Gene expression validation of novel biomarkers in gliomas

• Grant number: 09/08497-6
• Support Opportunities: Scholarships abroad - New Frontiers
• Effective date (Start): March 23, 2010
• Effective date (End): March 22, 2011
• Field of knowledge: Health Sciences - Medicine - Pathological Anatomy and Clinical Pathology
• Principal Investigator: Luciano Neder Serafini
• Grantee: Luciano Neder Serafini
• Host Investigator: Catherine L. Nutt
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Research place: Harvard University, Boston, United States

Abstract

Malignant gliomas are the most common and lethal primary human brain tumors. Due to the infiltrative growth of these tumors, surgical cure is not a viable option and the majority of these tumors are resistant to standard radiotherapy and chemotherapeutic approaches. A key factor contributing to the refractory nature of malignant gliomas is tumor heterogeneity. The WHO classification system for CNS tumors remains inadequate, primarily due to tumor heterogeneity and because pathological diagnosis remains quite subjective. Furthermore, even when a histology-based diagnosis is virtually indisputable, the corresponding predicted clinical behavior does not always concur with the patient's clinical course. In addition, treatment options for the most aggressive glial tumors have recently expanded to include targeted molecular therapies. Much of the recent research of MGH Translational Glioma Working Group has focused on using gene expression profiling to investigate molecularly defined, clinically relevant subgroups of malignant glioma. We were the first to demonstrate that microarray-based classification was better suited than standard histology-based classification to distinguish between diagnostically challenging gliomas. We have also used gene expression profiling, DNA- and protein-based analyses to investigate intratumor molecular heterogeneity in malignant gliomas. Herein, we propose the following Aim: Validate tumor biomarkers capable of distinguishing these defined subgroups of malignant gliomas by immunohistochemistry in formalin-fixed, paraffin-embedded and frozen sections or, in some cases, by quantitative RT-PCR and in situ hybridization assays. This aim will 1) provide a practical, robust and objective means to detect relevant subgroups of malignant gliomas, providing improved clinical management of patients with these lethal tumors; 2) begin to lay the foundation for the development of novel targeted therapies for malignant gliomas; and 3) provide novel insights into the biological and clinical implications of glial tumor heterogeneity.The Molecular Pathology Unit of the Molecular Neuro-Oncology Laboratory (MPU) has access to large numbers of clinically annotated malignant gliomas. Specimens will be obtained from the Brain Tumor Center at the Massachusetts General Hospital that has available for over 1200 high-grade gliomas. Moreover, the group has also assembled two specific panels of glioblastomas (GBMs) for use in investigating these immunohistochemical (IHC) biomarkers. One panel is based on patient survival and another panel of GBMs consists of tissue from paired primary-recurrent samples. All IHC slides and panels will be reviewed by Dr. Neder. Immunoreactivity will be scored semi-quantitatively for the number of cells positive. For validation of gene expression results as well as for use as an alternative marker strategy, a TaqMan facility is available within the MPU for quantitative RT-PCR analyses. If a particular combination of IHC markers may not define our novel subgroups of malignant glioma in a manner that correlates with known prognostic and genetic criteria, we can return to utilizing mRNA expression levels for our diagnostic panels by using quantitative RT-PCR or in situ hybridization. We have access to both quantitative RT-PCR and in situ hybridization, having a TaqMan facility and an in situ hybridization core within the MPU, and Dr. Neder will have access for all these facilities. Reasons for this may include dissociation between mRNA expression and protein expression, or between mRNA detection and protein detection. Based on our initial experiences with this model in similar previous studies and, given the large number of tumors available in our archives, we are confident we will be able to generate significant results in this model of Translational Medicine as well as to establish a new research network. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

BORGES, CAROLINA BISINOTO; BERNARDES, EMERSON SOARES; LATORRACA, ELDER FRANCISCO; BECKER, ALINE PAIXAO; NEDER, LUCIANO; CHAMMAS, ROGER; ROQUE-BARREIRA, MARIA CRISTINA; MACHADO, HELIO RUBENS; DE OLIVEIRA, RICARDO SANTOS. Galectin-3 expression: a useful tool in the differential diagnosis of posterior fossa tumors in children. CHILD'S NERVOUS SYSTEM, v. 27, n. 2, p. 253-257, FEB 2011. (09/08497-6, 06/60642-2)