Review Genetics of glioblastoma multiforme: mitogenic signaling and cell cycle pathways converge Deepa Soni 1,2,3 MD MD, James AJ King 1,2 MBBS, PHD MBBS, PHD, Andrew H Kaye 1,2 MBBS, MD, FRACS MBBS, MD, FRACS, Christopher M Hovens 1 PHD PHD 1 Department of Surgery, 2 Department of Neurosurgery, University of Melbourne, Royal Melbourne Hospital, Parkville, Vic. 3050, Australia, 3 Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA MALIGNANT GLIOMA: CLINICAL BACKGROUND AND TREATMENT Although the overall incidence of primary malignant brain tumours, 6.6 per 100,000 1 is relatively low compared to other tumours, with a median survival time of less than 2 years, they are nonetheless among the most lethal forms of cancer. 2;3 Addition- ally, the fact that little is known about the etiology of malignant brain tumours as well as the paucity of identifiable risk factors in the disease makes their prevention and treatment especially challenging. Understanding the basic biology and tumorigenesis involved in the formation of malignant brain tumours is thus of paramount importance in developing new therapeutic options in their treatment. Glioblastoma Multiforme (GBM) is the leading cause of death among primary malignant brain tumours. 4 Currently there are no treatment standards for the management of GBM, and therapies vary considerably across centers. The role of surgical resection and its effect on survival remain controversial – even after 75 years of experience in the treatment of malignant gli- omas. 5 Neurosurgeons vary in their opinions and practice pat- terns, and the management of GBM ranges from biopsy to total resection, followed by radiation in all cases and adjuvant che- motherapy in some cases. For many neurosurgeons surgical resection of high-grade gliomas remains the mainstay of treat- ment. On the other hand, given the highly aggressive nature, high rate of recurrence, and infiltrative nature of GBM, radical resection of GBM is advocated only by some surgeons. None- theless, the fact remains that despite numerous retrospective studies and a few prospective studies on the topic, surgical resection of GBMs has not been shown to significantly correlate with survival. 5–7 Despite the varying treatment practices, it is well known that surgery and radiation treatment are superior to surgery alone, 8 with the former survival time being 32 weeks vs. 14 weeks. This study was paramount in establishing treatment guidelines that recommended that all patients should be treated with XRT regardless of whether or not they had a gross total resection, partial resection, biopsy or no surgical resection at all of their tumour. However, no prospective data exists investigating whe- ther surgical resection and radiation/chemotherapy versus biopsy and radiation/chemotherapy prolongs survival in GBM. Recently Sawaya et al. reported a 13-month median survival times for GBM patients undergoing surgery or biopsy. 9 The randomized, double- blind clinical trial comparing BCNU chemotherapy versus radiotherapy, as adjuvant treatment for GBM, 8 was paramount is setting treatment guidelines for the role of post-operative XRT in the treatment of malignant gliomas. However, similar standards have yet to be established for the role of surgical resection in the treatment of high-grade gliomas. Because of the limited availability and success of the current treatment of GBM, the elucidation of the molecular pathways involved in gliomagenesis has become a foremost priority over the past several years with the goal of developing biological therapies. Recent technological advancements, including the development of sophisticated, high-throughput genetic screening mechanisms, has facilitated the discovery of several pathways involved in glioma and brain tumor formation. The aim of this review, is thus both to provide an overview of the key cell sig- naling pathways involved in gliomagenesis as well as to introduce some potential molecular-targeted therapies for the treatment of GBM. PATHWAYS TO GLIOMA FORMATION Low-grade astrocytomas (WHO Grade II) display a marked pro- pensity to infiltrate into surrounding normal brain tissue, often preventing a complete surgical resection of the affected region. Standard therapeutic regimens of chemotherapy and radiation have yielded generally unsatisfactory results. The impetus for new therapeutic strategies has been driven by the ever-increasing knowledge base concerning the genetics of glioma progression. Glioblastoma multiforme (GBM; WHO Grade IV astrocytoma) is commonly subdivided on the basis of clinical presentation into either primary/de novo GBM or secondary GBM. Primary GBM presents as high grade GBM in the absence of clinically detectable earlier lower grade lesions, whilst secondary GBM develops pro- gressively from lower grade astrocytoma over a clinical course of generally 5–10 years. 10;11 The distinction in the clinical course of the presentation of these tumours is also mirrored in the genetic lesions that correlate with the developmental stages of astrocytoma development. In spite of the documented differences in particular genetic abnormalities associated with primary or secondary glio- blastoma, these differences can all be grouped into genetic abnormalities that affect two fundamental cellular processes, that of signal transduction and control of the cell cycle (Table 1). DEREGULATED SIGNALLING Two key components of growth factor signalling pathways, the growth factors themselves and/or their cognate receptors are often overexpressed or mutated in gliomas (Fig. 1). The platelet-derived growth factor (PDGF) A and B, epidermal growth factor (EGF), transforming growth factor-a (TGF-a), and insulin like-growth factor-1 (IGF-1) are commonly found associated with gliomas and thought to provide an autocrine and/or paracrine boost to tumour growth. 12–18 The corresponding receptors EGFR, PDGFR-a/-b and IGFR are often associated with these tumours, with amplification and/or mutation of EGFR linked with primary GBM and over- expression of PDGFR-a is linked with progression of secondary GBM. Activation of the receptors leads to propagation of the stimulus down three main intracellular protein cascades, the RAS/ Journal of Clinical Neuroscience (2005) 12(1), 1–5 0967-5868/$ - see front matter ª 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2004.04.001 Received 19 March 2004 Accepted 26 April 2004 Correspondence to: Deepa Soni MD, University of Melbourne, Royal Melbourne Hospital, Parkville, Vic. 3050, Australia. 1