to specifically target a particular pathway that has relevance in cancer. [Mol Cancer Ther 2006;5(9):2417–27]

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

³ http://www-genome.wi.mit.edu/MPR.

⁴ http://www.broad.mit.edu/mpr/publications/projects/Global_Cancer_Map/GCM_Total.res.

Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 5/ 2/06; revised 6/19/06; accepted 7/26/06.