Giselle Y. López

Glioblastoma is the most common malignant primary brain tumor. Overall, the prognosis for patients with this disease is poor, with a median survival of <2 years. There is a slight predominance in males, and incidence increases with age. The standard approach to therapy in the newly diagnosed setting includes surgery followed by concurrent radiotherapy with temozolomide and further adjuvant temozolomide. Tumor-treating fields, delivering low-intensity alternating electric fields, can also be given concurrently with adjuvant temozolomide. At recurrence, there is no standard of care; however, surgery, radiotherapy, and systemic therapy with chemotherapy or bevacizumab are all potential options, depending on the patient's circumstances. Supportive and palliative care remain important considerations throughout the disease course in the multimodality approach to management. The recently revised classification of glioblastoma based on molecular profiling, notably isocitrate dehydrogenase (IDH) mutation status, is a result of enhanced understanding of the underlying pathogenesis of disease. There is a clear need for better therapeutic options, and there have been substantial efforts exploring immunotherapy and precision oncology approaches. In contrast to other solid tumors, however, biological factors, such as the blood-brain barrier and the unique tumor and immune microenvironment, represent significant challenges in the development of novel therapies. Innovative clinical trial designs with biomarker-enrichment strategies are needed to ultimately improve the outcome of patients with glioblastoma.

// Yuchen Jiao 1,* , Patrick J. Killela 2,* , Zachary J. Reitman 2,* , B. Ahmed Rasheed 2 , Christopher M. Heaphy 1 , Roeland F. de Wilde 1 , Fausto J. Rodriguez 1 , Sergio Rosemberg 3 , Sueli Mieko Oba-Shinjo 3 , Suely Kazue Nagahashi Marie 3 , Chetan Bettegowda 1 , Nishant Agrawal 1 , Eric Lipp 2 , Christopher J. Pirozzi 2 , Giselle Y. Lopez 2 , Yiping He 2 , Henry S. Friedman 2 , Allan H. Friedman 2 , Gregory J. Riggins 1 , Matthias Holdhoff 1,4 , Peter Burger 1 , Roger E. McLendon 2 , Darell D. Bigner 2 , Bert Vogelstein 1 , Alan K. Meeker 1 , Kenneth W. Kinzler 1 , Nickolas Papadopoulos 1 , Luis A. Diaz Jr 1,4 , Hai Yan 2 1 Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, The Johns Hopkins Kimmel Cancer Center, the Department of Oncology, the Department of Pathology, the Department of Neurosurgery, the Johns Hopkins Medical Institutions, Baltimore, Maryland, USA 2 The Preston Robert Tisch Brain Tumor Center at Duke, The Pediatric Brain Tumor Foundation Institute, the Department of Pathology, the Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA 3 The Department of Pathology, the Department of Neurology, School of Medicine, University of Sao Paulo, Sao Paulo, Sao Paulo, Brazil 4 The Swim Across America Laboratory at Johns Hopkins, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA * Denotes equal contribution Correspondence: Hai Yan, email: // Luis Diaz, email: // Keywords : ALT, IDH1, IDH2, Mixed Gliomas Received : July 31, 2012, Accepted : August 2, 2012, Published : August 3, 2012 Abstract Mutations in the critical chromatin modifier ATRX and mutations in CIC and FUBP1 , which are potent regulators of cell growth, have been discovered in specific subtypes of gliomas, the most common type of primary malignant brain tumors. However, the frequency of these mutationsin many subtypes of gliomas, and their association with clinical features of the patients, is poorly understood. Here we analyzed these loci in 363 brain tumors. ATRX is frequently mutated in grade II-III astrocytomas (71%), oligoastrocytomas (68%), and secondary glioblastomas (57%), and ATRX mutations are associated with IDH1 mutations and with an alternative lengthening of telomeres phenotype. CIC and FUBP1 mutations occurred frequently in oligodendrogliomas (46% and 24%, respectively) but rarely in astrocytomas or oligoastrocytomas (&lt;10%). This analysis allowed us to define two highly recurrent genetic signatures in gliomas: IDH1/ATRX (I-A) and IDH1/CIC/FUBP1 (I-CF). Patients with I-CF gliomas had a significantly longer median overall survival (96 months) than patients with I-A gliomas (51 months) and patients with gliomas that did not harbor either signature (13 months). The genetic signatures distinguished clinically distinct groups of oligoastrocytoma patients, which usually present a diagnostic challenge, and were associated with differences in clinical outcome even among individual tumor types. In addition to providing new clues about the genetic alterations underlying gliomas, the results have immediate clinical implications, providing a tripartite genetic signature that can serve as a useful adjunct to conventional glioma classification that may aid in prognosis, treatment selection, and therapeutic trial design.

Point mutations at Arg132 of the cytoplasmic NADP(+)-dependent isocitrate dehydrogenase 1 (IDH1) occur frequently in gliomas and result in a gain of function to produce the "oncometabolite" D-2-hydroxyglutarate (D-2HG). The mutated IDH1 allele is usually associated with a wild-type IDH1 allele (heterozygous) in cancer. Here, we identify 2 gliomas that underwent loss of the wild-type IDH1 allele but retained the mutant IDH1 allele following tumor progression from World Health Organization (WHO) grade III anaplastic astrocytomas to WHO grade IV glioblastomas. Intratumoral D-2HG was 14-fold lower in the glioblastomas lacking wild-type IDH1 than in glioblastomas with heterozygous IDH1 mutations. To characterize the contribution of wild-type IDH1 to cancer cell D-2HG production, we established an IDH1-mutated astrocytoma (IMA) cell line from a WHO grade III anaplastic astrocytoma. Disruption of the wild-type IDH1 allele in IMA cells by gene targeting resulted in an 87-fold decrease in cellular D-2HG levels, showing that both wild-type and mutant IDH1 alleles are required for D-2HG production in glioma cells. Expression of wild-type IDH1 was also critical for mutant IDH1-associated D-2HG production in the colorectal cancer cell line HCT116. These insights may aid in the development of therapeutic strategies to target IDH1-mutated cancers.