Colorectal cancer molecular biology moves into clinical practice

Department of Laboratory Medicine, University of Washington, Washington, USA.
Gut (Impact Factor: 14.66). 10/2010; 60(1):116-29. DOI: 10.1136/gut.2009.206250
Source: PubMed


The promise of personalised medicine is now a clinical reality, with colorectal cancer genetics at the forefront of this next major advance in clinical medicine. This is no more evident than in the recent advances in testing of colorectal cancers for specific molecular alterations in order to guide treatment with the monoclonal antibody therapies cetuximab and panitumumab, which target the epidermal growth factor receptor. In this review, genetic mechanisms of colorectal cancer and how these alterations relate to emerging biomarkers for early detection and risk stratification (diagnostic markers), prognosis (prognostic markers) and the prediction of treatment responses (predictive markers) are examined.

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    • "Among these, the AOM model has been extensively used to examine the chemopreventive effect of numerous compounds on colon cancer[36]. Administration of AOM to rodents induces the development of the ACF colonic preneoplastic lesions that may progress into cancer with time[1]. Indeed, ACF represent the earliest identifiable intermediate precancerous lesions during colon carcinogenesis in both laboratory animals and humans[37]. "

    Full-text · Article · Jan 2016
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    • "For therapy purposes, anti-VEGF-A antibodies have been employed in addition to standard chemotherapy agents. Despite all the efforts, the prognosis of patients with advanced stage disease has not been significantly improved [54] [55]. hERG1 protein is highly expressed in colorectal adenocarcinomas with respect to hyperplastic lesions of the colon [11] and in CRC cell lines [11] [33] and it was demonstrated that the protein is not expressed in small adenomas and sigma diverticulitis [56]. "
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    ABSTRACT: Because of their high incidence and mortality solid cancers are a major health problem worldwide. Although several new biomarkers and potential targets for therapy have been identified through biomolecular research in the last years, the effects on patients’ outcome are still unsatisfactory. Increasing evidence indicates that hERG1 potassium channels are overexpressed in human primary cancers of different origin and several associations between hERG1 expression and clinicopathological features and/or outcome are emerging. Aberrant hERG1 expression may be exploited either for early diagnosis (especially in those cancers where it is expressed in the initial steps of tumor progression) or for therapy purposes. Indeed, hERG1 blockage impairs tumor cell growth both in vitro and in vivo in preclinical mouse model. hERG1-based tumor therapy in humans, however, encounters the major hindrance of the potential cardiotoxicity that many hERG1 blockers exert. In this review we focus on recent advances in translational research in some of the most frequent human solid cancers (breast, endometrium, ovary, pancreas, esophagus, stomach, and colorectum) that have been shown to express hERG1 and that are a major health problem.
    Full-text · Article · Sep 2015
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    • "In CRC, p53 mutation occurs in about 40–50% of cases91011. Mutated p53 loses its tumor suppressive function, which is a critical event in the adenoma to carcinoma transition during colon carcinogenesis[12]. Scientists have been enthusiastic in developing different strategies to reactivate mutated p53 in cancer cells as an anti-cancer therapy[13,14]. "
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    ABSTRACT: PRIMA-1met (APR-246) is a methylated derivative and structural analog of PRIMA-1 (p53 re-activation and induction of massive apoptosis). PRIMA-1met has been reported to restore both the wild type (wt) structure and function of mutant p53. Here, we show that PRIMA-1met is highly effective at limiting the growth of CRC cells regardless of p53 status. However, PRIMA-1met induces robust apoptosis only in CRC cells with mutant p53. Upregulation of Noxa, a proapoptotic molecule, is crucial for PRIMA-1met mediated activity. In human xenograft model of disease, PRIMA-1met effectively suppresses CRC tumor growth. Our results uncover distinct mechanisms of PRIMA-1met in CRC with different p53 status, thus providing a mechanistic rationale to evaluate the clinical efficacy of PRIMA-1met in CRC patients with different p53 status.
    Preview · Article · Jul 2015 · Oncotarget
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