Intratumoral Heterogeneity and Longitudinal Changes in Gene Expression Predict Differential Drug Sensitivity in Newly Diagnosed and Recurrent Glioblastoma

Abstract

Background: Inevitable recurrence after radiochemotherapy is the major problem in the treatment of glioblastoma, the most prevalent type of adult brain malignancy. Glioblastomas are notorious for a high degree of intratumor heterogeneity manifest through a diversity of cell types and molecular patterns. The current paradigm of understanding glioblastoma recurrence is that cytotoxic therapy fails to target effectively glioma stem cells. Recent advances indicate that therapy-driven molecular evolution is a fundamental trait associated with glioblastoma recurrence. There is a growing body of evidence indicating that intratumor heterogeneity, longitudinal changes in molecular biomarkers and specific impacts of glioma stem cells need to be taken into consideration in order to increase the accuracy of molecular diagnostics still relying on readouts obtained from a single tumor specimen. Methods: This study integrates a multisampling strategy, longitudinal approach and complementary transcriptomic investigations in order to identify transcriptomic traits of recurrent glioblastoma in whole-tissue specimens of glioblastoma or glioblastoma stem cells. In this study, 128 tissue samples of 44 tumors including 23 first diagnosed, 19 recurrent and 2 secondary recurrent glioblastomas were analyzed along with 27 primary cultures of glioblastoma stem cells by RNA sequencing. A novel algorithm was used to quantify longitudinal changes in pathway activities and model efficacy of anti-cancer drugs based on gene expression data. Results: Our study reveals that intratumor heterogeneity of gene expression patterns is a fundamental characteristic of not only newly diagnosed but also recurrent glioblastomas. Evidence is provided that glioblastoma stem cells recapitulate intratumor heterogeneity, longitudinal transcriptomic changes and drug sensitivity patterns associated with the state of recurrence. Conclusions: Our results provide a transcriptional rationale for the lack of significant therapeutic benefit from temozolomide in patients with recurrent glioblastoma. Our findings imply that the spectrum of potentially effective drugs is likely to differ between newly diagnosed and recurrent glioblastomas and underscore the merits of glioblastoma stem cells as prognostic models for identifying alternative drugs and predicting drug response in recurrent glioblastoma. With the majority of recurrent glioblastomas being inoperable, glioblastoma stem cell models provide the means of compensating for the limited availability of recurrent glioblastoma specimens.

Recurrent Glioblastoma: From Molecular Landscape to New Treatment Perspectives

“…Similarities between primary and rGBM are also apparent at RNA level, where unsupervised analysis highlighted a significant overlap between primary and rGBM [ 30 ]. Expression-based molecular subtypes are also relatively stable during tumor progression [ 31 , 32 ].…”

DNA repair pathway activation features in follicular and papillary thyroid tumors, interrogated using 95 experimental RNA sequencing profiles

“…DNA repair mechanisms restore damaged DNA and may have a dual effect on the tumor: they prevent new somatic mutations and may restrict tumor development, but they also restore tumor cells with damaged DNA after chemo and radiation therapy [ 19 ]. Thus, when planning the chemo and/or radiation therapy, the possibility of DNA repair must be taken into account [ 20 ]. Low activities of DNA repair genes can make tumor cells more sensitive to the therapy, but at the same time not-repaired damaged tumor cells can form more new clones of treatment resistant cells [ 21 , 22 ].…”

Molecular Mechanisms of Treatment Resistance in Glioblastoma

“…Taken together, the findings from the above studies suggest that, although tumoral heterogeneity in glioblastomas remains mostly stable over time, subclonal mutations may result in differential drug sensitivity in a minority of cases at the time of recurrence [ 60 ]. Future efforts should continue to optimize and refine individualized treatments for patients based on their tumors’ unique mutational profiles.…”