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A Time-Based and Intratumoral Proteomic Assessment of a Recurrent Glioblastoma Multiforme.

ABSTRACT: Tumors consist of cells in different stages of transformation with molecular and cellular heterogeneity. By far, heterogeneity is the hallmark of glioblastoma multiforme (GBM), the most malignant and aggressive type of glioma. Most proteomic studies aim in comparing tumors from different patients, but here we dive into exploring the intratumoral proteome diversity of a single GBM. For this, we profiled tumor fragments from the profound region of the same patient's GBM but obtained from two surgeries a year's time apart. Our analysis also included GBM's fragments from different anatomical regions. Our quantitative proteomic strategy employed 4-plex iTRAQ peptide labeling followed by a four-step strong cation chromatographic separation; each fraction was then analyzed by reversed-phase nano-chromatography coupled on-line with an Orbitrap-Velos mass spectrometer. Unsupervised clustering grouped the proteomic profiles into four major distinct groups and showed that most changes were related to the tumor's anatomical region. Nevertheless, we report differentially abundant proteins from GBM's fragments of the same region but obtained 1?year apart. We discuss several key proteins (e.g., S100A9) and enriched pathways linked with GBM such as the Ras pathway, RHO GTPases activate PKNs, and those related to apoptosis, to name a few. As far as we know, this is the only report that compares GBM fragments proteomic profiles from the same patient. Ultimately, our results fuel the forefront of scientific discussion on the importance in exploring the richness of subproteomes within a single tissue sample for a better understanding of the disease, as each tumor is unique.

SUBMITTER: de Aquino PF

PROVIDER: S-EPMC4992702 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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A Time-Based and Intratumoral Proteomic Assessment of a Recurrent Glioblastoma Multiforme.

de Aquino Priscila F PF Carvalho Paulo Costa PC Nogueira Fábio C S FC da Fonseca Clovis Orlando CO de Souza Silva Júlio Cesar Thomé JC Carvalho Maria da Gloria da Costa Mda G Domont Gilberto B GB Zanchin Nilson I T NI Fischer Juliana de Saldanha da Gama Jde S

Frontiers in oncology 20160822

Tumors consist of cells in different stages of transformation with molecular and cellular heterogeneity. By far, heterogeneity is the hallmark of glioblastoma multiforme (GBM), the most malignant and aggressive type of glioma. Most proteomic studies aim in comparing tumors from different patients, but here we dive into exploring the intratumoral proteome diversity of a single GBM. For this, we profiled tumor fragments from the profound region of the same patient's GBM but obtained from two surge ...[more]

PMID: 27597932

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Project description:The treatment of patients with malignant brain tumors remains a major oncological problem. The median survival of patients with glioblastoma multiforme (GBM), the most malignant type, is only 15 months after initial diagnosis and even less after tumor recurrence. Improvements of standard treatment including surgery and radio-chemotherapy have not lead to major improvements. Therefore, alternative therapeutics such as oncolytic viruses that specifically target and destroy cancer cells are under investigation. Preclinical data of oncolytic parvovirus H-1 (H-1PV) infection of glioma cells demonstrated strong cytotoxic and oncosuppressing effects, leading to a phase I/IIa trial of H-1PV in patients with recurrent GBM (ParvOryx01). ParvOryx01 is the first trial with a replication competent oncolytic virus in Germany.ParvOryx01 is an open, non-controlled, two groups, intra-group dose escalation, single center, phase I/IIa trial. 18 patients with recurrent GBM will be treated in 2 groups of 9 patients each. Treatment group 1 will first receive H-1PV by intratumoral injection and second by administration into the walls of the tumor cavity during tumor resection. In treatment group 2 the virus will initially be injected intravenously and afterwards, identical to group 1, into the surrounding brain tissue during tumor removal. Main eligibility criteria are: age of 18 years, unifocal recurrent GBM, amenable to complete or subtotal resection. Dose escalation will be based on the Continual Reassessment Method. The primary objective of the trial is local and systemic safety and tolerability and to determine the maximum tolerated dose (MTD). Secondary objectives are proof of concept (PoC) and Progression-free Survival (PFS) up to 6 months.This is the first trial with H-1PV in patients with recurrent GBM. The risks for the participants appear well predictable and justified. Furthermore, ParvOryx01 will be the first assessment of combined intratumoral and intravenous application of an oncolytic virus. Due to its study design the trial will not only generate data on the local effect of H-1PV but it will also investigate the penetration of H-1PV into the tumor after systemic delivery and obtain safety data from systemic delivery possibly supporting clinical trials with H-1PV in other, non-CNS malignancies.ClinicalTrials.gov Identifier: NCT01301430.

Project description:Median survival for patients with recurrent GBM is <6 months. Front-line systemic therapy is temozolomide but resistance due to O6-methylguanine-DNA-methyltransferase (MGMT) activity is implicated in poor outcomes. Dianhydrogalactitol (VAL-083) is a structurally unique bi-functional DNA alkylating agent that accumulates in brain tumor tissue. In in vitro studies, VAL-083 demonstrated activity in pediatric and adult GBM cell lines, as well as GBM cancer stem cells. Notably, VAL-083 overcomes resistance to MGMT in vitro. Previous clinical studies suggest that VAL-083 has anti-tumor activity against a range of tumors, including GBM. In light of extensive safety data from clinical trials and promising efficacy in CNS tumors, we initiated a new clinical study to establish the maximum tolerated dose (MTD) and identify a dose and dosing regimen for future efficacy trials in GBM. Early in the development of VAL-083, a cumulative IV dose of 125 mg/m2 delivered in a 35 day cycle in combination with radiation was shown superior to radiation alone in brain cancer (Eagan, et al. 1979). In the present study, the cumulative dose in a 33 day cycle ranges from 9 mg/m2 (cohort 1) to 240 mg/m2 (cohort 7). Six dose cohorts have completed the trial with no drug-related serious adverse events: MTD was not yet reached. Enrollment for cohort 7 (33 day cumulative dose: 240 mg/m2) has been initiated and higher doses may be explored; the results will determine the design of the safety and efficacy registration trial. METHODS: Open-label, single-arm Phase I/II dose-escalation study in patients with histologically-confirmed initial diagnosis of malignant GBM. The study utilizes a 3 + 3 dose-escalation design. Patients receive VAL-083 IV on days 1, 2, and 3 of a 21 day cycle. GBM patients previously been treated with surgery and/or radiation, if appropriate, must have failed both bevacizumab and temozolomide, unless contraindicated. ClinicalTrials.gov Identifier NCT01478178.

Dataset Information

A Time-Based and Intratumoral Proteomic Assessment of a Recurrent Glioblastoma Multiforme.

Publications

A Time-Based and Intratumoral Proteomic Assessment of a Recurrent Glioblastoma Multiforme.

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