pharmaceuticals Review Drug Repurposing Opportunities in Pancreatic Ductal Adenocarcinoma Rita Rebelo 1,2,† ,Bárbara Polónia 1,2,†,Lúcio Lara Santos 3,4, M. Helena Vasconcelos 1,2,5,* and Cristina P. R. Xavier 1,2,5,* 1 Cancer Drug Resistance Group, IPATIMUP—Institute of Molecular Pathology and Immunology, University of Porto, 4200-135 Porto, Portugal; [email protected] (R.R.); [email protected] (B.P.) 2 i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal 3 Experimental Pathology and Therapeutics Group, IPO—Instituto Português de Oncologia, 4200-072 Porto, Portugal; [email protected] 4 ICBAS—Biomedical Sciences Institute Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal 5 Department of Biological Sciences, FFUP—Faculty of Pharmacy of the University of Porto, 4200-135 Porto, Portugal * Correspondence: [email protected] (M.H.V.); [email protected] (C.P.R.X.) † These authors equally contributed to this work. Abstract: Pancreatic ductal adenocarcinoma (PDAC) is considered one of the deadliest tumors worldwide. The diagnosis is often possible only in the latter stages of the disease, with patients already presenting an advanced or metastatic tumor. It is also one of the cancers with poorest prognosis, presenting a five-year survival rate of around 5%. Treatment of PDAC is still a major challenge, with cytotoxic chemotherapy remaining the basis of systemic therapy. However, no major advances have been made recently, and therapeutic options are limited and highly toxic. Thus, novel therapeutic options are urgently needed. Drug repurposing is a strategy for the development of novel treatments using approved or investigational drugs outside the scope of the original clinical indication. Citation: Rebelo, R.; Polónia, B.; Santos, L.L.; Vasconcelos, M.H.; Since repurposed drugs have already completed several stages of the drug development process, a Xavier, C.P.R. Drug Repurposing broad range of data is already available. Thus, when compared with de novo drug development, drug Opportunities in Pancreatic Ductal repurposing is time-efficient, inexpensive and has less risk of failure in future clinical trials. Several Adenocarcinoma. Pharmaceuticals repurposing candidates have been investigated in the past years for the treatment of PDAC, as single 2021, 14, 280. https://doi.org/ agents or in combination with conventional chemotherapy. This review gives an overview of the 10.3390/ph14030280 main drugs that have been investigated as repurposing candidates, for the potential treatment of PDAC, in preclinical studies and clinical trials. Academic Editor: Mary Meegan Keywords: drug repurposing; pharmacology; pancreatic cancer; therapeutic strategies Received: 24 February 2021 Accepted: 17 March 2021 Published: 20 March 2021 1. Drug Repurposing: An Attractive and Challenging Approach Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in Drug repurposing has been emerging as an interesting alternative to the conventional published maps and institutional affil- drug discovery process. Additionally referred to as “drug repositioning”, “drug reprofil- iations. ing”, “drug redirecting”, “drug rediscovery” or “drug re-tasking”, this is a strategy for the development of novel treatments using approved or investigational drugs outside the scope of the original clinical indication [1–3]. Interestingly, the recent development and increasing interest observed in genomic and proteomic technologies for the assessment of cancer specific biological pathways has led to the discovery of several new drug targets, Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. providing excellent opportunities for drug repurposing, since almost every drug used This article is an open access article in human therapy has the potential to address more than one target [3]. The increasing distributed under the terms and interest in this approach relies on the fact that, by finding new applications for clinically conditions of the Creative Commons approved drugs, drug repurposing is able to overcome the major issues associated with Attribution (CC BY) license (https:// conventional drug discovery, which include substantial costs, slow pace and high risk of creativecommons.org/licenses/by/ failure [3,4]. According to Nosengo (2016), the estimated cost for a repurposed drug to 4.0/). reach the market is US$300 million, whereas, for a new drug, it is estimated to be ~$2 to $3 Pharmaceuticals 2021, 14, 280. https://doi.org/10.3390/ph14030280 https://www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 14 Pharmaceuticals 20212021,, 14,, 280 280 2 of2 of36 35 ~$2billion to $3 [5 billion]. Interestingly, [5]. Interestingly, the Food the and Food Drug and Administration Drug Administration (FDA) approval (FDA) forapproval new drugs for newhas decreaseddrugs has decreased in the past in years, the past especially years, es whenpecially compared when compared to the 1990s to [the6]. 1990s [6]. InIn fact, fact, clinically approvedapproved drugsdrugs have have previously previously completed completed several several stages stages of the of drugthe drugdevelopment development process; process; hence, hence, data regardingdata rega dosing,rding dosing, safety, safety, toxicity, toxicity, drug interactions, drug interac- side tions,effects, side pharmacodynamics effects, pharmacodynamics and pharmacokinetics and pharmacokinetics is often available is often [1– 3available]. Therefore, [1–3]. the Therefore,need for large the need investments for large and investments the time frame and the for time drug frame development for drug candevelopment be significantly can bereduced significantly [1,3]. As reduced depicted [1,3]. in As Figure depicted1, while in newFigure drug 1, while discovery new drug and development discovery and might de- velopmenttake up to 10might to 17 take years up forto 10 a drugto 17 toyears reach for the a drug market, to reach the timeline the market, for drug the timeline repurposing for drugis only repurposing about 3 to is 12 only years about [4]. Additionally,3 to 12 years [4]. the Additionally, previous evidence the previous on the effectevidence of these on thedrugs effect in preclinicalof these drugs models in preclinical and in humans models reduces and in thehumans riskof reduces failure the in upcomingrisk of failure clinical in upcomingtrials [1]. Nevertheless,clinical trials [1]. despite Nevertheless, its great despite advantages, its great drug advantages, repurposing drug can repurposing face several canobstacles, face several particularly obstacles, in drug particularly licensing, in clinicaldrug licensing, adoption clinical or even adoption during theor even development during theof clinicaldevelopment trials [1of,2 clinical]. These trials problems [1,2]. Th mightese problems be explained might by be the explained existence by of regulatorythe exist- enceexclusivities, of regulatory which exclusivities, increase drug which market increa protectionse drug market beyond protection the patent beyond term, the or bypatent drug term,withdrawal or by drug from withdrawal the market, from which the hampers market, drug which supply hampers for clinical drug supply trials, asfor well clinical as by trials,complications as well as in by the complications label extension in the in label medicines extension that in are medicines authorized that through are authorized national throughprocedures national [1,2]. procedures [1,2]. FigureFigure 1. 1. SchematicSchematic comparison comparison between between the the processes processes and and timeline timeline of ofde denovo novo drugdrug development development andand drug drug repurposing. repurposing. Nonetheless,Nonetheless, drug drug repurposing repurposing represents represents a relatively a relatively unexplored unexplored source source of new of ther- new apies,therapies, being being a very a veryattractive attractive option, option, especially especially in neglected in neglected areas areasof medicine, of medicine, where where the lackthe lackof commercial of commercial interest interest delays delays drug de drugvelopment. development. Moreover, Moreover, drug repurposing drug repurposing candi- datescandidates that are that off-patent are off-patent offer an offer additional an additional advantage. advantage. The competitive The competitive environment environment in the pharmaceuticalin the pharmaceutical industry industry leads to leads a severe to a mark severedown markdown in their inprices, their which prices, facilitates which facilitates access toaccess medicines to medicines for the general for the population general population and reduces and the reduces public the health public burden health [2]. burden [2]. Initially,Initially, drug drug repurposing repurposing was largelylargely aa serendipitousserendipitous processprocess or or was was based based on on clinical clin- icalside side effects effects and and off-label off-label use use [1, 3[1,3].]. One One of theof the first first cases cases of of drug drug repurposing repurposing was was thalido- tha- lidomide,mide, a sedative a sedative and and antiemetic antiemetic drug drug that that was was found found to to be be effective effective in in the the treatment treatment of oferythema erythema nodosum nodosum leprosum leprosum and, and, later, later, in multiplein multiple myeloma. myeloma. This This led led to theto the development develop- mentof analogs, of analogs, such such as lenalidomide as lenalidomide and an pomalidomide,d