Repurposing Examples and Studies
Choe, S. H., et. al. (2021) Milken Institute
Many promising medicines, despite strong safety data and pharmaceutical characteristics, are discontinued by drug companies for nonscientific reasons, including strategic, organizational, and financial considerations. Gaining access to these shelved drugs—to investigate intended or new indications—is challenging. Meanwhile, patients and families wait for new therapies for their conditions.
A new approach to solving this challenge assigns patient advocacy groups and other nonprofit organizations as matchmakers between discontinued drug assets and capital sources. The lessons learned from piloting this approach offer a potential template for others focused on identifying and accessing discontinued assets for clinical development.
Ambati, J., et. al. (2020) Nature Communications
Abstract: Innate immune signaling through the NLRP3 inflammasome is activated by multiple diabetes-related stressors, but whether targeting the inflammasome is beneficial for diabetes is still unclear. Nucleoside reverse-transcriptase inhibitors (NRTI), drugs approved to treat HIV-1 and hepatitis B infections, also block inflammasome activation. Here, we show, by analyzing five health insurance databases, that the adjusted risk of incident diabetes is 33% lower in patients with NRTI exposure among 128,861 patients with HIV-1 or hepatitis B (adjusted hazard ratio for NRTI exposure, 0.673; 95% confidence interval, 0.638 to 0.710; P < 0.0001; 95% prediction interval, 0.618 to 0.734). Meanwhile, an NRTI, lamivudine, improves insulin sensitivity and reduces inflammasome activation in diabetic and insulin resistance-induced human cells, as well as in mice fed with high-fat chow; mechanistically, inflammasome-activating short interspersed nuclear element (SINE) transcripts are elevated, whereas SINE-catabolizing DICER1 is reduced, in diabetic cells and mice. These data suggest the possibility of repurposing an approved class of drugs for prevention of diabetes
Anderson, P.I., et al. (2020) International Journal of Infectious Diseases
Abstract: Viral diseases are one of the leading causes of morbidity and mortality in the world. Virus-specific vaccines and antiviral drugs are the most powerful tools to combat viral diseases. However, broad-spectrum antiviral agents (BSAAs, i.e. compounds targeting viruses belonging to two or more viral families) could provide additional protection of the general population from emerging and re-emerging viral diseases, reinforcing the arsenal of available antiviral options. Here, we review discovery and development of BSAAs and summarize the information on 120 safe-in-man agents in a freely accessible database (https://drugvirus.info/). Future and ongoing pre-clinical and clinical studies will increase the number of BSAAs, expand the spectrum of their indications, and identify drug combinations for treatment of emerging and re-emerging viral infections as well as co-infections.
Anton, R.F., Latham, P., Voronin, K., Book, S., Hoffman, M., Prisciandaro, J., and Bristol, E. (2020) JAMA Internal Medicine
Key Points:
Question: Is gabapentin efficacious in the treatment of alcohol use disorder in adults with a history of alcohol withdrawal symptoms?
Findings: In this randomized clinical trial, gabapentin compared with placebo significantly increased the number of people with total abstinence and reduced drinking. This effect was most significantly observed in those with greater pretreatment alcohol withdrawal symptoms—41% of participants with high alcohol withdrawal symptoms had total abstinence on gabapentin compared with 1% of participants in the placebo arm.
Meaning: This study showed that gabapentin is efficacious in promoting abstinence and reducing drinking in individuals with alcohol use disorder and especially so in those with more alcohol withdrawal symptoms.
Ford, K., et. al. (2020) Cancer Research
Abstract: Determining mechanisms of resistance to αPD-1/PD-L1 immune-checkpoint immunotherapy is key to developing new treatment strategies. Cancer-associated fibroblasts (CAF) have many tumor-promoting functions and promote immune evasion through multiple mechanisms, but as yet, no CAF-specific inhibitors are clinically available. Here we generated CAF-rich murine tumor models (TC1, MC38, and 4T1) to investigate how CAFs influence the immune microenvironment and affect response to different immunotherapy modalities [anticancer vaccination, TC1 (HPV E7 DNA vaccine), αPD-1, and MC38] and found that CAFs broadly suppressed response by specifically excluding CD8+ T cells from tumors (not CD4+ T cells or macrophages); CD8+ T-cell exclusion was similarly present in CAF-rich human tumors. RNA sequencing of CD8+ T cells from CAF-rich murine tumors and immunochemistry analysis of human tumors identified significant upregulation of CTLA-4 in the absence of other exhaustion markers; inhibiting CTLA-4 with a nondepleting antibody overcame the CD8+ T-cell exclusion effect without affecting Tregs. We then examined the potential for CAF targeting, focusing on the ROS-producing enzyme NOX4, which is upregulated by CAF in many human cancers, and compared this with TGFβ1 inhibition, a key regulator of the CAF phenotype. siRNA knockdown or pharmacologic inhibition [GKT137831 (Setanaxib)] of NOX4 “normalized” CAF to a quiescent phenotype and promoted intratumoral CD8+ T-cell infiltration, overcoming the exclusion effect; TGFβ1 inhibition could prevent, but not reverse, CAF differentiation. Finally, NOX4 inhibition restored immunotherapy response in CAF-rich tumors. These findings demonstrate that CAF-mediated immunotherapy resistance can be effectively overcome through NOX4 inhibition and could improve outcome in a broad range of cancers.
Grobler, JA, et al. (2020) Cell Host & Microbe
Abstract: When SARS-CoV-2 emerged at the end of 2019, no approved therapeutics or vaccines were available. An urgent need for countermeasures during this crisis challenges the current paradigm of traditional drug discovery and development, which usually takes years from start to finish. Approaches that accelerate this process need to be considered. Here we propose the minimum data package required to move a compound into clinical development safely. We further define the additional data that should be collected in parallel without impacting the rapid path to clinical development. Accelerated paths for antivirals, immunomodulators, anticoagulants, and other agents have been developed and can serve as “roadmaps” to support prioritization of compounds for clinical testing. These accelerated paths are fueled by a skewed risk-benefit ratio and are necessary to advance therapeutic agents into human trials rapidly and safely for COVID-19. Such paths are adaptable to other potential future pandemics.
Morró, M., Vilà, L., Franckhauser, S., Mallol, C., Elias, G., Ferré, T., Molas, M., Casana, E., Rodó, J., Pujol, A., Téllez, N., Bosch, F., and Casellas, A. (2020) Diabetes
Abstract: Vitamin D deficiency has been associated with increased incidence of diabetes, both in humans and in animal models. In addition, an association between vitamin D receptor (VDR) gene polymorphisms and diabetes has also been described. However, the involvement of VDR in the development of diabetes, specifically in pancreatic β-cells, has not been elucidated yet. Here, we aimed to study the role of VDR in β-cells in the pathophysiology of diabetes. Our results indicate that Vdr expression was modulated by glucose in healthy islets and decreased in islets from both type 1 diabetes and type 2 diabetes mouse models. In addition, transgenic mice overexpressing VDR in β-cells were protected against streptozotocin-induced diabetes and presented a preserved β-cell mass and a reduction in islet inflammation. Altogether, these results suggest that sustained VDR levels in β-cells may preserve β-cell mass and β-cell function and protect against diabetes.
Sawyer, B.T., Qamar, L., Yamamoto, T.M., McMellen, A., Watson, Z.L., Richer, J.K., Behbakht, K., Schlaepfer, I.R., and Bitler, B.G. (2020) Molecular Cancer Research
Abstract: Epithelial-derived high-grade serous ovarian cancer (HGSOC) is the deadliest gynecologic malignancy. Roughly 80% of patients are diagnosed with late-stage disease, which is defined by wide-spread cancer dissemination throughout the pelvic and peritoneal cavities. HGSOC dissemination is dependent on tumor cells acquiring the ability to resist anoikis (apoptosis triggered by cell detachment). Epithelial cell detachment from the underlying basement membrane or extracellular matrix leads to cellular stress, including nutrient deprivation. In this report, we examined the contribution of fatty acid oxidation (FAO) in supporting anoikis resistance. We examined expression Carnitine Palmitoyltransferase 1A (CPT1A) in a panel of HGSOC cell lines cultured in adherent and suspension conditions. With CPT1A knockdown cells, we evaluated anoikis by caspase 3/7 activity, cleaved caspase 3 immunofluorescence, flow cytometry, and colony formation. We assessed CPT1A-dependent mitochondrial activity and tested the effect of exogenous oleic acid on anoikis and mitochondrial activity. In a patient-derived xenograft model, we administered etomoxir, an FAO inhibitor, and/or platinum-based chemotherapy. CPT1A is overexpressed in HGSOC, correlates with poor overall survival, and is upregulated in HGSOC cells cultured in suspension. CPT1A knockdown promoted anoikis and reduced viability of cells cultured in suspension. HGSOC cells in suspension culture are dependent on CPT1A for mitochondrial activity. In a patient-derived xenograft model of HGSOC, etomoxir significantly inhibited tumor progression.
Janes, J., et. al. (2018) PNAS
Abstract: The chemical diversity and known safety profiles of drugs previously tested in humans make them a valuable set of compounds to explore potential therapeutic utility in indications outside those originally targeted, especially neglected tropical diseases. This practice of “drug repurposing” has become commonplace in academic and other nonprofit drug-discovery efforts, with the appeal that significantly less time and resources are required to advance a candidate into the clinic. Here, we report a comprehensive open-access, drug repositioning screening set of 12,000 compounds (termed ReFRAME; Repurposing, Focused Rescue, and Accelerated Medchem) that was assembled by combining three widely used commercial drug competitive intelligence databases (Clarivate Integrity, GVK Excelra GoStar, and Citeline Pharmaprojects), together with extensive patent mining of small molecules that have been dosed in humans. To date, 12,000 compounds (∼80% of compounds identified from data mining) have been purchased or synthesized and subsequently plated for screening. To exemplify its utility, this collection was screened against Cryptosporidium spp., a major cause of childhood diarrhea in the developing world, and two active compounds previously tested in humans for other therapeutic indications were identified. Both compounds, VB-201 and a structurally related analog of ASP-7962, were subsequently shown to be efficacious in animal models of Cryptosporidium infection at clinically relevant doses, based on available human doses. In addition, an open-access data portal (https://reframedb.org) has been developed to share ReFRAME screen hits to encourage additional follow-up and maximize the impact of the ReFRAME screening collection.
Shameer, K., Readhead, B., Dudley, J.T. (2015) Current Topics in Medicinal Chemistry
Abstract: Drug repositioning is an important component of therapeutic stratification in the precision medicine paradigm. Molecular profiling and more sophisticated analysis of longitudinal clinical data are refining definitions of human diseases, creating needs and opportunities to re-target or reposition approved drugs for alternative indications. Drug repositioning studies have demonstrated success in complex diseases requiring improved therapeutic interventions as well as orphan diseases without any known treatments. An increasing collection of available computational and experimental methods that leverage molecular and clinical data enable diverse drug repositioning strategies. Integration of translational bioinformatics resources, statistical methods, chemoinformatics tools and experimental techniques (including medicinal chemistry techniques) can enable the rapid application of drug repositioning on an increasingly broad scale. Efficient tools are now available for systematic drug-repositioning methods using large repositories of compounds with biological activities. Medicinal chemists along with other translational researchers can play a key role in various aspects of drug repositioning. In this review article, we briefly summarize the history of drug repositioning, explain concepts behind drug repositioning methods, discuss recent computational and experimental advances and highlight available open access resources for effective drug repositioning investigations. We also discuss recent approaches in utilizing electronic health record for outcome assessment of drug repositioning and future avenues of drug repositioning in the light of targeting disease comorbidities, underserved patient communities, individualized medicine and socioeconomic impact.