Transcriptional changes induced by bevacizumab combination therapy in responding and non-responding recurrent glioblastoma patients

Thomas Urup; Line Mærsk Staunstrup; Signe Regner Michaelsen; Kristoffer Vitting-Seerup; Marc Bennedbæk; Anders Toft; Lars Rønn Olsen; Lars Jønson; Shohreh Issazadeh-Navikas; Helle Broholm; Petra Hamerlik; Hans Skovgaard Poulsen; Ulrik Niels Lassen

doi:10.1186/s12885-017-3251-3

Transcriptional changes induced by bevacizumab combination therapy in responding and non-responding recurrent glioblastoma patients

Thomas Urup, Line Mærsk Staunstrup, Signe Regner Michaelsen, Kristoffer Vitting-Seerup, Marc Bennedbæk, Anders Toft, Lars Rønn Olsen, Lars Jønson, Shohreh Issazadeh-Navikas, Helle Broholm, Petra Hamerlik, Hans Skovgaard Poulsen, Ulrik Niels Lassen

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Abstract

BACKGROUND: Bevacizumab combined with chemotherapy produces clinical durable response in 25-30% of recurrent glioblastoma patients. This group of patients has shown improved survival and quality of life. The aim of this study was to investigate changes in gene expression associated with response and resistance to bevacizumab combination therapy.

METHODS: Recurrent glioblastoma patients who had biomarker-accessible tumor tissue surgically removed both before bevacizumab treatment and at time of progression were included. Patients were grouped into responders (n = 7) and non-responders (n = 14). Gene expression profiling of formalin-fixed paraffin-embedded tumor tissue was performed using RNA-sequencing.

RESULTS: By comparing pretreatment samples of responders with those of non-responders no significant difference was observed. In a paired comparison analysis of pre- and posttreatment samples of non-responders 1 gene was significantly differentially expressed. In responders, this approach revealed 256 significantly differentially expressed genes (72 down- and 184 up-regulated genes at the time of progression). Genes differentially expressed in responders revealed a shift towards a more proneural and less mesenchymal phenotype at the time of progression.

CONCLUSIONS: Bevacizumab combination treatment demonstrated a significant impact on the transcriptional changes in responders; but only minimal changes in non-responders. This suggests that non-responding glioblastomas progress chaotically without following distinct gene expression changes while responding tumors adaptively respond or progress by means of the same transcriptional changes. In conclusion, we hypothesize that the identified gene expression changes of responding tumors are associated to bevacizumab response or resistance mechanisms.

Original language	English
Article number	278
Journal	BMC Cancer
Volume	17
Number of pages	10
ISSN	1471-2407
DOIs	https://doi.org/10.1186/s12885-017-3251-3
Publication status	Published - 18 Apr 2017

Keywords

Adult
Aged
Antineoplastic Agents
Bevacizumab
Brain Neoplasms
Female
Gene Expression Profiling
Glioblastoma
Humans
Male
Middle Aged
Neoplasm Recurrence, Local
Transcription, Genetic
Young Adult
Journal Article

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Urup, T., Staunstrup, L. M., Michaelsen, S. R., Vitting-Seerup, K., Bennedbæk, M., Toft, A., Olsen, L. R., Jønson, L., Issazadeh-Navikas, S., Broholm, H., Hamerlik, P., Poulsen, H. S., & Lassen, U. N. (2017). Transcriptional changes induced by bevacizumab combination therapy in responding and non-responding recurrent glioblastoma patients. BMC Cancer, 17, Article 278. https://doi.org/10.1186/s12885-017-3251-3

Urup, T, Staunstrup, LM, Michaelsen, SR, Vitting-Seerup, K, Bennedbæk, M, Toft, A, Olsen, LR, Jønson, L, Issazadeh-Navikas, S, Broholm, H, Hamerlik, P, Poulsen, HS & Lassen, UN 2017, 'Transcriptional changes induced by bevacizumab combination therapy in responding and non-responding recurrent glioblastoma patients', BMC Cancer, vol. 17, 278. https://doi.org/10.1186/s12885-017-3251-3

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title = "Transcriptional changes induced by bevacizumab combination therapy in responding and non-responding recurrent glioblastoma patients",

abstract = "BACKGROUND: Bevacizumab combined with chemotherapy produces clinical durable response in 25-30% of recurrent glioblastoma patients. This group of patients has shown improved survival and quality of life. The aim of this study was to investigate changes in gene expression associated with response and resistance to bevacizumab combination therapy.METHODS: Recurrent glioblastoma patients who had biomarker-accessible tumor tissue surgically removed both before bevacizumab treatment and at time of progression were included. Patients were grouped into responders (n = 7) and non-responders (n = 14). Gene expression profiling of formalin-fixed paraffin-embedded tumor tissue was performed using RNA-sequencing.RESULTS: By comparing pretreatment samples of responders with those of non-responders no significant difference was observed. In a paired comparison analysis of pre- and posttreatment samples of non-responders 1 gene was significantly differentially expressed. In responders, this approach revealed 256 significantly differentially expressed genes (72 down- and 184 up-regulated genes at the time of progression). Genes differentially expressed in responders revealed a shift towards a more proneural and less mesenchymal phenotype at the time of progression.CONCLUSIONS: Bevacizumab combination treatment demonstrated a significant impact on the transcriptional changes in responders; but only minimal changes in non-responders. This suggests that non-responding glioblastomas progress chaotically without following distinct gene expression changes while responding tumors adaptively respond or progress by means of the same transcriptional changes. In conclusion, we hypothesize that the identified gene expression changes of responding tumors are associated to bevacizumab response or resistance mechanisms.",

keywords = "Adult, Aged, Antineoplastic Agents, Bevacizumab, Brain Neoplasms, Female, Gene Expression Profiling, Glioblastoma, Humans, Male, Middle Aged, Neoplasm Recurrence, Local, Transcription, Genetic, Young Adult, Journal Article",

author = "Thomas Urup and Staunstrup, {Line M{\ae}rsk} and Michaelsen, {Signe Regner} and Kristoffer Vitting-Seerup and Marc Bennedb{\ae}k and Anders Toft and Olsen, {Lars R{\o}nn} and Lars J{\o}nson and Shohreh Issazadeh-Navikas and Helle Broholm and Petra Hamerlik and Poulsen, {Hans Skovgaard} and Lassen, {Ulrik Niels}",

year = "2017",

month = apr,

day = "18",

doi = "10.1186/s12885-017-3251-3",

language = "English",

volume = "17",

journal = "BMC Cancer",

issn = "1471-2407",

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TY - JOUR

T1 - Transcriptional changes induced by bevacizumab combination therapy in responding and non-responding recurrent glioblastoma patients

AU - Urup, Thomas

AU - Staunstrup, Line Mærsk

AU - Michaelsen, Signe Regner

AU - Vitting-Seerup, Kristoffer

AU - Bennedbæk, Marc

AU - Toft, Anders

AU - Olsen, Lars Rønn

AU - Jønson, Lars

AU - Issazadeh-Navikas, Shohreh

AU - Broholm, Helle

AU - Hamerlik, Petra

AU - Poulsen, Hans Skovgaard

AU - Lassen, Ulrik Niels

PY - 2017/4/18

Y1 - 2017/4/18

N2 - BACKGROUND: Bevacizumab combined with chemotherapy produces clinical durable response in 25-30% of recurrent glioblastoma patients. This group of patients has shown improved survival and quality of life. The aim of this study was to investigate changes in gene expression associated with response and resistance to bevacizumab combination therapy.METHODS: Recurrent glioblastoma patients who had biomarker-accessible tumor tissue surgically removed both before bevacizumab treatment and at time of progression were included. Patients were grouped into responders (n = 7) and non-responders (n = 14). Gene expression profiling of formalin-fixed paraffin-embedded tumor tissue was performed using RNA-sequencing.RESULTS: By comparing pretreatment samples of responders with those of non-responders no significant difference was observed. In a paired comparison analysis of pre- and posttreatment samples of non-responders 1 gene was significantly differentially expressed. In responders, this approach revealed 256 significantly differentially expressed genes (72 down- and 184 up-regulated genes at the time of progression). Genes differentially expressed in responders revealed a shift towards a more proneural and less mesenchymal phenotype at the time of progression.CONCLUSIONS: Bevacizumab combination treatment demonstrated a significant impact on the transcriptional changes in responders; but only minimal changes in non-responders. This suggests that non-responding glioblastomas progress chaotically without following distinct gene expression changes while responding tumors adaptively respond or progress by means of the same transcriptional changes. In conclusion, we hypothesize that the identified gene expression changes of responding tumors are associated to bevacizumab response or resistance mechanisms.

AB - BACKGROUND: Bevacizumab combined with chemotherapy produces clinical durable response in 25-30% of recurrent glioblastoma patients. This group of patients has shown improved survival and quality of life. The aim of this study was to investigate changes in gene expression associated with response and resistance to bevacizumab combination therapy.METHODS: Recurrent glioblastoma patients who had biomarker-accessible tumor tissue surgically removed both before bevacizumab treatment and at time of progression were included. Patients were grouped into responders (n = 7) and non-responders (n = 14). Gene expression profiling of formalin-fixed paraffin-embedded tumor tissue was performed using RNA-sequencing.RESULTS: By comparing pretreatment samples of responders with those of non-responders no significant difference was observed. In a paired comparison analysis of pre- and posttreatment samples of non-responders 1 gene was significantly differentially expressed. In responders, this approach revealed 256 significantly differentially expressed genes (72 down- and 184 up-regulated genes at the time of progression). Genes differentially expressed in responders revealed a shift towards a more proneural and less mesenchymal phenotype at the time of progression.CONCLUSIONS: Bevacizumab combination treatment demonstrated a significant impact on the transcriptional changes in responders; but only minimal changes in non-responders. This suggests that non-responding glioblastomas progress chaotically without following distinct gene expression changes while responding tumors adaptively respond or progress by means of the same transcriptional changes. In conclusion, we hypothesize that the identified gene expression changes of responding tumors are associated to bevacizumab response or resistance mechanisms.

KW - Adult

KW - Aged

KW - Antineoplastic Agents

KW - Bevacizumab

KW - Brain Neoplasms

KW - Female

KW - Gene Expression Profiling

KW - Glioblastoma

KW - Humans

KW - Male

KW - Middle Aged

KW - Neoplasm Recurrence, Local

KW - Transcription, Genetic

KW - Young Adult

KW - Journal Article

U2 - 10.1186/s12885-017-3251-3

DO - 10.1186/s12885-017-3251-3

M3 - Journal article

C2 - 28420326

SN - 1471-2407

VL - 17

JO - BMC Cancer

JF - BMC Cancer

M1 - 278

ER -

Transcriptional changes induced by bevacizumab combination therapy in responding and non-responding recurrent glioblastoma patients

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Keywords

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