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Longitudinal heterogeneity in glioblastoma: moving targets in recurrent versus primary tumors.

ABSTRACT: BACKGROUND:Molecularly targeted therapies using receptor inhibitors, small molecules or monoclonal antibodies are routinely applied in oncology. Verification of target expression should be mandatory prior to initiation of therapy, yet, determining the expression status is most challenging in recurrent glioblastoma (GBM) where most patients are not eligible for second-line surgery. Because very little is known on the consistency of expression along the clinical course we here explored common drug targets in paired primary vs. recurrent GBM tissue samples. METHODS:Paired surgical tissue samples were derived from a homogeneously treated cohort of 34 GBM patients. All patients received radiotherapy and temozolomide chemotherapy. Verification of common drug targets included immunohistological analysis of PDGFR-?, FGFR-2, FGFR-3, and mTOR-pathway component (phospho-mTORSer2448) as well as molecular, MLPA-based analysis of specific copy number aberrations at the gene loci of ALK, PDGFRA, VEGFR2/KDR, EGFR, MET, and FGFR1. RESULTS:Paired tumor tissue exhibited significant changes of expression in 9 of the 10 investigated druggable targets (90%). Only one target (FGFR1) was found "unchanged", since dissimilar expression was observed in only one of the 34 paired tumor tissue samples. All other targets were variably expressed with an 18-56% discordance rate between primary and recurrent tissue. CONCLUSIONS:The high incidence of dissimilar target expression status in clinical samples from primary vs. recurrent GBM suggests clinically relevant heterogeneity along the course of disease. Molecular target expression, as determined at primary diagnosis, may not necessarily present rational treatment clues for the clinical care of recurrent GBM. Further studies need to analyze the therapeutic impact of longitudinal heterogeneity in GBM.

SUBMITTER: Schafer N

PROVIDER: S-EPMC6425567 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Longitudinal heterogeneity in glioblastoma: moving targets in recurrent versus primary tumors.

Schäfer Niklas N Gielen Gerrit H GH Rauschenbach Laurèl L Kebir Sied S Till Andreas A Reinartz Roman R Simon Matthias M Niehusmann Pitt P Kleinschnitz Christoph C Herrlinger Ulrich U Pietsch Torsten T Scheffler Björn B Glas Martin M

Journal of translational medicine 20190320 1

<h4>Background</h4>Molecularly targeted therapies using receptor inhibitors, small molecules or monoclonal antibodies are routinely applied in oncology. Verification of target expression should be mandatory prior to initiation of therapy, yet, determining the expression status is most challenging in recurrent glioblastoma (GBM) where most patients are not eligible for second-line surgery. Because very little is known on the consistency of expression along the clinical course we here explored com ...[more]

PMID: 30894200

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Project description: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.

Dataset Information

Longitudinal heterogeneity in glioblastoma: moving targets in recurrent versus primary tumors.

Publications

Longitudinal heterogeneity in glioblastoma: moving targets in recurrent versus primary tumors.

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