FANCD2 re-expression is associated with glioma grade and chemical inhibition of the Fanconi Anaemia pathway sensitises gliomas to chemotherapeutic agents.

Abhijit A Patil,Angela Cox,David Jellinek,Ryan D Beveridge,Thomas A Carroll,Parag Sayal,Anthony Roylance,Malee Fernando,Spencer J Collis,Katie N Myers,Marie-Lise Depondt,Deepti H Kriplani

doi:10.18632/oncotarget.2225

Abstract

Brain tumours kill more children and adults under 40 than any other cancer. Around half of primary brain tumours are glioblastoma multiforme (GBMs) where treatment remains a significant challenge, where survival rates have improved little over the last 40 years, thus highlighting an unmet need for the identification/development of novel therapeutic targets and agents to improve GBM treatment. Using archived and fresh glioma tissue, we show that in contrast to normal brain or benign schwannomas GBMs exhibit re-expression of FANCD2, a key protein of the Fanconi Anaemia (FA) DNA repair pathway, and possess an active FA pathway. Importantly, FANCD2 expression levels are strongly associated with tumour grade, revealing a potential exploitable therapeutic window to allow inhibition of the FA pathway in tumour cells, whilst sparing normal brain tissue. Using several small molecule inhibitors of the FA pathway in combination with isogenic FA-proficient/deficient glioma cell lines as well as primary GBM cultures, we demonstrate that inhibition of the FA pathway sensitises gliomas to the chemotherapeutic agents Temozolomide and Carmustine. Our findings therefore provide a strong rationale for the development of novel and potent inhibitors of the FA pathway to improve the treatment of GBMs, which may ultimately impact on patient outcome.

Highlights

Brain tumours are the biggest cancer killers of the under 40s with over 400,000 new cases diagnosed worldwide each year
Given that the Fanconi Anaemia (FA) pathway responds to lesions that impede on-going DNA replication [12], is down-regulated in differentiated cells [8], expressed in highly proliferative tissue, but not expressed in normal brain tissue [9, 10]; we hypothesised that FA protein expression would be elevated in glioblastoma multiforme (GBM) and might potentially correlate with clinical grade
Comparable data was obtained using a commercial tissue microarray, in which normal brain tissue was devoid of any FANCD2 expression, and expression was more prevalent with increasing tumour grade (Figure 1C)

Summary

Introduction

Brain tumours are the biggest cancer killers of the under 40s with over 400,000 new cases diagnosed worldwide each year. They represent the commonest site for solid tumours in childhood under the age of 15 [1]. There is an unmet need for the development of novel targets and agents to improve GBM treatment. The underlying molecular mechanisms driving inherent or acquired resistance of GBM to DNA damaging agents has yet to be determined. There is precedence for determination of expression levels/activity of DDR factors in GBM that could account for resistance to therapeutic agents, as well as highlighting novel drug targets as a means to augment the cytotoxicity of current therapeutic regimes

Methods

Results

Conclusion