Posttranslational protein modifications: current implications for cancer detection, prevention, and therapeutics.

Over the last several years major advances in sensitive high throughput technologies have been made in the fields of genomics and proteomics. The hunt for diagnostic and prognostic cancer biomarkers exploits these recent technology platforms. Although the recent developments and use of genomics and proteomics offer much promise in the search for molecular markers of early stage cancers, these methods are inadequate to probe the dynamic nature of signaling processes that cells exhibit during their transformation to become neoplastic. The diverse realm of posttranslational modification (PTM) of proteins encompasses many of the critical signaling events occurring during neoplastic transformation. PTMs offer a plethora of candidates for biomarker detection that complement discoveries using strictly proteomics or genomics platforms. Furthermore the potential to pharmacologically impede tumor growth by administration of an agent that interrupts a specific PTM driving oncogenic progression has been the basis of numerous clinical trials currently underway. To draw greater attention to the opportunities afforded by innovative research in PTMs, a 2-day workshop was conducted August 2002 in Bethesda, MD. The goals of this meeting were to address several topics where PTMs play roles in cancer progression, consider what technologies can be applied to clinical prevention or detection of cancer, and assess what PTMs could be pursued for development of promising surrogate markers. Since that time some advancement has been made in technological developments to study PTMs, identifying the central roles they play in cancer progression, and determining their amenability as either a cancer biomarker or therapeutic target. A limiting factor in PTM research is that technologies to screen vast numbers of molecules for a particular type of modification are often not available, although recent developments of specific probes and multiplexed platforms may now make broader scale PTM surveying feasible (1–6). For the most part, research in PTM as it relates to biomarker discovery has required the study of discreet modifications on specific proteins of importance to cancer biology. This one by one approach clearly takes time, but the rewards are not to be underestimated in terms of application to cancer detection and treatment. This review highlights the areas where PTMs are of prime importance for cancer diagnosis and treatment. Table I lists many of the more prominent examples where PTM of specific proteins has relevance toward these aspects of clinical practice in oncology. This review highlights the major aspects of PTMs currently investigated by many laboratories. By providing this overview, it should be apparent that PTMs are key to understanding cancer biology and thus should receive special attention for applications in translational research. PTMs that are currently most germane to clinical applications in cancer medicine are briefly introduced below.