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Synthetic Genetic Approaches in Colorectal Cancer: Exploiting and Targeting Genome Instability

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Genomic Instability and Cancer Metastasis

Part of the book series: Cancer Metastasis - Biology and Treatment ((CMBT,volume 20))

Abstract

Colorectal cancer is the third leading cause of cancer-related deaths throughout the world. Surgery is effective against early stage tumors but advanced stage tumors lack an effective targeting strategy. For nearly 50 years, 5-fluorouracil has been the standard of care for advanced disease, but the overall 5-year survival rate remains at only 6 %. Accordingly, novel therapeutic strategies are urgently needed to decrease morbidity and mortality rates. Synthetic genetic approaches are well established in model organisms, and have recently garnered much attention in humans for their potential implications in cancer targeting. Synthetic lethality and synthetic dosage lethality are innovative strategies designed to specifically exploit and kill cancer cells based on the loss-of-function associated with tumor suppressors or the gain-of-function associated with oncogenes, respectively. By definition, these approaches are highly specific and restricted to tumor cells, and are expected to decrease side effects associated with current strategies. Both synthetic genetic approaches have been applied extensively in pre-clinical studies and numerous candidate drug targets have been identified, including some that have entered clinical trials. The focus of this chapter is to present the pathways that drive tumorigenesis in colorectal cancer, and describe how synthetic lethality and synthetic dosage lethality can exploit these origins for enhanced killing of tumor cells. Finally, we summarize the current status of the field and relate how these novel strategies can be custom-tailored to target advanced stage colorectal cancer as we enter the personalized medicine era.

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Abbreviations

5-FU:

5-Flurouracil

APC:

Adenomatous polyposis coli

CIMP:

CpG island methylator phenotype

CIN:

Chromosome instability

CRC:

Colorectal cancer

DNA:

Deoxyribonucleic acid

KRAS:

Kirsten rat sarcoma viral oncogene homolog

MMR:

Mismatch repair

MSI:

Microsatellite instability

nCIN:

Numerical CIN

sCIN:

Structural CIN

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Authors and Affiliations

  1. Manitoba Institute of Cell Biology, Department of Biochemistry and Medical Genetics, University of Manitoba, R3E 0V9, Winnipeg, MB, Canada

    Babu V. Sajesh, Amy L. Cisyk & Kirk J. McManus

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  1. Babu V. Sajesh
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  2. Amy L. Cisyk
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  3. Kirk J. McManus
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Correspondence to Kirk J. McManus .

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  1. Child & Family Research Institute, University of British Columbia, Pediatrics, Vancouver, British Columbia, Canada

    Chris Maxwell

  2. Dept of Cellular & Physiological Sciences, University of British Columbia, Dept. of Cellular & Physiological Sciences, Vancouver, British Columbia, Canada

    Cal Roskelley

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Sajesh, B., Cisyk, A., McManus, K. (2015). Synthetic Genetic Approaches in Colorectal Cancer: Exploiting and Targeting Genome Instability. In: Maxwell, C., Roskelley, C. (eds) Genomic Instability and Cancer Metastasis. Cancer Metastasis - Biology and Treatment, vol 20. Springer, Cham. https://doi.org/10.1007/978-3-319-12136-9_9

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