6 - Implications of homologous recombination defectiveness in ovarian cancer

Summary

Introduction

Major advances have taken place in our understanding of the biology of cancer but it has often seemed that this has not been translated into breakthroughs in new treatments, particularly in ovarian cancer where first-line management for the disease has not changed in 20 years.

The benefits of an increasing knowledge of the biology of the disease should, however, be two-fold — identifying new targets against which drugs can be developed and being able to identify which tumours are most likely to respond to these drugs. To be able to move away from the ‘one size fits all’ mentality of current cytotoxic therapy towards an individualised, targeted therapy remains the holy grail of current cancer medicine.

The story of the development of polyadenosine diphosphate-ribose polymerase (PARP) inhibitors and their link with the homologous recombination (HR) DNA repair pathway is the first real example in ovarian cancer of this process being carried through from the laboratory to the clinic. This chapter outlines the DNA repair pathways involved in PARP inhibitor sensitivity, how deficiencies in these pathways are exploited by PARP inhibitors and finally how aberrations of these pathways may be identified and thus used as predictive biomarkers for treatment. The aim of this work is ultimately to allow PARP inhibitor therapy to be targeted to a group of tumours that have a very high chance of responding.

DNA damage repair pathways

The development of a cancer is defined by a pattern of genetic abnormality affecting a cell.