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Current Challenges and Opportunities in Treating Glioblastomas

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Current Challenges and Opportunities in Treating Glioblastomas Supplemental Material can be found at: /content/suppl/2018/04/23/70.3.412.DC1.html 1521-0081/70/3/412–445$35.00 https://doi.org/10.1124/pr.117.014944 PHARMACOLOGICAL REVIEWS Pharmacol Rev 70:412–445, July 2018 Copyright © 2018 by The Author(s) This is an open access article distributed under the CC BY-NC Attribution 4.0 International license. ASSOCIATE EDITOR: ERIC L. BARKER Current Challenges and Opportunities in Treating Glioblastomas Andrea Shergalis, Armand Bankhead, III, Urarika Luesakul, Nongnuj Muangsin, and Nouri Neamati Department of Medicinal Chemistry, College of Pharmacy, North Campus Research Complex, Ann Arbor, Michigan (A.S., U.L., N.N.); Biostatistics Department and School of Public Health, University of Michigan, Ann Arbor, Michigan (A.B.); and Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok, Thailand (U.L., N.M.) Abstract ...................................................................................413 I. Introduction . ..............................................................................413 II. Current Treatment Options for Glioblastoma ...............................................414 III. Molecular Diagnostic Signature of Glioblastoma . ..........................................419 IV. Characteristics of Protein Expression in Glioblastoma . .....................................419 V. Emerging Targets in Glioblastoma . ......................................................422 A. Biomarker Identification . ............................................................422 B. Drug Discovery Targets ................................................................422 Downloaded from 1. Gene Expression Associated with Reduced Patient Survival . .........................423 a. BOC cell adhesion associated, oncogene regulated (BOC) . .........................426 b. C-Type lectin domain family 4 member G pseudogene 1 (CLEC4GP1) . .............426 c. ELOVL fatty acid elongase 6 (ELOVL6). ..........................................426 d. Epiregulin (EREG) ................................................................427 by guest on September 25, 2021 e. Estrogen receptor 2 (ESR2). ......................................................427 f. Follicular dendritic cell secreted protein (FDCSP) . ...............................427 g. Furin .............................................................................427 h. Fucosyltransferase 8 antisense RNA 1 (FUT8-AS1) . ...............................429 i. Granzyme B (GZMB) . ............................................................429 j. Iroquois homeobox 3 (IRX3). ......................................................429 k. Lipopolysaccharide-induced tissue-necrosis-factor factor (LITAF) ...................429 l. NudE neurodevelopment protein 1 like 1 (NDEL1)..................................429 m. NK3 homeobox 1 (NKX3-1) . ......................................................430 n. Podocan like 1 (PODNL1)..........................................................430 o. Protein tyrosine phosphatase, receptor type N (PTPRN). .........................430 p. Quiescin sulfhydryl oxidase 1 (QSOX1). ..........................................430 q. Semaphorin 4F (SEMA4F). ......................................................430 r. Tyrosine hydroxylase (TH). ......................................................431 s. Vascular endothelial growth factor C (VEGFC).....................................431 t. Chromosome 20 open reading frame 166 antisense RNA 1 (C20orf166AS1). .......431 2. Protein Targets Identified via Proteomic Approaches . ...............................431 3. Target Validation. ..................................................................432 C. Synthetic Lethality. ..................................................................432 D. Preclinical Models of Glioblastoma .....................................................432 VI. Blood-Brain Barrier........................................................................433 A. Characteristics of the Blood-Brain Barrier ...............................................433 B. Blood-Brain Barrier Computational Modeling for Drug Discovery ........................434 VII. Drug Discovery Challenges in GBM . ......................................................435 Address correspondence to: Dr. Nouri Neamati, North Campus Research Complex, Bldg. 520, Rm 1363, 1600 Huron Pkwy, Ann Arbor, MI 48109-2800. E-mail: [email protected] This work was supported by the National Institutes of Health, National Cancer Institute [Grant CA193690]. https://doi.org/10.1124/pr.117.014944. s This article has supplemental material available at pharmrev.aspetjournals.org. 412 Current Challenges and Opportunities in Treating GBM 413 VIII. Advances in Drug Delivery.................................................................437 A. Nanocarriers . ........................................................................437 1. General Properties of Nanoparticles. ................................................437 2. Nanocarriers in Clinical Trials . ......................................................437 B. Prodrugs. ..............................................................................438 IX. Conclusions and Future Directions . ......................................................439 Acknowledgments. ........................................................................441 References . ..............................................................................441 Abstract——Glioblastoma multiforme (GBM), the survival outcomes. Importantly, nine of these genes most common and aggressive primary brain tumor, exhibit higher expression in GBM versus low-grade has a high mortality rate despite extensive efforts glioma and may be involved in disease progression. In to develop new treatments. GBM exhibits both intra- this review, we discuss these proteins in the context and intertumor heterogeneity, lending to resistance and of GBM disease progression. We also conducted eventual tumor recurrence. Large-scale genomic and computational multi-parameter optimization to assess proteomic analysis of GBM tumors has uncovered the blood-brain barrier (BBB) permeability of small potential drug targets. Effective and “druggable” targets molecules in clinical trials for GBM treatment. Drug must be validated to embark on a robust medicinal delivery in the context of GBM is particularly chemistry campaign culminating in the discovery of challenging because the BBB hinders small molecule clinical candidates. Here, we review recent developments transport. Therefore, we discuss novel drug delivery in GBM drug discovery and delivery. To identify GBM drug methods, including nanoparticles and prodrugs. Given targets, we performed extensive bioinformatics analysis the aggressive nature of GBM and the complexity of usingdatafromTheCancerGenomeAtlasproject.We targeting the central nervous system, effective discovered 20 genes, BOC, CLEC4GP1, ELOVL6, EREG, treatment options are a major unmet medical need. ESR2, FDCSP, FURIN, FUT8-AS1, GZMB, IRX3, LITAF, Identification and validation of biomarkers and drug NDEL1, NKX3-1, PODNL1, PTPRN, QSOX1, SEMA4F, TH, targets associated with GBM disease progression VEGFC,andC20orf166AS1 that are overexpressed in a present an exciting opportunity to improve treatment subpopulation of GBM patients and correlate with poor of this devastating disease. I. Introduction an efficient approach to identify and vet potential drugs at the preclinical stage to prevent late stage failure. Glioblastoma multiforme (GBM) is the most malig- Genomic- and proteomic-scale analysis can identify nant primary central nervous system tumor, and the proteins and pathways involved in the development of prognosis for patients is often bleak. Currently, there are no curative treatment options for GBM, and despite chemotherapeutic resistance mechanisms responsible rigorous therapeutic research, the survival rate of for recurrent disease. patients diagnosed with GBM remains low. Median With the advent of TCGA (The Cancer Genome Atlas) overall survival is 15–23 months and 5-year survival is consortium and resources, genomic analysis of cancers less than 6%, which is the lowest long-term survival rate is at the forefront of drug discovery. Additionally, of malignant brain tumors (Ostrom et al., 2016). An proteomics is gaining widespread use in drug discovery estimated 79,270 new cases of primary brain and other efforts. Quantitative proteomics can measure the ex- central nervous system (CNS) tumors were expected to pression and, in some cases, posttranslational modifi- be diagnosed in 2017 (Ostrom et al., 2016). To improve cation status of up to and over 8000 proteins in the cell therapeutic options, studies to identify and validate at any given time. The advent of novel proteomic single protein targets are underway. However, in most techniques in the last decade, in tandem with the cases, targeted compounds that perform well in pre- resources allocated to address the lack of a cure for clinical studies have failed expensive Phase III clinical GBM, will accelerate the discovery of a treatment and trials in humans. Ultimately, several major factors are shed light on the feasibility of precision medicine. responsible for drug failure, including poor pharmaco- The target and mechanism of action of many Food and kinetic properties, emergence of resistance pathways, Drug Administration (FDA)-approved drugs are not complex intratumoral heterogeneity, and suboptimal fully established. Of the approximately
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