Facing the Future of Brain Tumor Clinical Research Mark R. Gilbert 1 , Terri S. Armstrong 2 , Whitney B. Pope 3 , Martin J. van den Bent 4 , and Patrick Y. Wen 5 Abstract This edition of CCR Focus provides critical reviews of several important areas in the field, including the application of findings from genomic investigations of brain tumors to improve diagnosis, clinical trial design, and ultimately optimizing individual patient treatment. Another article is a critical review provided by experts in the field that discusses the recent clinical trials using angiogenesis inhibitors, possible explanations for the results, and how to move forward. There is a concise discussion of the application of immunotherapy to brain tumors by key investigators in this field, reflecting the potential opportunities as well as the disease-specific challenges. Finally, leading pediatric brain tumor investigators provide an overview of the field and insights about the recent seminal discoveries in two pediatric brain tumors, supporting the paradigm that laboratory investigations lead to more precise diagnosis, prognosis, and ultimately better treatment. Herein, an overview of the recent advances and challenges in the area of clinical and translational brain tumor research is provided to set the stage for the contributions that follow. See all articles in this CCR Focus section, "Discoveries, Challenges, and Progress in Primary Brain Tumors." Clin Cancer Res; 20(22); 5591–600. Ó2014 AACR. Introduction Malignant primary brain tumors remain an important area of clinical research. Most of these cancers remain incur- able despite decades of laboratory and clinical investigation. These tumors are somewhat unique in that they rarely spread outside the central nervous system (CNS). Despite this finding, surgery is not curative even in low-grade (WHO grade 2) tumors because of their infiltrative nature (1). However, the extent of tumor resection is important as it has prognostic significance in many CNS cancers, and in some tumors, such as medulloblastoma and low-grade gli- oma, dictates subsequent therapies (2). Following surgery, radiotherapy remains the cornerstone of most brain tumor treatment regimens (3). Enhancing tumor targeting with new radiation modalities such as intensity-modulated radio- therapy or alternative radiation sources such as heavy particle therapy (i.e., proton, carbon ion) may improve the risk to benefit ratio in brain tumors (4). The progress in developing effective chemotherapy regi- mens for primary brain tumors lags behind that of other cancers. For the most common and most aggressive brain tumor, glioblastoma (WHO grade 4), the only systemic chemotherapy that has proven survival benefit is temozo- lomide, an oral alkylating agent. Even with the first-line use of temozolomide, the survival benefit is only measured in months (5). Over the past several decades, many novel treatment agents have been tested; some of these studies are listed in Table 1. These included established and novel cytotoxic chemotherapy agents, antiangiogenic agents, sig- nal transduction modulators, biologic agents, and immu- notherapies (6). Early studies recognized that drug delivery across the blood–brain barrier may limit the efficacy of many therapeutic agents; novel routes of delivery have been tried. These include direct tumor injection, intra-arterial delivery, tumor perfusion using convection-enhanced delivery, and implantation of slow release vehicles (i.e., polifeprosan 20 with carmustine wafer; refs. 7, 8). Despite all of these efforts, the portfolio of effective agents remains quite limited. The challenges that exist in finding effective treatments for patients with brain tumors stem from inherent hetero- geneity and continual genomic transformation of the can- cer, the unique microenvironment consisting of glial cells, microglia, and others, and the variable integrity of the blood–brain barrier, leading to issues with drug delivery. Furthermore, although preclinical testing often demon- strates high rates of efficacy for new agents, this has not yet translated to more effective treatment regimens. Although preclinical models are improving, they do not fully reca- pitulate the challenging aspects of the human disease such as genomic heterogeneity and tumor invasiveness (9). The testing of new regimens in clinical trials in this patient population is further complicated by limitations in 1 Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 2 University of Texas Health Science Center School of Nursing and Department of Neuro-Oncology, The Uni- versity of Texas MD Anderson Cancer Center, Houston, Texas. 3 Depart- ment of Radiology, David Geffen School of Medicine at UCLA, Los Angeles, California. 4 Erasmus MC—Cancer Institute, Rotterdam, the Netherlands. 5 Dana-Farber Cancer Institute, Boston, Massachusetts. Corresponding Author: Mark R. Gilbert, Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Box 0100, Houston, TX 77030. Phone: 713-792-8288; Fax: 713- 794-4999; E-mail: mrgilbert@mdanderson.org doi: 10.1158/1078-0432.CCR-14-0835 Ó2014 American Association for Cancer Research. 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