Grantee: Massachusetts General Hospital-Molecular Neuro-Oncology Laboratory, Charlestown, MA, USA
Researcher: Catherine L. Nutt, Ph.D.
Grant Title: Molecular profile-based investigation of chemosensitive anaplastic oligodendrogliomas
https://doi.org/10.37717/220020086
Program Area: Researching Brain Cancer
Grant Type: Research Award
Amount: $300,000
Year Awarded: 2005
Duration: 2 years
In modern clinical neuro-oncology, no variable affects prognostic estimation and therapeutic decisions more than tumor classification. Among diffuse gliomas, oligodendrogliomas generally have a more favorable prognosis than astrocytic tumors. In addition, oligodendrogliomas remain the only subtype that commonly responds to chemotherapy, with approximately two-thirds of cases responding dramatically to PCV (procarbazine, CCNU and vincristine) treatment. The most widely used method of brain tumor classification is that of the World Health Organization (WHO). In the majority of cases, the WHO classification system provides a means for placing tumors into specific, relevant categories. However, although the classification of a glial tumor as an anaplastic oligodendroglioma (WHO grade III oligodendroglioma) can suggest an average clinical course for patients with these specific lesions, this classification alone can not predict the clinical behavior of an individual patient's tumor.
Advances in molecular genetics have aided in both the classification and clinical management of these tumors. In particular, allelic loss of chromosome 1p in anaplastic oligodendrogliomas has been demonstrated to be a powerful predictor of chemotherapeutic response to PCV treatment and combined losses of 1p and 19q predict longer survival in patients with anaplastic oligodendroglioma. Currently, however, 1p/19q testing is not readily available in all institutions. In addition, loss of 1p does not identify all tumors that respond to PCV treatment, emphasizing the need for additional, more practical markers of chemosensitivity in these tumors. Moreover, the molecular pathway(s) responsible for chemotherapeutic response in these lesions remains unknown. Characterizing these pathways will be significant in understanding the biology of treatment response in oligodendroglial tumors and could lay the foundation for the development of targeted molecular therapies for gliomas that are resistant to conventional therapies.
The advent of gene expression microarray technology has allowed us to monitor simultaneously the expression of thousands of genes in tumors. We have used this technology to define genes associated specifically with chemosensitive anaplastic oligodendrogliomas and with loss of chromosome 1p. Using these genes, we will develop immunohistochemical markers capable of identifying those anaplastic oligodendrogliomas most likely to respond to chemotherapy. In addition, by examining the expression level patterns of these genes across individual tumors, we will characterize the molecular pathway(s) activated/repressed in chemosensitive anaplastic oligodendrogliomas. Finally, using these novel insights into key molecular pathways, we will investigate the phenotypic consequences of altering these pathways in vitro.
The proposed project could have a substantial impact in the field of neuro-oncology. Accurate immunohistochemical markers for chemosensitive oligodendrogliomas would be directly and immediately applicable to clinical practice, greatly aiding therapeutic decisions. Furthermore, the biological insights obtained from these investigations could lay the foundation for development of new, targeted molecular therapies, not only for anaplastic oligodendrogliomas but for glial tumors in general.