The role of receptor tyrosine kinases in mediating glioblastoma resistance to radiotherapy and temozolomide
Year: 2020
Type: dissertation
Abstract: Glioblastoma is the most common and aggressive form of malignant glioma.Currently, despite treatment with surgery followed by radiotherapy and the chemotherapeutic agent temozolomide (TMZ), mean patient survival time is approximately 12 months and the 5-year survival rate is close to 0%.A key factor for the dismal prognosis is tumour recurrence posttreatment which is largely due to: 1) the infiltrative nature of glioblastoma rendering complete resection impossible and 2) glioblastoma cell resistance to radio-chemotherapy.In this thesis we aimed to investigate the cellular mechanisms of receptor tyrosine kinases in conferring resistance to therapy.We first performed a literature search and found that almost all studies that advocated for the utility of targeting RTKs in overcoming treatment resistance did not employ both therapeutic agents comprising standard therapy -radiotherapy and TMZ.We next generated an in vitro glioblastoma resistant model via short-term treatment with radiotherapy and TMZ and found that these cells had down-regulated RTK activity in addition to down-regulated protein and gene expression of the commonly altered and studied epidermal growth factor receptor (EGFR) and MET receptor.After generating an in vitro glioblastoma recurrent model via long-term treatment we demonstrated that the surviving sub-population of cells also displayed down-regulated EGFR and MET expression compared to treatment naïve cells.Furthermore, we also showed that the resistant cell population already pre-exists within the parental population which suggests the possibility of pre-emptively targeting the inherently resistant population.Interestingly, we also observed differential microRNA expression in radiotherapy-and TMZtreated cells and, specifically, found that miR-221 confers resistance to glioblastoma cells and is capable of down-regulating EGFR expression.We validated this relationship in a human cohort of 105 primary and 36 recurrent glioblastoma patients, showing a significant inverse relationship between miR-221 and EGFR.Consistently, we showed that high miR-221 and low-EGFR expression at recurrence is associated with a poorer prognosis. LIST OF ABBREVIATIONS* p-value ≤ 0.05 ** p-value ≤ 0.01 *** p-value ≤ 0.001 [17]Table 1-1: Proposed subtypes of glioblastoma A) According to Verhaak et al. [64] Classical Proneural Mesenchymal Neural Ch 7 amplification + Ch 10 loss paired, 100% rate Locus 4q12 amplification, altered and over-expressed PDGFRA NF1 mutated, deleted, low expression Neuron marker expression: NEFL, SYT1, GABRA1 EGFR amplification rate = 97% IDH1 mutation Over-expression of MET and CHI3L1 EGFR over-expression P53 mutation High CD44 12/22 EGFRvIII or point mutation Lack of paired Ch 7 amplification + Ch 10 loss, rate 54% High NF-kB signalling Lack p53,PDGFRA, IDH1 mutation Oligodendrocyte marker OLIG2 CDKN2A deletion Over-expression of Notch, Sonic Hedgehog and Nestin Median age: 55.7 years Median age: 51.8 years Median age: 57.7 years Median age: 63.8 years Median Survival (TCGA vs. validation set: 12.2 vs. 12.2 months Median Survival (TCGA vs. validation set: 11.3 months vs. 16.2 months Median Survival (TCGA vs. validation set: 11.8 months vs. 15 month Median Survival (TCGA vs. validation set: 13.1 months vs. 15.0 months B) According to Phillips et al. [65] Proneural Proliferation Mesenchymal Mostly WHO Grade III, 31% GBM 20% were GBM 49% were GBM 36% of GBM necrosis Lack necrosis 7.5% of GBM necrosis Mean Age = 49 years Mean age = 50.7 years Mean age= 40.5 years Ch10 gain PTEN loss Over-expressed VEGF/VEGFR PTEN loss Lower AKT activation Ch7 amplification, Ch10 loss Ch7 amplification, Ch10 loss EGFR amplification EGFR amplification
Author: Mohamed Zammam Areeb
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W3045416801