In search of effective therapies to overcome resistance to Temozolomide in brain tumours.

Kaouthar Bouzinab,Richard Grundy,Helen Summers,Emily Vitterso,Malcolm F G Stevens,Lyudmila Turyanska,Tracey D Bradshaw,Marianne B Ashford,Christopher J Moody,Pavel Gershkovich,Jihong Zhang,Lisa C D Storer,Neil R Thomas

doi:10.20517/cdr.2019.64

Abstract

Glioblastoma multiforme is the most common and lethal brain tumour-type. The current standard of care includes Temozolomide (TMZ) chemotherapy. However, inherent and acquired resistance to TMZ thwart successful treatment. The direct repair protein methylguanine DNA methyltransferase (MGMT) removes the cytotoxic O6-methylguanine (O6-MeG) lesion delivered by TMZ and so its expression by tumours confers TMZ-resistance. DNA mismatch repair (MMR) is essential to process O6-MeG adducts and MMR-deficiency leads to tolerance of lesions, resistance to TMZ and further DNA mutations. In this article, two strategies to overcome TMZ resistance are discussed: (1) synthesis of imidazotetrazine analogues - designed to retain activity in the presence of MGMT or loss of MMR; (2) preparation of imidazotetrazine-nanoparticles to deliver TMZ preferably to the brain and tumour site. Our promising results encourage belief in a future where better prognoses exist for patients diagnosed with this devastating disease.

Highlights

According to Cancer Research UK statistics from all forms of brain cancers, 10 year survival is 13%; 5 and 1 year survival figures are 19% and 40% respectively
Because of the appalling prognoses associated with high grade gliomas (HGG) such as glioblastoma multiforme (GBM) and DPIG, novel imidazotetrazine analogues or drug delivery formulations that can deliver an alkylating agent to O6-guanine that is neither removed by methylguanine DNA methyltransferase (MGMT) nor tolerated by mismatch repair (MMR)-deficient tumours are attractive prospects for future treatment
Two approaches have been attempted in our laboratories: (1) Analogues of TMZ have been synthesised that retain the same mode of action of TMZ but whose activity is not thwarted by MGMT presence or MMR deficiency [Tables 1, 2 and 3]

Summary

INTRODUCTION

According to Cancer Research UK statistics from all forms of brain cancers, 10 year survival is 13%; 5 and 1 year survival figures are 19% and 40% respectively. MTT assays were initially employed to investigate antitumour activity of naked and AFt-encapsulated TMZ against isogenic GBM - U373V (vector control; MGMT-ve) and U373M (stably transfected with MGMT; MGMT+ve), paediatric SF188 high-grade glioma and DNA MMR-deficient CRC HCT 116 cancer cell lines as well as non-transformed MRC-5 fibroblasts. This hypothesis is further supported by results obtained from MTT assays performed in MGMT+ paediatric brain tumour cell lines. Because of the appalling prognoses associated with HGG such as GBM and DPIG, novel imidazotetrazine analogues or drug delivery formulations that can deliver an alkylating agent to O6-guanine that is neither removed by MGMT nor tolerated by MMR-deficient tumours are attractive prospects for future treatment. With collaborators at the University of Bristol, and the Childrens Brain Tumour Research Centre, University of Nottingham, we are investigating the feasibility of AFt-encapsulated formulations for CED

CONCLUSION

Findings

Methods