Abstract
While treatment with surgery, radiotherapy and/or chemotherapy may prolong life for patients with glioblastoma, recurrence is inevitable. What is still being discovered is how much these treatments and recurrence of disease affect the molecular profiles of these tumors and how these tumors adapt to withstand these treatment pressures. Understanding such changes will uncover pathways used by the tumor to evade destruction and will elucidate new targets for treatment development. Nineteen matched pre-treatment and post-treatment glioblastoma tumors were subjected to gene expression profiling (Fluidigm, TaqMan assays), MGMT promoter methylation analysis (pyrosequencing) and protein expression analysis of the DNA repair pathways, known to be involved in temozolomide resistance (immunohistochemistry). Gene expression profiling to molecularly subtype tumors revealed that 26% of recurrent post-treatment specimens did not match their primary diagnostic specimen subtype. Post-treatment specimens had molecular changes which correlated with known resistance mechanisms including increased expression of APEX1 (p < 0.05) and altered MGMT methylation status. In addition, genes associated with immune suppression, invasion and aggression (GPNMB, CCL5, and KLRC1) and polarization toward an M2 phenotype (CD163 and MSR1) were up-regulated in post-treatment tumors, demonstrating an overall change in the tumor microenvironment favoring aggressive tumor growth and disease recurrence. This was confirmed by in vitro studies that determined that glioma cell migration was enhanced in the presence of M2 polarized macrophage conditioned media. Further, M2 macrophage-modulated migration was markedly enhanced in post-treatment (temozolomide resistant) glioma cells. These findings highlight the ability of glioblastomas to evade not only the toxic onslaught of therapy but also to evade the immune system suggesting that immune-altering therapies may be of value in treating this terrible disease.
Highlights
Glioblastoma is the most common and aggressive form of brain cancer and has a very grim prognosis
methylguanine DNA methyltransferase (MGMT) Promoter Methylation Status Changed in 10% of Cases Following Treatment and Recurrence of Disease
MGMT promoter methylation status showed that 21% of primary tumors (4/19) had a methylated promoter and this did not correlate with response to treatment or overall survival (Table 1)
Summary
Glioblastoma (grade IV astrocytoma) is the most common and aggressive form of brain cancer and has a very grim prognosis. Despite aggressive treatment involving maximal surgical resection, radiation and concomitant and adjuvant chemotherapy with temozolomide (TMZ), the median survival time is approximately 15 months, and the five-year survival rate remains at a staggering 3–5% [1] While these multimodal treatments may prolong life, recurrence is inevitable with tumors either being inherently resistant, as is the case in approximately 50% of glioblastomas [2] or acquiring resistance [3]. Studies investigating mechanisms of resistance have uncovered common themes including dysregulation in DNA repair enzymes, including increased levels of O6-methylguanine DNA methyltransferase (MGMT), and over-expression or amplification of EGFR, and loss of p53 and PTEN [reviewed in [4]] Such investigations have generally been performed on the initial pre-treatment tumor where only inherent resistance mechanisms would be observed. Identifying such changes will highlight the importance of testing recurrent samples which may have important consequences to patient management
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