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

  • Babu V. Sajesh
  • Amy L. Cisyk
  • Kirk J. McManusEmail author
Chapter
Part of the Cancer Metastasis - Biology and Treatment book series (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.

Keywords

Colorectal cancer Metastatic disease Chromosome instability Genome instability Therapeutic targeting Treatment Synthetic genetic approaches Synthetic lethality Synthetic dosage lethality Personalized medicine 

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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Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Manitoba Institute of Cell Biology, Department of Biochemistry and Medical GeneticsUniversity of ManitobaWinnipegCanada

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