A Molecular Signature associated with prolonged survival in Glioblastoma patients treated with Regorafenib

Alessandra Santangelo; Marzia Rossato; Giuseppe Lombardi; Salvatore Benfatto; Denise Lavezzari; Gian Luca De Salvo; Stefano Indraccolo; Maria Cristina Dechecchi; Paola Prandini; Roberto Gambari; Chiara Scapoli; Gianfranco Di Gennaro; Mario Caccese; Marica Eoli; Roberta Rudà; Alba Ariela Brandes; Toni Ibrahim; Simona Rizzato; Ivan Lolli; Giuseppe Lippi; Massimo Delledonne; Vittorina Zagonel; Giulio Cabrini

doi:10.1093/neuonc/noaa156

A Molecular Signature associated with prolonged survival in Glioblastoma patients treated with Regorafenib

Alessandra Santangelo, Marzia Rossato, Giuseppe Lombardi, Salvatore Benfatto, Denise Lavezzari, Gian Luca De Salvo, Stefano Indraccolo, Maria Cristina Dechecchi, Paola Prandini, Roberto Gambari, Chiara Scapoli, Gianfranco Di Gennaro, Mario Caccese, Marica Eoli, Roberta Rudà, Alba Ariela Brandes, Toni Ibrahim, Simona Rizzato, Ivan Lolli, Giuseppe LippiMassimo Delledonne, Vittorina Zagonel, Giulio Cabrini

Research output: Contribution to journal › Article › peer-review

Abstract

BACKGROUND: Patients with glioblastoma (GBM) have a dramatically poor prognosis. The recent REGOMA trial suggested an overall survival benefit of regorafenib in recurrent GBM patients. Considering the extreme genetic heterogeneity of GBMs, we aimed to identify molecular biomarkers predictive of differential response to the drug.

METHODS: Total RNA was extracted from tumor samples of patients enrolled in the REGOMA trial. Genome-wide transcriptome and miRNA profiles were associated with patients' Overall Survival (OS) and Progression Free Survival (PFS).

RESULTS: At first step, a set of 11 gene transcripts (HIF1A, CTSK, SLC2A1, KLHL12, CDKN1A, CA12, WDR1, CD53, CBR4, NIFK-AS1, RAB30-DT) and 10 miRNAs (miR-93-5p, miR-203a-3p, miR-17-5p, let-7c-3p, miR-101-3p, miR-3607-3p, miR-6516-3p, miR-301a-3p, miR-23b-3p, miR-222-3p) was filtered by comparing survival between regorafenib and lomustine arms. As second step, a minisignature of two gene transcripts (HIF1A, CDKN1A) and three miRNAs (miR-3607-3p, miR-301a-3p, miR-93-5p) identified a subgroup of patients showing prolonged survival after regorafenib administration (median OS range 10.6 - 20.8 months).

CONCLUSIONS: The study provides evidence that a signature based on the expression of five biomarkers could help identifying a subgroup of GBM patients exhibiting a striking survival advantage when treated with regorafenib. Despite the presented results must be confirmed in larger replication cohorts, the study highlights potential biomarker options to help guiding the clinical decision among regorafenib and other treatments in patients with relapsing GBM.

Original language	English
Article number	noaa156
Number of pages	13
Journal	Neuro-Oncology
Volume	1
Issue number	13
DOIs	https://doi.org/10.1093/neuonc/noaa156
Publication status	E-pub ahead of print - Jul 14 2020

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Santangelo, A., Rossato, M., Lombardi, G., Benfatto, S., Lavezzari, D., De Salvo, G. L., Indraccolo, S., Dechecchi, M. C., Prandini, P., Gambari, R., Scapoli, C., Di Gennaro, G., Caccese, M., Eoli, M., Rudà, R., Brandes, A. A., Ibrahim, T., Rizzato, S., Lolli, I., ... Cabrini, G. (2020). A Molecular Signature associated with prolonged survival in Glioblastoma patients treated with Regorafenib. Neuro-Oncology, 1(13), [noaa156]. https://doi.org/10.1093/neuonc/noaa156

A Molecular Signature associated with prolonged survival in Glioblastoma patients treated with Regorafenib. / Santangelo, Alessandra; Rossato, Marzia; Lombardi, Giuseppe; Benfatto, Salvatore; Lavezzari, Denise; De Salvo, Gian Luca ; Indraccolo, Stefano; Dechecchi, Maria Cristina; Prandini, Paola; Gambari, Roberto; Scapoli, Chiara; Di Gennaro, Gianfranco; Caccese, Mario ; Eoli, Marica; Rudà, Roberta; Brandes, Alba Ariela; Ibrahim, Toni; Rizzato, Simona; Lolli, Ivan; Lippi, Giuseppe; Delledonne, Massimo; Zagonel, Vittorina; Cabrini, Giulio.

In: Neuro-Oncology, Vol. 1, No. 13, noaa156, 14.07.2020.

Research output: Contribution to journal › Article › peer-review

Santangelo, A, Rossato, M, Lombardi, G, Benfatto, S, Lavezzari, D, De Salvo, GL , Indraccolo, S, Dechecchi, MC, Prandini, P, Gambari, R, Scapoli, C, Di Gennaro, G, Caccese, M , Eoli, M, Rudà, R, Brandes, AA, Ibrahim, T, Rizzato, S, Lolli, I, Lippi, G, Delledonne, M, Zagonel, V & Cabrini, G 2020, 'A Molecular Signature associated with prolonged survival in Glioblastoma patients treated with Regorafenib', Neuro-Oncology, vol. 1, no. 13, noaa156. https://doi.org/10.1093/neuonc/noaa156

Santangelo, Alessandra ; Rossato, Marzia ; Lombardi, Giuseppe ; Benfatto, Salvatore ; Lavezzari, Denise ; De Salvo, Gian Luca ; Indraccolo, Stefano ; Dechecchi, Maria Cristina ; Prandini, Paola ; Gambari, Roberto ; Scapoli, Chiara ; Di Gennaro, Gianfranco ; Caccese, Mario ; Eoli, Marica ; Rudà, Roberta ; Brandes, Alba Ariela ; Ibrahim, Toni ; Rizzato, Simona ; Lolli, Ivan ; Lippi, Giuseppe ; Delledonne, Massimo ; Zagonel, Vittorina ; Cabrini, Giulio. / A Molecular Signature associated with prolonged survival in Glioblastoma patients treated with Regorafenib. In: Neuro-Oncology. 2020 ; Vol. 1, No. 13.

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title = "A Molecular Signature associated with prolonged survival in Glioblastoma patients treated with Regorafenib",

abstract = "BACKGROUND: Patients with glioblastoma (GBM) have a dramatically poor prognosis. The recent REGOMA trial suggested an overall survival benefit of regorafenib in recurrent GBM patients. Considering the extreme genetic heterogeneity of GBMs, we aimed to identify molecular biomarkers predictive of differential response to the drug.METHODS: Total RNA was extracted from tumor samples of patients enrolled in the REGOMA trial. Genome-wide transcriptome and miRNA profiles were associated with patients' Overall Survival (OS) and Progression Free Survival (PFS).RESULTS: At first step, a set of 11 gene transcripts (HIF1A, CTSK, SLC2A1, KLHL12, CDKN1A, CA12, WDR1, CD53, CBR4, NIFK-AS1, RAB30-DT) and 10 miRNAs (miR-93-5p, miR-203a-3p, miR-17-5p, let-7c-3p, miR-101-3p, miR-3607-3p, miR-6516-3p, miR-301a-3p, miR-23b-3p, miR-222-3p) was filtered by comparing survival between regorafenib and lomustine arms. As second step, a minisignature of two gene transcripts (HIF1A, CDKN1A) and three miRNAs (miR-3607-3p, miR-301a-3p, miR-93-5p) identified a subgroup of patients showing prolonged survival after regorafenib administration (median OS range 10.6 - 20.8 months).CONCLUSIONS: The study provides evidence that a signature based on the expression of five biomarkers could help identifying a subgroup of GBM patients exhibiting a striking survival advantage when treated with regorafenib. Despite the presented results must be confirmed in larger replication cohorts, the study highlights potential biomarker options to help guiding the clinical decision among regorafenib and other treatments in patients with relapsing GBM.",

author = "Alessandra Santangelo and Marzia Rossato and Giuseppe Lombardi and Salvatore Benfatto and Denise Lavezzari and {De Salvo}, {Gian Luca} and Stefano Indraccolo and Dechecchi, {Maria Cristina} and Paola Prandini and Roberto Gambari and Chiara Scapoli and {Di Gennaro}, Gianfranco and Mario Caccese and Marica Eoli and Roberta Rud{\`a} and Brandes, {Alba Ariela} and Toni Ibrahim and Simona Rizzato and Ivan Lolli and Giuseppe Lippi and Massimo Delledonne and Vittorina Zagonel and Giulio Cabrini",

note = "{\textcopyright} The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.",

year = "2020",

month = jul,

day = "14",

doi = "10.1093/neuonc/noaa156",

language = "English",

volume = "1",

journal = "Neuro-Oncology",

issn = "1522-8517",

publisher = "Oxford University Press",

number = "13",

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TY - JOUR

T1 - A Molecular Signature associated with prolonged survival in Glioblastoma patients treated with Regorafenib

AU - Santangelo, Alessandra

AU - Rossato, Marzia

AU - Lombardi, Giuseppe

AU - Benfatto, Salvatore

AU - Lavezzari, Denise

AU - De Salvo, Gian Luca

AU - Indraccolo, Stefano

AU - Dechecchi, Maria Cristina

AU - Prandini, Paola

AU - Gambari, Roberto

AU - Scapoli, Chiara

AU - Di Gennaro, Gianfranco

AU - Caccese, Mario

AU - Eoli, Marica

AU - Rudà, Roberta

AU - Brandes, Alba Ariela

AU - Ibrahim, Toni

AU - Rizzato, Simona

AU - Lolli, Ivan

AU - Lippi, Giuseppe

AU - Delledonne, Massimo

AU - Zagonel, Vittorina

AU - Cabrini, Giulio

PY - 2020/7/14

Y1 - 2020/7/14

N2 - BACKGROUND: Patients with glioblastoma (GBM) have a dramatically poor prognosis. The recent REGOMA trial suggested an overall survival benefit of regorafenib in recurrent GBM patients. Considering the extreme genetic heterogeneity of GBMs, we aimed to identify molecular biomarkers predictive of differential response to the drug.METHODS: Total RNA was extracted from tumor samples of patients enrolled in the REGOMA trial. Genome-wide transcriptome and miRNA profiles were associated with patients' Overall Survival (OS) and Progression Free Survival (PFS).RESULTS: At first step, a set of 11 gene transcripts (HIF1A, CTSK, SLC2A1, KLHL12, CDKN1A, CA12, WDR1, CD53, CBR4, NIFK-AS1, RAB30-DT) and 10 miRNAs (miR-93-5p, miR-203a-3p, miR-17-5p, let-7c-3p, miR-101-3p, miR-3607-3p, miR-6516-3p, miR-301a-3p, miR-23b-3p, miR-222-3p) was filtered by comparing survival between regorafenib and lomustine arms. As second step, a minisignature of two gene transcripts (HIF1A, CDKN1A) and three miRNAs (miR-3607-3p, miR-301a-3p, miR-93-5p) identified a subgroup of patients showing prolonged survival after regorafenib administration (median OS range 10.6 - 20.8 months).CONCLUSIONS: The study provides evidence that a signature based on the expression of five biomarkers could help identifying a subgroup of GBM patients exhibiting a striking survival advantage when treated with regorafenib. Despite the presented results must be confirmed in larger replication cohorts, the study highlights potential biomarker options to help guiding the clinical decision among regorafenib and other treatments in patients with relapsing GBM.

AB - BACKGROUND: Patients with glioblastoma (GBM) have a dramatically poor prognosis. The recent REGOMA trial suggested an overall survival benefit of regorafenib in recurrent GBM patients. Considering the extreme genetic heterogeneity of GBMs, we aimed to identify molecular biomarkers predictive of differential response to the drug.METHODS: Total RNA was extracted from tumor samples of patients enrolled in the REGOMA trial. Genome-wide transcriptome and miRNA profiles were associated with patients' Overall Survival (OS) and Progression Free Survival (PFS).RESULTS: At first step, a set of 11 gene transcripts (HIF1A, CTSK, SLC2A1, KLHL12, CDKN1A, CA12, WDR1, CD53, CBR4, NIFK-AS1, RAB30-DT) and 10 miRNAs (miR-93-5p, miR-203a-3p, miR-17-5p, let-7c-3p, miR-101-3p, miR-3607-3p, miR-6516-3p, miR-301a-3p, miR-23b-3p, miR-222-3p) was filtered by comparing survival between regorafenib and lomustine arms. As second step, a minisignature of two gene transcripts (HIF1A, CDKN1A) and three miRNAs (miR-3607-3p, miR-301a-3p, miR-93-5p) identified a subgroup of patients showing prolonged survival after regorafenib administration (median OS range 10.6 - 20.8 months).CONCLUSIONS: The study provides evidence that a signature based on the expression of five biomarkers could help identifying a subgroup of GBM patients exhibiting a striking survival advantage when treated with regorafenib. Despite the presented results must be confirmed in larger replication cohorts, the study highlights potential biomarker options to help guiding the clinical decision among regorafenib and other treatments in patients with relapsing GBM.

U2 - 10.1093/neuonc/noaa156

DO - 10.1093/neuonc/noaa156

M3 - Article

C2 - 32661549

VL - 1

JO - Neuro-Oncology

JF - Neuro-Oncology

SN - 1522-8517

IS - 13

M1 - noaa156

ER -

A Molecular Signature associated with prolonged survival in Glioblastoma patients treated with Regorafenib

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