Repurposed Drugs in Treating Glioblastoma Multiforme: Clinical Trials Update S. Yadavalli, PhD,* V. M. Yenugonda, PhD,† and S. Kesari, MD, PhD† Key Words: Brain cancer, glioblastoma, repurposed drugs (Cancer J 2019;25: 139–146) G lioblastoma (GBM) is the most common and lethal primary malignant brain tumors in adults with distinct molecular fea- tures and has a median survival of less than 15 months, and 5-year survival is less than 10%. 1 Despite standard care therapy options available such as surgery, radiation, and chemotherapy, the major- ity of patients have been shown to recur in the primary site. This can be partly attributed to several reasons including genetic hetero- geneity, infiltrative nature, hypoxic tumor environment, resistant stem cells, and immunosuppressive microenvironment. 2 Many targeted therapies failed in clinical trials because either the intended target is wrong, or they do not effectively cross the blood-brain barrier (BBB). 3,4 A plethora of monotherapy and combination chemo- therapy strategies have been evaluated in patients with recurrent GBM. Despite some minor improvements in progression-free sur- vival, no obvious increase in survival has been associated with any particular regimen. Little progress has been made toward develop- ing effective treatments for brain cancer to overcome drug resis- tance in the past 30 years, and lack of new drug development necessitates the discovery of novel therapeutics for treating GBM. 5 However, the longer time and higher cost involvement of new drug development with low success rate are a major limi- tation for discovering novel therapeutics for treating brain cancer. In recent years, a new concept of drug-repositioning technology was introduced in treating primary and recurrent brain cancer pa- tients based on molecular signature of the patient tumor. Drug re- positioning or drug repurposing is a way of developing new drugs with new medical uses that are already in the market or fail to commercialize for reasons other than safety at the clinical stage. Drug repurposing is also an advantage in terms of reducing cost and time by escaping phase I trials. However, often drug repurposing involves changes in modifying structure and preparation to im- prove pharmacological properties such as drug delivery rate, drug efficacy, and stability. Such drugs are generally called new drugs, the newly developed drug through drug repositioning regarded as a new drug, and as an independent drug development strategy. 6–8 Altogether, this suggests that drug repositioning may be one means of expediting better therapeutic index in GBM cancers. 9,10 Most studies to date have been based on phenomenological clini- cal findings, rather than based on mechanism of action. Even if the drug has proven to be safe, separate phases II and III clinical trials is required for US Food and Drug Administration approval for new indication of the existing drug. There are several drugs successfully repurposed for the new indication in treating several diseases. 11 On the other hand, drug reposi- tioning is a useful strategy in terms of expanding the market of existing drugs by identifying new indications of old drugs and also extending the life span of drugs through the increase of patent period. Currently, drug-repositioning technology is attracting attention in terms of cost efficiency of new drug de- velopment in advanced countries including the United States and others, and investment is also on the increase. According to Pharma2018, the total research and development cost of pharmaceutical companies in 2018 is estimated at $171.4 billion, of which approximately $90 billion to $125 billion is estimated to be invested in repositioning. Collectively, drug repositioning has become a very useful strategy for filling drug innovation development gap. 12 The rationale of drug repositioning lies, in part, on the ability of small molecules to target distinct targets or pathways in cells. Because multiple pathways are involved in cancer initiation or progression, the new drug development or repurposing strategy follows the targeting multiple targets or pathways by the same molecule. This concept is also known as “poly-pharmacology. ” This is in contrast to the traditional approach in drug discovery where the goal is to identify 1 drug solely for 1 target, with the hope that this high selectivity can enhance efficacy of the drug and reduce off-target toxicities. 13 Many signaling pathways regu- late stemness, proliferation, and migration of glioma stem cells (GSCs); understanding of GSC biology may help in rendering them more sensitive to chemotherapy and radiation therapy. Hence, it is prerequisite that we examine repurposing drugs for their efficacy in eliminating GSCs in brain tumors. 14,15 In recent years, there are several FDA approved drugs and discontinued drugs outside of oncology has shown activity in GBM 16,17 (Table 1). Many of these warrant clinical investiga- tion as a complementary approach to commercially driven clin- ical research. The data on molecular mechanism of action and molecular profiling of the tumors can assist in patient stratifi- cation to eliminate these malignant brain tumors. In this report, we focus on recent drug repositioning in GBM, with emphasis on novel uses of psychiatric and nonpsychiatric drugs, which are known to cross the BBB. In this line of research, Curtana Pharmaceuticals developed a series of compounds from a com- putational strategy that were moderately cytotoxic toward sev- eral GBM cancer stem cell lines and functional novel inhibitors of Olig2 pathways. Now, we are hoping to identify novel repurposing drugs that can easily penetrate BBB and target nu- merous mechanisms attributed in drug resistance of GBM and improve overall survival rate. From the *Lynx Bioscience LLC, Irving, TX; and †John Wayne Cancer Institute & Pacific Neuroscience Institute at Providence Saint John's Health Center, Santa Monica, CA. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Reprints: Santosh Kesari, MD, PhD, 2200 Santa Monica Blvd, Santa Monica, CA 90404. E‐mail: kesaris@jwci.org. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 1528-9117 REVIEW ARTICLE The Cancer Journal • Volume 25, Number 2, March/April 2019 www.journalppo.com 139 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.