E!10688 Fusion of Bioinformatics and phosphoproteomics to design novel Glioma Treatment Strategies

Glioblastoma is a highly heterogeneous brain tumor with a very poor prognosis for treatment because of the diffuse infiltrating nature of the tumor. The current project focus on technology-based on phosphor-peptide profiling and bioinformatics analysis to characterize glioblastoma tumor tissue with the purpose of better predicting the outcome of the treatment regime and guidance to select individualized therapies. Crucial diagnostic information allows healthcare providers to personalize the treatment regime of the tumour patient. The main goal of the project is the development of a validated diagnostic workflow for resected tumor tissues from glioblastoma patients. The product combines two unique technologies: A) The mass spectrometry platform to determine phosphor-proteomic profiles from Pepscope and the Erasmus Medical Center B) The Coremine bioinformatic analysis from PubGene The combined workflow including both the mass spectrometry and the bioinformatics analysis will be offered as a complete service named GlioPhos. This will make possible to provide information to support diagnostic and therapeutic decisions that can be made for individual patients as a tumor phenotype-based alternative to non-targeted chemotherapies, which generally cause severe side-effects. In the first part of the project primary cell cultures and cell lines were used for the optimization of the sample preparation protocols, mass spectrometry analyses and the data analyses. From the cell lines, the complete genome has been sequenced and in addition, many simulation/inhibition experiments on this cell culture have been performed with various kinase inhibitors. We have developed bioinformatics methods and tools to provide an integrated analysis and interpretation of the proteome and phosphor-peptide profile data from mass spectrometry. This offers a unique opportunity to obtain a very detailed and very direct picture of deregulated kinases and pathways in cancer cells. Sample analyses method is developed to measure the proteome and phosphor-proteome of biological samples both from cell line and tissue origin. All the data obtained both from standard procedure and the proteome and phosphor-proteome profiling are combined and used as input for bioinformatics tools. The complete diagnostic procedure from operation theatre to bioinformatics analysis has been developed and validated based on a relative low number of tissue samples. These results have been summarized in a submitted manuscript (waiting approval), and in connection with this publication, a web site has been set up where readers can test the pathway analyzer tool developed by PubGene. Unfortunately, the number of samples used in the validation was limited and further evaluation using a larger cohort of patients is expected to be necessary for successful commercialization of the complete pipeline. As a temporary solution, we are currently looking into how the commercialization of PubGene?s pathway analyzer tool can be offered as of a stand-alone tool as a first phase of the commercialization strategy.

This project has facilitated the transfer scientific knowledge and expertise between the partners and strengthened PubGene's network of expertise. Through the project we have gained a better understanding of how precision medicine can be further improved for very complex types of cancer by leveraging the knowledge form multiple omics data sets. This is of particular interest for high-grade glioblastomas, where there currently are few if any solution good treatment options apart from surgery. The collaboration in this project will be of great value for PubGene in the future and will help us develop new applications and improve existing tools. The results have been summarized in a submitted manuscript (waiting approval), and in connection with this publication a web site has been set up where readers can test the pathway analyzer tool developed by PubGene. We believe this to be an important showcase highlighting the capabilities of PubGene competence in the precision medicine field.

We will develop a diagnostic workflow including a bioinformatics analysis for glioblastoma multiforme (GBM) based on the characterization of phosphopeptide profiles. Crucial diagnostic information allows healthcare providers to personalize the treatment regime of the primary brain tumor patient. Glioblastoma is a highly heterogeneous tumor with a very poor prognosis. Surgical resection is often incomplete, because of the diffuse infiltrating nature of this brain tumor, leaving the necessity for adjuvant therapy. In this project we will develop a technology based on phosphopeptide profiling and bioinformatics analysis to characterize glioblastoma tumor tissue with the purpose of better predict the outcome of the treatment regime and a guidance to select individualized therapies. The product, designated GlioPhos, will be provided as a service, comprised of a combination of MS-based technology and bioinformatics analysis. In addition the combined product will also be offered as stand alone products. GlioPhos will be marketed to the pharmaceutical industry, hospitals and research facilities through direct sales channels. Additionally, the service will be made available through a network of distributors that are dedicated to the Life Science and Diagnostics segment.