Repurposing of drugs for triple negative breast cancer: an overview

Andrea Spini1,2, Sandra Donnini3, Pan Pantziarka4, Sergio Crispino4,5 and Marina Ziche1

1Department of Medicine, Surgery and Neuroscience, University of Siena, Siena 53100, Italy 2Service de Pharmacologie Médicale, INSERM U1219, University of Bordeaux, Bordeaux 33000, France 3Department of Life Sciences, University of Siena, Siena 53100, Italy 4Anticancer Fund, Strombeek Bever 1853, Belgium 5ASSO, Siena, Italy

Abstract

Breast cancer (BC) is the most frequent cancer among women in the world and it remains a leading cause of cancer death in women globally. Among BCs, triple negative breast cancer (TNBC) is the most aggressive, and for its histochemical and molecular charac- teristics is also the one whose therapeutic opportunities are most limited. The REpur- posing Drugs in Oncology (ReDO) project investigates the potential use of off patent non-cancer drugs as sources of new cancer therapies. Repurposing of old non-cancer drugs, clinically approved, off patent and with known targets into oncological indications, Review offers potentially cheaper effective and safe drugs. In line with this project, this article describes a comprehensive overview of preclinical or clinical evidence of drugs included in the ReDO database and/or PubMed for repurposing as anticancer drugs into TNBC therapeutic treatments.

Keywords: triple negative breast cancer, repositioning, non-cancer drug, preclinical studies, clinical studies

Background

Correspondence to: Marina Ziche Breast cancer (BC) is the most frequent cancer among women in the world. Triple nega- Email: [email protected] tive breast cancer (TNBC) is a type of BC that does not express oestrogen receptors, pro- 2020, :1071 gesterone receptors and epidermal growth factor receptors-2/Neu (HER2) and accounts ecancer 14 https://doi.org/10.3332/ecancer.2020.1071 for the 16% of BCs approximatively [1, 2]. Due to its lack of response to hormone and tar- geted therapies, the number of therapeutic opportunities is limited [3, 4]. TNBC patients Published: 13/07/2020 Received: 12/02/2020 are difficult to treat, with unfavourable prognosis and are generally administered with the standard chemotherapy. At the moment, novel treatment approaches, such as immu- Publication costs for this article were supported by ecancer (UK Charity number 1176307). notherapy, as well the repurposing of old drugs currently used for indications other than TNBC, is under investigation. In this context, we have previously reviewed the preclinical Copyright: © the authors; licensee and clinical anticancer efficacy and safety of beta blockers in TNBC [5]. ecancermedicalscience. This is an Open Access article distributed under the terms of the Drug repurposing is the application of an old drug to a new disease indication: this holds Creative Commons Attribution License (http:// creativecommons.org/licenses/by/3.0), which the promise of rapid clinical impact at a lower cost than de novo drug development [6]. In permits unrestricted use, distribution, and oncology, where new treatments in the last years are becoming more expensive due to reproduction in any medium, provided the original the introduction of innovative therapies such as targeted therapies and immunotherapies, work is properly cited.

ecancer 2020, 14:1071; www.ecancer.org; DOI: https://doi.org/10.3332/ecancer.2020.1071 1 treatments there is an increased interest at the use of already clinically approved non-cancer drugs, off patent and with known targets, as possible cancer ecancer 2020, 14:1071; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1071 cacy andsafety on TNBC Table 1showsreferences all17clinical collected (theofarticle Spera et alanalyses two different retrospective studiesonbeta blockers effi- Clinical studies diabetes, insomniaandother. for drugs with preclinical evidence of efficacy on model TNBC were various and heterogeneous including epilepsy, analgesia, hypertension, acid acetylsalicylic and eightto studies theanti-angiogenic, anti-proliferative andanti-apoptotic effects of zoledronic acid.Main indications roquine, eleven to theanti-proliferative andanti-invasive effectsof simvastatin, eight to theanti-inflammatory andanti-angiogenic effects of anti-proliferative, pro-apoptoticand immune-stimulating effectsof metformin, thirteen to thecytotoxic andanti-metastatic effects of chlo- drugs (31.3%)present intheReDO_DB.For 42of the84drugs,only onereference was retrieved (Table S2). Thirteen referred studies to the Using thePubMed database, we found preclinicalevidence on models(cellTNBC linesandxenograft modelsof forTNBC) of 84out 268old Preclinical studies gov ondrugrepurposing for TNBC We found 188preclinical referencesstudies (see Supplementary Material), 18clinicalreferences [10–26]and16references onclinicaltrials. trials, present inliterature ontherepurposing of old-licensed drugsfor TNBC. Theof aim paper this isto give toand scientists clinicians a comprehensive overview preclinical about includingclinical andclinicalstudies, and outcomes; 3)clinicaltrials.gov: number of studiesper drug. cological studystudies: 2) clinical activity; country, type, study period,population studies,exclusion criteria, age, followarms, treatments up, performed onMarch 2019,andtheinformation extracted were thefollowing: 1)preclinical number studies: of per studies drugandpharma- Moreover, clinicaltrials.gov [9] was searched for ongoing or completed clinicalstudiesondrugrepurposing and TNBC. All searches were defined were included. The articlesthat were not written inEnglish were excluded. respectively. Both stringsare provided inthesupplementary file(Table S1).Observational or clinicaltrialsfor which a cohortTNBC was retrieved inthefirst search. The string was composedby three blocksconcerning keywords related to repurposingTNBC, andstudy type, An additionalsearch string was usedto investigate potential clinicalevidence drugsnot about includedinReDO_DB or references not cal evidence of anticancer activity for TNBC. The strings were composed by thename of thedrugsandspecifickeywords related to TNBC. ReDO_DBfor Specifically,TNBC. from starting eachdrugpresent inReDO_DB, we searched inPubMed for preclinical published - andclini In line project,this with we searchedin PubMed forpreclinical published or clinicalevidence of anticancer activity for alldrugsincludedinthe published evidence of anticancer activity. At present, data of 268drugshave database beenincludedintheREDO (ReDO_DB) [8]. cationsas sources of new cancer strategies. ReDOproject has usedaliterature-based approach to identify licensed non-cancer drugs with in thetreatment of cancer. The REpurposingDrugs in Oncology (ReDO) project investigates thepotential useof licensed non-cancer medi- 26]. Outcomes retrieved from clinicalstudies were grouped, whenever possible,inpharmacological categories in andsummarised formin of beta blockers (BB) ease registries patients [24] (see Figure 1for more details). Retrospectiveranged studies from 1995toof 2016,andsixout eleven studiesanalysed aUSA cohort of of 18 were retrospective [10–13,17,19,20,22,25,26],six studies were phaseIIand[14–16,18,21,23]one was aphaseIclinicaltrial evidence ontwelve licensed drugs was found, andofdrugs, eleven these of out 268(4.1%) were includedinReDO_DB. Eleven studiesout [10], oneof tetramolybdate [14],oneof itraconazole [22],oneof esomeprazole [23],oneof mifepristone [24]andtwo of statins [25, [10, 12,19,20,25,26].Eightstudies were performedusing medicalrecords [10,12,17,19,20,22,25,26] , one was basedondis- [7]. One study bypublished Pantziarka et al [11] andtwo reportedresults the of previous trials[13].Ofclinical the18clinicalstudiescollected, four analysed theefficacy [11–13], five of non-steroidal anti-inflammatory drugs(NSAIDs) [17–21],two of zoledronic acid , and the articles ofarticles [13], andthe Hagasewa etal [9]. [8], point the spotlight on this matter building upa project aboutdrugrepurposing [15] andIshikawa etal [16] analysed thesamecohortof patients). Clinical [15, 16],oneof met - Table 2. 2

Review ecancer 2020, 14:1071; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1071 Table 1. Characteristics of clinical studies about repurposing of old drugs for TNBC treatment.

Reference Study type Database used (if observational) and Country Study period Population Main exclusion criteria Drugs of data source type interest

Bayraktar et al Retrospective Breast Cancer Management System USA 1995–2007 Women with –Metastatic or bilateral disease Metformin 2012 [10] study (Medical records and pharmacy data) TNBC who re- –Prior history of cancer ceived adjuvant –Resolved gestational diabetes chemotherapy –Diabetes diagnosed after adj chemotherapy

Botteri et al 2013 Retrospective Breast Cancer and Cardiology Division Italy 1997–2008 Postmeno- History of invasive cancer or Beta [11] cohort study Databases of the European Institute of pausal women metastatic disease blockers Oncology of Milan (Disease registries) operated for early primary TNBC

Melhem-Bertrand Retrospective Breast Cancer Management System USA 1995–2007 Women with –BB after neoadjuvant chemo- Beta et al 2011 [12] cohort study Database (Medical chart and pharmacy invasive TNBC therapy blockers data) treated with –Unknown receptors expression neoadjuvant status anthracylines –Incomplete records longer than and taxane 9 months between neoadjuvant chemotherapy initiation and surgery –Bilateral BC

Spera et al 2017 Retrospective Data from a randomised, double blind Multicentric – Women with – Beta (1) [13] cohort study clinical trial (ROSE/TRIO-012) advanced blockers TNBC

Spera et al 2017 Retrospective Data from a randomised, double blind Multicentric – Women with – Beta (2) [13] cohort study clinical trial (BCIRG-005) node positive blockers TNBC

Chan et al 2017 Phase II, open – – – Women with –Patients who have had chemo- Tetrathio- [14] label, single arm stage II/III therapy or radiotherapy within 6 molybdate study TNBC weeks prior to entering the study –Pregnant women

Hasegawa et al Phase II, open – Multicentric 2010–2012 Women with –Bilateral breast cancer or inflam- Zoledronic acid 2015 [15] label, randomised (Japan) stage IIA/IIIB matory breast cancer study TNBC –Distant metastasis –History of chemotherapy, endo- crine therapy, or radiotherapy

Ishikawa et al Phase II, open – Multicentric 2010–2012 Women with –Bilateral breast cancer or inflam- Zoledronic acid 2017 [16] label, randomised (Japan) stage IIA/IIIB matory breast cancer study TNBC –Distant metastasis –History of chemotherapy, endo- crine therapy, or radiotherapy

Retsky et al 2012 Retrospective Data from medical records Belgium 2003–2008 Women who –Previous ipsilateral surgery for Ketorolac [17] study underwent breast cancer were excluded mastectomy with axillary dissection 3

Review ecancer 2020, 14:1071; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1071 Table 1. Characteristics of clinical studies about repurposing of old drugs for TNBC treatment. (continued)

Chow et al 2013 Phase II, multicen- – – 2006–2010 Women with –Distant metastasis Celecoxib [18] tre, open-label, primary breast –Multiple, bilateral breast cancer single-arm study cancer –Postmenopausal patients with (OOTR-N001 both positive estrogen and study) progesterone receptor status and negative lymph node involvement –Pregnant women or women with suspected pregnancy –Prior history of invasive breast cancer

Shiao et al 2017 Retrospective Data from University of texas USA 1998–2016 Women with –Stage I patients Aspirin/Clopi- [19] study Southwestern (UTSW) TNBC registry stageII/III dogrel (Medical records) TNBC

Williams 2018 Retrospective Electronical medical records USA 2005–2013 Women with –Not clear use of aspirin Aspirin [20] study primary oper- –Not surgery able stages I-III –Not primary breast cancer –Lack of follow up

Pierga et al 2010 Phase II, ran- – – 2004–2000 Women with – Celecoxib [21] domised study stageII/III (Remagus 02) breast cancer

Tsubamoto et al Retrospective Kohnan hospitals (Medical records) Japan 2008–2012 Women with –Visceral (lungs, brain, and liver) Itraconazole 2014 [22] study TNBC metastasis

Wang et al 2015 Phase II, open – – – Women with –Brain metastases Esomeprazol [23] label, randomised metastatic –Prior chemotherapy in the meta- study or recurrent static setting breast cancer

Nanda et al 2016 Phase I, ran- – USA – Metastatic –Allergy or hypersensitivuty to Mifepristone [24] domised or locally ad- mifepristone, paclitaxel vanced breast –Received more than 4 prior cancer cytotoxic therapies for metastatic disease or prior nab-paclitaxel or mifepistone. –Pregnant or breast feeding

Lacerda et al Retrospective IBC database - Breast Cancer Manage- USA 1995–2011 Patients with –Stage IV patients Statins 2014 [25] study ment System at MD Anderson Cancer Inflammatory –Patients who did not receive adj Center (Medical records) breast cancer postmastectomy radiotherapy –Patients with locoregional recur- rence prior to radiation

Shaitelman et al Retrospective Data from MD Anderson Cancer Cen- USA 1997–2012 Women with – Statins 2017 [26] study ter (Medical records) invasive, non-metastatic TNBC 4

Review ecancer 2020, 14:1071; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1071 survival (Hazard ratio =0.69;95%CI,0.35–1.34; (BCIRG-005)trial blind clinical about women node positivewith didnotTNBC show any significantbenefit of relapse free survival andoverall ratio = 0.87; 95%CI0.58–1.31; p=0.504). The second study presented by Spera et al compared to not users about progression free survival (Hazard ratio = 0.52; 95% CI, 0.34–0.80; p= 0.002) notbut in overall survival (Hazard of a randomised, doubleblind clinical trial(ROSE/TRIO-012),showed significant benefit in women advancedwith using TNBC BBs when significant (0.32: 95%CI0.12–0.90;p=0.031;0.42:0.18–0.97;0.042,respectively). The study of Spera et al users. Breast cancer related events where lowerusers inBB (13.6% versus 27.9%;p=0.02)andhazard ratio of metastasis andBCdeath were diagnosed andoperated for early primary betweenTNBC 1997and2008,BBusers showed significant benefit when compared to not BB tive study of Botteri 0.30 (95%CI,0.10–0.87;p=0.027)andhazard ratioof overall survival was 0.35(95%CI,0.12–1.00;p=0.05)[12]. Also, intheretrospec chemotherapy between 1995 and 2007.Hazard ratio of recurrence free survival for women administered chemotherapywith plusBBs was USA, women with invasive receivingTNBC neoadjuvantchemotherapy plusBBs were compared to patients receiving only neoadjuvant study of Melhem-Bertrandt chemotherapy), andon women advancedwith or nodalpositive StudyTNBC. populations ranged from 35patients to 1,417patients. In the BBs were evaluated onpostmenopausal women operatedwith early primary on TNBC, women with invasive (receivingTNBC neoadjuvant Beta blockers (BBs) per drug/pharmacological classes. Figure 1. Type of studiesper drug. This shows thenumber of clinicaltrials(only phase1and2studies were found) andobservational studies conducted etal [11] using Breast Cancer and Cardiology Division Databases in Italy and analysing 800 postmenopausal women et al , using medical chart and pharmacychart medical [12], using data from theBreastCancer ManagementSystem Database inthe = 0.269; 0.73; 95% CI,0.35–1.48;p=0.38,respectively).p =0.269;0.73; [13] using alsodata from another randomised, double [13], usingdata 5 -

Review ecancer 2020, 14:1071; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1071 Table 2. Outcomes for each clinical study.

Average age Population size Effect size Reference ARM1 ARM2 ARM3 (years) of TNBC Follow up Outcome Outcome size (TNBC) measures patients

Bayraktar et Diabetic Diabetic Not 1,448 patients ARM1: Median 62 months 1) Distant metasta- 1) ARM1, ARM2, ARM3 0.73 –Five years es- al 2012 [10] patients patients diabeticpa- –ARM1: 63 53 sis free survival (0.58–0.83), 0.66 (0.52–0.77), timates rates Metformin + Adj chemo tients –ARM2: 67 ARM2: Median 2) Overall survival 0.60 (0.57–0.62); p = 0.23 between the Adj chemo + alone –ARM3: 1,318 51 3) Recurrence free 1) ARM2 versus ARM1: 1.63 three groups ARM3: Median survival (95% CI: 0.87–3.06) p = 0.13; –Hazard ratio Adj chemo: Adj chemo: 58 ARM3 versus ARM1: 1.62 –anthracy - –anthracy - (95%CI: 0.97–2.71) p = 0.06 cline +/- cline +/- 2) ARM1, ARM2, ARM3: 0.65 taxane taxane (0.51–0.76), 0.64 (0.5–0.75), –single- –single- 0.54 (0.51–0.56); p = 0.38 agent agent 2) ARM2 versus ARM1: 1.37 taxane taxane (95% CI: 0.78–2.40) p = 0.27; –other –other ARM3 versus ARM1: 1.36 (95% CI: 0.87–2.10) p = 0.17 3) ARM1, ARM2, ARM3: 0.67 (0.52–0.79) 0.69 (0.55–0.79), 0.66 (0.63–0.69); p = 0.58 3) ARM2 versus ARM1: 1.22 (95% CI: 0.66–2.28) p = 0.52; ARM3 versus ARM1: 1.28 (95% CI: 0.79–2.08) p = 0.31

Botteri et al Beta blockers Beta blockers – 800 patients ARM1: Mean ARM1: 1) Breast Cancer- 1) 13,6% versus 27.9%; p = –Five-year 2013 [11] users non users 62 median 72 related events 0.015 cumulative ARM2: Mean months 2) Distant metas- 2) 0.32 (95% CI: 0.12–0.90; p incidence 59 ARM2: tasis = 0.031) –Hazard ratio median 68 3) Breast Cancer 3) 0.42 (95% CI: 0.18–0.97; p months death = 0.042)

Melhem- Beta blockers Beta blockers – 1.417 patients ARM1: Mean ARM1: 1) Recurrence free 1) 0.30; 95% CI: 0.10–0.87; p Hazard ratio Bertrand et + neoadj non users –ARM1: 102 47.5 Median 55 survival = 0.027 al 2011 [12] therapy –ARM2: 1311 ARM2: Mean months 2) Overall survival 2) 0.35; 95% CI: 0.12–1.00; 55 ARM2: p = 0.05 Median 63 months

Spera et al Beta blockers Beta blockers – 1144 patients ARM1: Median Median: 25.1 1) Progression free 1) 0.52; 95%CI: 0.34–0.80; p Hazard ratio 2017 1 [13] users non users –ARM1: 152 60 months survival = 0.002 –ARM2: 991 ARM2: Median 2) Overall survival 2) 0.87; 95%CI: 0.58–1.31; p 53 = 0.504

Spera et al Beta blockers Beta blockers – 35 patients – – 1) Relapse free 1) 0.69; 95%CI: 0.35–1.34; p Hazard ratio 2017 - 2 users non users survival = 0.269 [13] 2) Overall survival 2) 0.73; 95%CI: 0.35–1.48; p = 0.384 6

Review ecancer 2020, 14:1071; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1071 Table 2. Outcomes for each clinical study. (continued)

Chan et al Tetramyolib- – – 36 patients – Median 6.3 Event free survival Stage II/III patients 90% (95% Two-year 2017 [14] date years CI: 78%–100%) event free rate Stage IV patients: 69% (95% CI: 49%–96%)

Hasegawa et Zoledronic Chemothera- – 34 patients – – Pathological ARM1: 6/17(35.3%) CI: 12.6– Pathological al 2015 [15] acid + Neo- py alone complete response 58.0; ARM2: 2/17(11.8%) CI: complete re- adj chemo- rates 0.0–27.1; p = 0.112 sponse rates therapy Chemo- Chemo- therapy: therapy: Four cycles Four cycles of of FEC100 FEC100 ev- every 3 weeks ery 3 weeks followed by followed by 12 cycles of 12 cycles of paclitaxel at paclitaxel at 80 mg/m2 80 mg/m2

Ishikawa et al Zoledronic Chemothera- – 34 patients – – Three years disease ARM1: 94.1%; ARM2: 70.6%; Percentage 2017 [16] acid + Neoadj py alone free survival p = 0.077 chemo- therapy Chemo- therapy: Chemo- Four cycles therapy: of FEC100 Four cycles followed by of FEC100 paclitaxel followed by paclitaxel

Retsky et al Ketorolac Chemothera- – Not specified – 27.3 months Disease free Far superior disease-free sur- – 2012 [17] + Chemo- py alone survival vival in the first few years after therapy surgery (no data shown)

Chow et al Celecoxib – – 2 patients – – 1) Pathological 1) 0% Percentage 2013 [18] (200mg) complete response 2) 50% + Neoadj 2) Near Patho- chemo: logical complete response Chemo- therapy: Four cycles of FEC followed by four cycles of docetaxel 7

Review ecancer 2020, 14:1071; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1071 Table 2. Outcomes for each clinical study. (continued)

Shiao et al Antiplatelet Not antiplate- – 222 patients ARM1: Median ARM1: Me- 1) Five years Dis- 1) ARM1: 80.4%; ARM2: –Percentage 2017 [19] users + let users + –ARM1 65 55 dian: 41.3 ease free survival 62.3%; 0.503 (0.261–0.970) –Hazard ratio Possible che- Possible che- –ARM2 157 ARM2: Median ARM2: Me- 2) Five years Over- p = 0.04 motherapy motherapy 50 dian 40.9 all survival 2) ARM1: 77.2%; ARM2: 3) Five years 69%;0.652 (0.343–1.239) p Distant metastasis = 0.192 rate 3) ARM1: 8.8%; ARM2: 31.9%; 0.310 (0.132–0.729) p = 0.007

Williams et al Aspirin users Not aspirin – 147 patients – – 1) Overall survival No specific outcome for TNBC Hazard ratio 2018 [20] + Possible users + –ARM1: 33 2) Disease free comparing ARM1 versus chemother- Possible che- –ARM2: 114 survival ARM2 apy motherapy

Pierga et al Celecoxib Chemo- – 78 patients – – Pathological com- 29.5% (95% CI: 19.7%–40.9%) Pathological 2010 [21] + Chemo- therapy –ARM1: 44 plete response complete re- therapy –ARM2: 34 sponse rates Chemo- Chemo- therapy: therapy: Eight cycles of Eight cycles EC-D of EC-D

Tsubamoto Itraconazole – – 13 patients Median: 45 – 1) Response rates 1) 62% (95% CI: 35%–88%) Pathological et al 2014 + Chemo- 2) Progression free 2) 10.8 months (95% CI: complete re- [22] therapy survival 7.6–15.3 months) sponse rates 3) Overall survival 3) 20.4 months (95% CI: Chemother- 13.1–41.4 months) apy : docetaxel, carbo- platin, and gemcitabine, vinorelbine, bevacizumab

Wang et al Esomepra- Esomeprazole Chemotherapy 15 patients – – Time to progres- 1) 10.7 (ARM1+ARM2) and Median time 2015 [23] zole low dose high dose –ARM1: 2 sion 5.8 months (ARM3); p = 0.011 (80mg) + che- (100mg) + Docetaxel –ARM2: 6 motherapy chemo- followed by –ARM3: 7 therapy cisplatin Chemo- therapy: Chemo- Docetaxel therapy: followed by Docetaxel cisplatin followed by cisplatin 8

Review ecancer 2020, 14:1071; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1071 Table 2. Outcomes for each clinical study. (continued)

Nanda et al Mifepristone Mifepristone Placebo 4 patients – – Treatment re- Three patients have partial – 2016 [24] (300mg) + (300mg) + –No informa- sponse response, and one patient Paclitaxel Paclitaxel tion on treat- complete response ments

Lacerda et al Statins + Postmas- – –ARM1: 16 – Median: 2.5 3 years Risk of No specific outcome for TNBC – 2014 [25] Postmas- tectomy –ARM2: 86 years locoregional recur- tectomy radiation rence radiation

Shaitelman Statin users Statin users Not statin users -ARM1: 293 – Median: 75.1 ARM1 versus 1) 0.82 (95% CI: 0.57–1.16) Relative risk et al 2017 (patients with -ARM2: 576 months ARM3 2) 0.70 (95% CI: 0.47–1.03) [26] lipid/choles- 1)Recurrence 3) 0.60 (95% CI: 0.36–1.03) terol values) 2)BCa Death 4) 0.51 (95% CI: 0.28–0.93)

ARM2 versus ARM3 3)Recurrence 4)BCa Death multicentresingle armstudy open-label of Chow etal were shownfor inthe article patients.TNBC The second study, aphaseII completecal responserates, comparisonno specific but on thisoutcome plus celecoxib. The authors stated that celecoxib did not improve pathologi- stagewith II/III comparingTNBC chemotherapy alone chemotherapywith of Pierga et al Celecoxib was analysed intwofirst,II randomisedthe studies:aphase study NSAIDs 70.6%). zoledronicwith acid was higher compared toother the (94.1% arm versus alone (p = 0.077) despite the fact that the percentage of patients in treatment acid showed nosignificant benefitcompared to theneoadjuvant treatment the 3 years diseasefree survival, neoadjuvant chemotherapy zoledronic plus 12.6–58.0) chemotherapywith alone(2/17(11.8%)CI:0.0–27.1). Also for comparing neoadjuvant chemotherapy plus zoledronic acid(6/17 (35.3%) CI: setting. Pathological complete response was not significant (p = 0.112) when zoledronicwith chemotherapy acidplus versus chemotherapy inneoadjuvant same cohortthe of patients(34 women stagewith IIA/IIIB treatedTNBC) phase II,openlabel,randomised studyanalysed but different outcomes in Theof articles Hasegawa et al[15]andIshikawa [16]referred to thesame Zoledronic acid free survival was 90%. stagewith II/III adjuvantduring TNBC setting, showed thattwo year event women treated tetrathiomolybdate.with The study, performed on36 women [14] was tochange assessthe in VEGFR2+endothelial progenitor cells in The primary endpointof studylabel singlearm II open phase of Chanet al Tetramolybdate comes wereobtained. non-diabeticgroup (0.38). Also, after adjustments, nosignificant survival out in themetformin group,64% inthenon-metformin groupand 54%inthe non-diabeticin the 66% group (p =0.58).Recurrence free survival was 65% vival was 67%inthemetformin group, 69%inthenon-metformin group and metformingroup in thenon-diabetic and60% group (p =0.23).Overall sur metastasisfree survival weremetforminin the 73% group, in thenon- 66% and 1318notdiabetic patients). The 5 years survival estimates for distant patients receiving metformin, 67diabeticpatients not receiving metformin in the USA between 1995 and 2007. In total, 1,448 patients (63 diabetic women receivedwho adjuvantchemotherapy orwith metforminwithout macy data from theBreast Cancer Management System Database compared The retrospective study of Bayraktar etand phar chart medical al[10]using Metformin [21] performed between 2004and2007, analysed 23 women , analysed women [18], 9 - - -

Review showed that statin use was predictive for OS(HR:0.10, when amultivariate analysis was performed (taking inconsideration cholesterol andtriglyceride values, stage andchemotherapy, theauthors compared to thenon-statinusers group(0.82 (0.57–1.16);0.70(0.47–1.03) relative riskof recurrence andbreastcancer death, respectively); stage I–III receivingTNBC statins at anyfrom time diagnosis. The authors showed that patients receiving statins didnot get any advantage The retrospective study of Shaitelman etal Statins nor any outcome information could beretrieved from thisarticle analysed (those patients were allocated to mifepristonepaclitaxel plus or placebo). Unfortunately, noinformation patients about allocation, In thePhase I, randomised study of Nanda andcolleagues performed inUSA, four women with metastatic or locally advanced TNBC were Mifepristone of patients receiving esomeprazole when compared to chemotherapy was significantly higher (10.7 versus 5.8months; p=0.011). receiving only chemotherapy, two esomeprazole low doseandsixesomeprazole highdose). The authors showed that tothe time progression The phaseII,openlabel,randomised study of Wang et al Esomeprazole overall survival was 20.4 months (95%CI:13.1–41.4months). made. The authors showed that response rate was 62%([CI], progression 35%–88%), free survival was 10.8months (95%CI, 7.6–15.3)and patients who progressed after prior chemotherapy were treated chemotherapywith incombination itraconazole.with No comparison was between 2008and2012to analye response rate, medianprogression-free survival andmedianoverall survival of thirteen patients. TNBC The of article Tsubamoto et al [22] reportedresults the of aretrospective study that usedmedicalrecords of theKohan in hospital Japan Itraconazole surgery’ butnodata were shown inparticular about TNBC. the authors saidthatgroup the receiving chemotherapyketorolac plus showed a‘far superior diseasefree survival inthefirst few years after axillaryNo dissection. informationthe cohort about (as for the number of patients with age,TNBC, etc…) was reported. Also, for theresults and 2008[27],in ketorolacwhich chemotherapy plus was compared to chemotherapy alonein women who underwent mastectomy with Finally, Retsky et al nosis (results were presented only for thetotal cohort of breast cancer patients andnot for subtype).TNBC thataspirin may havepathogenesison the animpact of donotbut TNBC seemto affect breastcancer survival when usedafter cancer diag- diagnosis, and14after diagnosis) to analyse overall survival anddisease-free survival between 2005and2013.Results of thisstudy indicated performed in USA used electronic medicalrecords of 147 women with primary operable stages I-III (114 TNBC never used aspirin, 19 before ratio was notsignificant between two the 0.652 (0.343–1.239);p=0.192). (HR: arms The second retrospective study of Williams et[20] al p = 0.04; anti-platelet 8.8%,no anti-platelet 31.9%,HR:0.310 (0.132–0.729); p = 0.007, respectively). Five years overall survival hazard hazardtasis ratios was significantly improved infavour offirst the arm(anti-platelet 80.4%,noanti-platelet 0.503(0.261–0.970); 62.3%, HR: patients in both arms(6.3%and7.1%,respectively) did not receive chemotherapy. Five years disease free survival and 5 years distant metas- Sixty-five women were treated anti-plateletwith therapy (as aspirinor clopidogrel) and157 with noanti-platelet therapy. A percentage of versity of Texas Southwestern registry, TNBC analysed acohortof 222 women with stage II/III intheUSATNBC between 2005abd2013. Aspirin was analysed in two retrospective studies. The first retrospective study of Shiao this cohort. primarywith breastcancer. Unfortunately, only two patients primarywith TNBC were includedandauthors could not show any result about ecancer 2020, 14:1071; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1071 [17] showed theupdated resultsof aretrospective study performed inBelgium usingmedicalrecords between 2003 used medical records[26] usedmedical from theMD Anderson Cancer Centre to investigate if women with p =0.026,95%CI:0.01–0.76). [23] analysed acohort of 15 women with metastatic or recurrent TNBC (seven [24]. et al[19] that collected medical records from Uni- 10

Review ecancer 2020, 14:1071; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1071 [25] didnot show any results for TNBC patients. improvementof for OS patientsstatinin the group (with exceptionthe of themultivariate analysis), while thesecond study of Lacerda et al retrieved only two retrospectiveon their studies useinthe cohort.TNBC The articleof Shaitelman etal Despite manytotrying studies evaluate theuseof statins inbreast cancer treatment [33–36],intheliterature search onPubMed, we (women with operable stage I-III TNBC). benefitin women stagewith II/IIIby theuseof aspirin, Williams et al The of articles Shiao etal ongoing. oftion TNBC women comparedwhen to notusers. Of note, two studiesontheuseof metformin inclinicaltrials.gov on patientsTNBC are efficacy inthetreatment of women with BayraktarTNBC. et al While BBs demonstrated to bebeneficialtreatmentin the of metformin,TNBC, apromising moleculeinpreclinical didnot studies, show any static potential. Unfortunately, authors didnot present results stratified for breast cancer sub-type. propranolol reduced intra-tumoral mesenchymaltransition andpromoted immunecell infiltration reducing biomarkers associated with meta- compared to placebo in60 women earlywith stage surgically-resectable breast cancer. [32]. The authors showed that thetreatment with patients.TNBC Oneblinded phaseIIrandomised triple trialevaluated the useof pre-operative propranolol (seven days before surgery) BBsplus [11–13].Unfortunately, inclinicaltrials.gov we found nostudiesthat specifically attempt to evaluate BBs within clinicaltrialsfor benefitsof thesedrugsin women advancedwith and inearlyTNBC primary patientsTNBC treated with thecombination of chemotherapy BetaBlockers (BBs)to seem bethemore promisingrepurposingin the drugs for thetreatment of TNBC. Three articlesshowed significant of thestudiesdidnot report any result for TNBC cohort isapartofwhen this abigger BCcohort. onlytrials clinical few ofa large used studies the of sample and gave cases explicit results ontherepurposing of olddrugsfor SomeTNBC. was produced fordatabasein the included drugs for treatment the of onlyTNBC, few of them were tested inclinicaltrials.Moreover, in gate already approved noncancer-drugsin theoncology setting.Using thisReDO_DB, we foundthat out despite alot of preclinical evidence hypothetical repurposed drugsand far from theaimof the ReDO project. The project, in particular, aims to drive scientist attention to investi- pharmacological approaches that, despite theinterest for theresearch [28–31],unless validated by preclinical studies,represent only future cancer. Thus, thedatabase doesnotpotential include repurposingcandidates identified through insilico modellingor other computational and tumour subtypes. The ReDO approachliteratureis basedonpublished anddoesnot aimto identify new active compounds against to the database new drugs for which there are preclinical evidence, and by giving visitors a specific PubMed search string for each tumour of non-cancer-drugsin oncology, andReDO_DBis apowerful tool that needto bedynamically implemented with recent findings,by adding fromstarting preclinicalevidence andgoing through current trials.ReDO clinical isanambitiousproject aimingto investigate therepurposing This review presentsan overview ofevidences allthe repurposingthe about of old,licensed, non-cancer-drugs inthetreatmentof TNBC, Future directions two for metformin, two for mifepristone, andthree for zoledronic acid. presentdrugs the only oneor fewon this published studies website. In total, three studiesare recruiting for theassessmentof atorvastatin, completedfortrials clinical TNBC. Searching the web site of clinicaltrials.gov (clinicaltrials.gov), we found only of 17drugsout 286presented intheReDo_DB with ongoing or Clinicaltrials.gov mastectomy radiation plusstatins (16patients). Unfortunately noinformation theoutcome about in patientsTNBC was shown. cancer who received adjuvant post-mastectomy radiotherapy. 102patients underwent post-mastectomy radiation (86patients) or post- 1995 and 2011, analysed the risk of loco-regional recurrence at 3 years associated to the use of statins, in patients with inflammatory breast The retrospective study of Lacerda et al and Williams [19] Table 3showsoflist the and therecruitment trials status for eachdrug. As shown in using Breast[25] using Cancer Management database at MD Anderson Cancer Centre inUSA between etal [20] showed conflicting results onaspirin. While thefirststudy showed asignificant survival [10] showed that metformin doesnot improve survival outcomes inapopula- [20] didnot show thisbenefit inthebreast cancer population examined [26] reported anon-significant Table 3,mostpartof 11

Review ecancer 2020, 14:1071; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1071 Table 3.Ongoing trialsfound inClinicaltrials.gov. Zoledronic acid Ritonavir Omeprazole Mifepristone Metformin Mebendazole Leflunomide Lansoprazole Indomethacin Imipramine Flucytosine Epalrestat Doxycycline Celecoxib Atorvastatin Acetylsalicylicacid Drugs (REDO_DB) metastases of malignancy, treat painfrom bone fractures andtreat hypercalcemia Osteoporosis, prophylaxis of skeletal Anti-retroviral Antacid Abortifacient Diabetes Parasitic infection Arthritis Antacid Analgesia Depression Candida and/or Cryptococcus Diabetes infection Respiratory/urinary tract/ophtalmic dysmenorrhea OA, RA, JRA, AS, acute pain,primary nary syndrome Coronary heartdisease,acute coro - attacks or strokes venous embolismandfurther heart Analgesia, swelling, prophylaxis of Main indication Bone resorption inhibitor HIV protease inhibitor ATPase inhibitor receptor antagonist Glucocorticoid receptor ntagonist|progesterone Insulin sensitizer Tubulin polymerisation inhibitor tyrosine kinasereceptor inhibitor Dihydroorotate dehydrogenase inhibitor|PDGFR ATPase inhibitor Cyclooxygenase inhibitor reuptake inhibitor Norepinephrine reputake inhibitor|serotonin Other antifungal Aldose reductase inhibitor Metalloproteinase inhibitor Cyclooxygenase inhibitor HMGCR inhibitor Cyclooxygenase inhibitor Mechanism of action Stopped dueto thelow accrual rate)) NCT02347163 (Recruitment Status : Active) NCT02595138 (Recruitment Status : Recruiting); NCT03358017 (Recruitment Status : Completed) NCT01009437 (Recruitment Status : Active) NCT02950259 (Recruitment Status : Completed) NCT02014337 (Recruitment Status : Recruiting) NCT02788981 (Recruitment Status : Status :Recruiting) Completed); NCT02201381(Recruitment NCT01650506 (Recruitment Status : Recruiting) NCT02201381 (Recruitment Status : Recruiting) NCT03709446 (Recruitment Status : yet recruiting) NCT03794596 (Recruitment Status :Not Active) NCT02950259 (Recruitment Status : yet recruiting) NCT03122444 (Recruitment Status :Not Active) NCT02576665 (Recruitment Status : Recruiting) NCT03244358 (Recruitment Status : Recruiting) NCT02201381 (Recruitment Status : Recruiting) NCT03599453 (Recruitment Status : Recruiting) NCT02201381 (Recruitment Status : Recruiting); NCT03872388 (Recruitment Status : Recruiting); NCT03358017 (Recruitment Status : (3)

Clinical trial.gov 12

Review ecancer 2020, 14:1071; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1071 This study was supported by Fondazione Decima Regio ‘Olga eRaimondo Curri’, Via Cimarra 44-B,Roma. Funding pretationof and discussion study results. draftedAS andSD themanuscripts. All authors revised andapproved thefinal version of thepaper. conceivedand SC MZ study. the extractedAS data. the thedatasupervised SD extraction. MZ,SD, SC, AS, andPP contributed to theinter Authors' contributions The authors declare that they have noconflict of interest Conflicts of interest still needto beassessedor proven for thetreatment of TNBC. From theliterature retrieved, BBs seemedto bethemore promising drugsfor therepurposing, while evidence other about drugsasNSAIDs for thisparticular typeof cancer. on TNBC. one data,on omics have repurposed included and havedrugs reported interesting casereports of responses from patients [38,39],however no the opportunity to investigate weather non-anticancer drugs might be effective in cancer treatment. Some precision medicine studies, based Drugrepurposing isahighly interestingnovel strategy foroncology the community andReDO_DB isapowerful tool that cangive authors Final remarks repurposing. tiveto studies beeffectivetreatment inthe of patients,TNBC randomised clinicaltrialsmight beimportantto confirm theevidence of the strong evidence, large retrospective cohortarestudies neededto evaluate effectiveness. Further, asfor BBs that have proven by retrospec Forcollected thosedrugs inReDO_DB favourablewith preclinicalevidence or whose retrospective clinicaltrials were not solarge to provide a promising pCR rate without adding toxicity. patients and 71.8 % (95%CI: 55.1–85.0) in all enrolled patients, demonstrating that the omeprazole in addition to neoadjuvant AC-T yields and thedrug was well tolerated with noknown grade 3or 4toxicities. Furthermore, thepCR rate was 71.4%(95% CI:51.3–86.8)inFASN+ was investigated. FASNpositivity significantly decreased omeprazolewith from 0.53(SD=0.25)at baselineto= 0.30;p0.02), 0.38(SD in combination anthracycline-taxanewith (AC-T) was administered to 42patients until surgery, andpathologic complete response (pCR) meeting. of omeprazole onpatients operablewith independentTNBC of baselineFatty acidsynthase (FASN) expression was presented at the ASCO Other authors showed significant results on the survival of patientsTNBC treated esomeprazole.with Recently, one phaseII study on activity [37] In vitro, protoninhibitors pump FASN inhibit activity andinduce apoptosis inbreastcancer cell lines.In thisstudy, omeprazole

Due to thelow number of therapeutic approvedopportunities for repurposingTNBC, of olddrugsseemsa valuable approach 13 - -

Review 17. 16. 15. 14. 13. 12. 11. 10. ecancer 2020, 14:1071; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1071 References

9. 8. 7. 6. 5. 4. 3. 1. 2. 2094-5 PMID: relapse:particular relevance to triplenegative subgroup BreastCancer Res Treat RetskyRogers M, and Demicheli R, R, negative breast cancer JSurg Res220 46–51 https://doi.org/10.1016/j.jss.2017.05.066 PMID: Ishikawa T, Akazawa K,andHasegawa Y, etal (2017)Survival outcomes of neoadjuvant chemotherapy with zoledronic acidfor HER2- org/10.1371/journal.pone.0143643 therapyneoadjuvantas alone treatment of HER2-negative primary breast cancer (JONIEstudy) Hasegawa Y, Tanino H,andHoriguchi J, et al(2015)Randomized controlled trialof zoledronic acidplus chemotherapy versus chemo- Res tetrathiomolybdate inpatients with breastcancer atfor highrisk recurrence andinpreclinical modelsof lungmetastases Chan N, Willis A, andKornhauser N,et al (2017) mdx264 PMID: tive breast cancer: aretrospective analysisof theROSE/TRIO-012 study AnnOncol SperaFresco G, and Fung R, H, 21632501 PMCID: vivalin patients with triple-negative breastcancer Melhem-Bertrandt A, Chavez-Macgregor M, and Lei X, 2654-3 PMID: pausal women.Breast cancer researchtreatment and Botteri E, Munzione E,and Rotmensz N,et al (2013) negative breast cancer Cancer 118 (5) 1202–1211https://doi.org/10.1002/cncr.26439 Bayraktar S,Hernadez-Aya LF, andLei X,et al.(2012)Effect of metformin on survival outcomes in diabetic patients with triple receptor- ClinicalTrials.gov [https://clinicaltrials.gov/] Date accessed: 31/03/19 12 886https://doi.org/10.3332/ecancer.2018.886 PantziarkaP, Verbaanderd C,andSukhatme V, et (2018) alReDO_DB: therepurposing drugsinoncology database pay? Isr J Health Policy Res 540https://doi.org/10.1186/s13584-016-0097-0 Goldstein DA, Stemmerand Gordon SM, N(2016)The costand value of cancer drugs—are new innovations outpacingour ability to 41–58 https://doi.org/10.1038/nrd.2018.168 Pushpakom S,Iorio F, and Eyers PA, etal (2019)Drug repurposing: progress, challenges andrecommendations a systematic review Neoplasma 66(6)963–970https://doi.org/10.4149/neo_2019_190110N34 PMID:31607128 Spini A, Roberto G,andGini R,et (2019)Evidence al of β-blockers drug repurposing for the treatment of triple negative breast cancer: Res DentR, Trudeauand PritchardM, KI, Gucalp Aand Traina TA(2011) Perou CM(2010) J Women’sHealth BrouckaertO, Wildiersand Floris H, G, theoncologist.2010-S5-39 23(3)666–676https://doi.org/10.1158/1078-0432.CCR-16-1326 13(15)4429–4434https://doi.org/10.1158/1078-0432.CCR-06-3045 PMID: 22622810 23912960 28520849 4 511–520.PMID: 3139371 Molecular stratificationof ripple-negative breast cancers etal Triple-negative breast cancer: adjuvant therapeutic options Chemother Res Pract (2017) Beta blockers improved and progression-free survival inpatients with advanced HER2nega- PMID: 23071421 PMCID: et al (2007) etal (2012)NSAID analgesic ketorolac usedperioperatively may suppress early breast cancer etal (2012)Update ontriple-negative breast cancer: prognosis andmanagement strategies Int 26633806 PMCID: Triple-negative breast cancer: clinicalfeatures and patterns of recurrence Influencingthe tumor microenvironment: aphaseIIstudy of copper depletion using J ClinOncol Therapeutic effect of beta-blockers in triple-negative breast cancer- postmeno BreastCancer Res Treat 140(3) 567–575 3469230 etal (2011) 4669153 29(19) 2645–2652https://doi.org/10.1200/JCO.2010.33.4441 PMID: Beta-blocker use is associated with improved relapse-free sur 134(2) 881–888https://doi.org/10.1007/s10549-012- 17671126 Oncologist 28(8) 1836–1841https://doi.org/10.1093/annonc/ 15(S5) 39–48 29180210 PLoS One 10(12)e0143643 https://doi. https://doi.org/10.1007/s10549-013- NatRev Drug Discov https://doi.org/10.1634/ 2011696208 Ecancermedicalscience Clin Cancer Clin Cancer 18(1) 14 -

Review ecancer 2020, 14:1071; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1071 19. 18. 20. 33. 32. 21. 31. 30. 24. 23. 22. 29. 28. 27. 26. 25. of distant metastasesin Stage triple-negativeIII IIand breastcancer patients Shiao J, Thomasand Rahimi KM, AS, et al(2017)Aspirin/antiplatelet agent useimproves disease-free survival andreduces therisk 1517/13543784.2013.766715 PMID: docetaxel for stagesinvasive- III II breastcancer: theOOTR-N001 study Chow LWC, TungSY, andNg T-Y, etal (2013)Concurrent celecoxib with 5-fluorouracil/epirubicin/cyclophosphamide followed by Williams AD, Li YR, andSo A, et (2018)Theal impact of use aspirin on breast cancer subtype and clinical course org/10.1007/s10549-016-4081-8 cohort study Ahern TP, Pedersenand L, TarpM, cancer: aPhase IIrandomized trial Hiller ColeJG, SW, andCrone EM, invasive breastcancer patients BreastCancer Res Treat followed by docetaxel with or celecoxibwithout or trastuzumab according to HER2status, asprimary chemotherapy for localized Pierga J-Y, Delalogeand Espié S, M, https://doi.org/10.1016/j.jss.2018.04.040 PMID: ease Bianchini G,Balko and MayerJM, IA,etal (2016)Triple-negative breast cancer: challenges andopportunitiesof aheterogeneous dis- cal studies Ocana A andPandiella A (2017)Targeting oncogenic vulnerabilities intriplenegative breast cancer: biological basesandongoing- clini mifepristonewithout for advancedbreast cancer Springerplus Nanda R, Stringer-Reasor and EM, Saha P, 4546346 therapy inmetastatic breastcancer JExpClinCancer Res Wang B-Y, Zhang J, and Wang J-L, breast cancer Anticancer Res 34(7)3839–3844PMID: Tsubamoto H,Sonoda T, andInoue(2014) ImpactK. of itraconazole onthesurvival of heavily pre-treated patients with triple-negative precision medicine TuranliKaragoz B, and Gulfidan K, G, 27632168 PMCID: target therapiesnegative intriple breastcancer PLoS One Vitali F, Cohen LD, andDemartini A, et al(2016)A network-based data integration approach to supportdrugrepurposing andmulti- mehy.2013.07.033 PMID: ity and methodology of a prospective randomized placebo-controlled trial Med Hypotheses Forget P, Berlière M,and van Maanen A, 2026–2032 https://doi.org/10.7150/jca.18743 PMID: ShaitelmanSF, Stauderand MC, Allen P, et al(2017)Impactof statin useonoutcomes intriplenegative breastCancer cancer J 3(7) 849–856https://doi.org/10.5966/sctm.2013-0204 ciated with improvedcontrol local ininflammatory breastcancer patients treated with postmastectomy radiation Lacerda L, Reddy JP, and Liu D, PMCID: Nat Rev ClinOncol 13(11)674–690https://doi.org/10.1038/nrclinonc.2016.66 PMID: 4929099 Oncotarget JNatl Cancer Inst 103(19)1461–1468https://doi.org/10.1093/jnci/djr291 PMID:21813413PMCID:3186780 Curr Pharm Des 24(32)3778–3790https://doi.org/10.2174/1381612824666181106095959 5025072 188(13):22218–34https://doi.org/10.18632/oncotarget.14731 23937996 et al (2014) etal (2015)Intermittent highdoseproton pumpinhibitor enhances theantitumor effects of- chemo etal (2011)Statin prescriptions andbreast cancer recurrence aDanish risk: nationwide prospective ClinCancer Res 26(8)1803–1811 https://doi.org/10.1158/1078-0432.CCR-19-2641 (2020) Pre-operative(2020) etpropranolol al reduces β-blockade with biomarkers breast of in metastasis et al(2010)A multicenter randomized phaseIIstudy of sequential epirubicin/cyclophosphamide etal (2018)A network-based cancer drugdiscovery: fromintegrated multi-omicsapproaches to 23394482 etal (2013) Simvastatin radiosensitizes differentiated andstem-like breast cancer cell linesandisasso- et al (2016) 30100043

122(2) 429–437https://doi.org/10.1007/s10549-010-0939-3 PMID:20480225 24982411 Perioperative ketorolacbreast inhighrisk cancer patients.Rationale, feasibil- 28819403 PMCID:5559964 PMID: A randomized Itrialof phase nanoparticlealbumin-boundpaclitaxel with or 34 85 5(1) 947https://doi.org/10.1186/s40064-016-2457-1 PMID: 11(9) e0162407https://doi.org/10.1371/journal.pone.0162407 PMID: https://doi.org/10.1186/s13046-015-0194-x PMID: 26297142 PMCID: 24833589 PMCID:4073823 Expert Opin Investig Drugs 22(3)299–307https://doi.org/10. Breast Cancer Res Treat 27184417 PMCID: 81(4) 707–712https://doi.org/10.1016/j. 161(3) 463–471https://doi. 5461122 PMID:30398107 J Surg Res Stem Cells Transl Med 230 71–79 27386391 8(11) 15

Review 39. 38. 37. 36. 35. ecancer 2020, 14:1071; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1071 34. tal cancer AnnOncol 27(5)801–806https://doi.org/10.1093/annonc/mdw060 PMID: JonesSchrader MR, and Shen KA, Y, etal (2016)Response to angiotensin blockade with irbesartaninapatient with metastatic colorec medical analyticsprovide proof of concept inacasestudy BrownBuryanekRE, J, andMcGuire MF (2017)Metforminand melatonin inadrenocortical carcinoma: morphoproteomics andbio - 38(suppl; abstr 584)https://doi.org/10.1200/JCO.2020.38.15_suppl.584 Sardesai SD, Thomas A, and Gallagher C, 9(10) ell0231 Murtola TJ, Visvanathanand K, ArtamaM, early stage breast cancer survivors KwanHabel ML, LA,andFlick ED, et al(2008)Post-diagnosis statin useand breast cancer recurrence in aprospective cohort study of PMID: among women with early stage breastcancer BoudreauDM, YuO, andChubak J, etal (2014)Comparative safety of cardiovascular medication useandbreast cancer outcomes 24557337 PMCID: 3988288 Breast Cancer Res Treat etal (2020) etal Statin breast useand cancer survival: anationwide cohort study from Finland BreastCancer Res Treat Inhibiting fatty acidsynthase inoperable triplenegative breast cancer AnnClinLab Sci 47(4)457–465PMID: 28801373 109(3) 573–579https://doi.org/10.1007/s10549-007-9683-8 144(2) 405–416https://doi.org/10.1007/s10549-014-2870-5 27022066 PMCID: 4843189 J ClinOncol PLoS One 16 -

Review ecancer 2020, 14:1071; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1071 Supplementary tables Table S2.Preclinical references for repurposing of drugsfor TNBC by ReDO DB. Acetazolamide phen Acetamino Drugs Table S1.Search strings. "Triple negative breast cancer"[Title/Abstract] OR"TNBC"[Title/Abstract] OR"Triple negative breast neoplasms"[Mesh] Pathology block Drugs block:allthedrugsandtheir synonyms intheRedo Database PubMED stingbasedonReDO_DB: 2blockscombined with AND "Clinical trial"[Publication type] OR"ClinicalStudy"[Publication Type] OR"Epidemiologic Studies"[Mesh] Type of study Block "Repurposing"[All Fields] OR"Repurpose"[All Fields] OR"Repositioning"[All fields] OR"Reposition"[All Fields] Intervention Block "Triple negative breast cancer"[Title/Abstract] OR"TNBC"[Title/Abstract] OR"Triple negative breast neoplasms"[Mesh] Pathology block PubMED String: 3blockscombined with AND - uretic, epilepsy Glaucoma, di- Analgesia Main indication Carbonic anhydrase inhibitor TRPA1 inhibitor Mechanism of action – –Ivanova L,Zandberga E,Siliņa K,Kalniņa Z, – 13;19(3). Paclitaxel Nanoparticles for Targeting Tumor Hypoxia. Int J Mol Sci. 2018Mar Synthesis andCharacterisation of Carbonic Anhydrase-IX Anchored Albumin- Tatiparti K,Sau S,Gawde KA,Iyer AK. Copper-Free “Click” Chemistry-Based cancer cells. Cancer Chemother Pharmacol. 2015Feb;75(2):235–46 of breast cancer anditssilencingsuppresses self-renewal capacity of breast tic relevance of carbonicanhydrase IXexpression isdistinctin various subtypes cancer cells: The possiblefunctionalimpacts.Gene. 2019 Jun 20;702:46–55. related expression of microRNAs inamodelof stem-like triple-negative breast acetaminophen-induced alterations inepithelial-to-mesenchymal transition- Afshar E,Hashemi-Arabi M,Salami S,Peirouvi T, Pouriran R.Screening of References Ābols A, Endzeliņš E,et al.Prognos- 17

Review ecancer 2020, 14:1071; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1071 Table S2.Preclinical references for repurposing of drugsfor TNBC by ReDO DB. Artesunate Aprepitant Amiloride Albendazole acid Acetylsalicylic Malaria Nausea, vomiting potassium zides, to conserve treatedthia- with hypertension heart failure or In congestive Parasitic infection attacks or strokes and further heart venous embolism ing, prophylaxis of Analgesia, swell- DNA synthesis inhibitor Tachykinin antagonist Sodium channelblocker Tubulin polymerisation inhibitor Cyclooxygenase inhibitor – – –Amith SR, – – – – – – – – – HER2-enriched SK-BR-3 breast cancer cells. ExpMol Pathol. 2019;107:10–22. causes cell cycle arrest andapoptosis of triple-negative MDA-MB-468 and Greenshields AL, Fernando W, Hoskin DW. The anti-malarial drugartesunate 2016;2016:1959270 Apoptosis and Triple-Negative Breast Cancer Chemoresistance. Biomed Res Int. Substance P Receptor Signaling Mediates Doxorubicin-Induced Cardiomyocyte Robinson P, Kasembeli M,Bharadwaj U, Engineer N,Eckols KT, Tweardy DJ. cells. Oncotarget. 2015 Jan 20;6(2):1262-75. novel co-adjuvant target inpaclitaxel therapy of triple-negative breast cancer Nov;19(8):3734–41. for Treatment of Triple-Negative Breast Cancer. AAPS PharmSciTech. 2018 Repositioning of Anti-parasitic Drugs inCyclodextrin Inclusion Complexes Priotti J, Baglioni MV, García A, Rico MJ, Leonardi D, LamasMC,et al. 15;83(6):723–32 negative breast cancer cells in vitro andin vivo. Biochem Pharmacol. 2012Mar gen sulfide-releasing aspirinsuppresses NF-κB signalinginestrogen receptor Chattopadhyay M,Kodela R,Nath N,Barsegian A, Boring D, Kashfi K.Hydro - diated through acetylation. Oncotarget. 2015Sep 15;6(27):23383–98 apoptosis intriple-negative breast cancer cells via RAGE binding, which isme Lee YR, KimKM, Jeon BH,ChoiS.Extracellularly secreted APE1/Ref-1 triggers 2017 05;114(49):13030–5 survival inestrogen receptor-negative breast cancer. Proc Natl Acad Sci USA. al. Coexpression of NOS2andCOX2 accelerates tumor growth andreduces Basudhar D, Glynn SA, Greer M,Somasundaram V, No JH, Scheiblin DA, et tors Inflamm. 2018;2018:6380643 matory Cytokines between 4T1Breast Cancer Cells andMacrophages. Media- Hsieh C-C, Wang C-H. Aspirin Disrupts theCrosstalk of Angiogenic andInflam mun Signal. 2019 Jan 4 suppresses tumor cell-induced angiogenesis andtheir incongruity. J Cell Com- Maity G,Chakraborty J, Ghosh A, Haque I,Banerjee S,Banerjee SK. Aspirin ing both neoplasticandmicroenvironment cells. Sci Rep. 2016 Jan 5;6:18673. pirin andatenolol enhance metformin activity againstbreast cancer by target- Talarico G,Orecchioni S,Dallaglio K,Reggiani F, Mancuso P, Calleri A, et al. As- cancer subtypes. Invest New Drugs. 2018;36(5):782–96. clinical effects of metformin andaspirinonthecell linesof different breast Amaral MEA,Nery LR,Leite CE,de Azevedo Junior WF, CamposMM.Pre- vention of triplenegative breast cancer. Breast Cancer Res. 201811;20(1):150. isomiR-140-3p-regulated mevalonic acidpathway asapotential target for pre - Bhardwaj A, Singh H, Trinidad CM, Albarracin CT, Hunt KK,Bedrosian I. The (continued) Wilkinson JM, Baksh S,Fliegel L. The Na⁺/H⁺ exchanger (NHE1)asa

- 18 -

Review ecancer 2020, 14:1071; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1071 Table S2.Preclinical references for repurposing of drugsfor TNBC by ReDO DB. Bepridil Bazedoxifene Azithromycin Auranofin Atorvastatin Atenolol Ascorbic acid angina chronic stable Hypertension and Osteoporosis tion, CAP, PID Bacterial infec RA drome coronary syn- disease, acute Coronary heart angina pectoris Hypertension, Scurvy - Calcium channelblocker modulator (SERM) selective estrogen receptor inhibitor Bacterial 50Sribosomalsubunit NFkB pathway inhibitor HMGCR inhibitor Adrenergic receptor antagonist Antioxidant – – – – – – – – – – – – Oncotarget. 2016 Jul 5;7(27):42110–25. tion of FOXO3 suppresses triple-negative breast cancer in vitro andin vivo. Park S-H,Chung YM, Ma J, Yang Q, Berek JS, Hu MC-T. Pharmacological activa - Treat.2019 Jun;175(3):553–66 GP130 inhibitor for treating triple-negative breast cancer. Breast Cancer Res Tian J, ChenX,Fu S,Zhang R,Pan L,Cao Y, et al.Bazedoxifene isanovel IL-6/ induce apoptosis inbreast cancer. Cancer Lett. 2019 Apr 28;448:11–9. inhibit cell viability, cell migration, colony formation, andtumor growth and Fu S,ChenX,Lo H-W, Lin J. Combined bazedoxifene andpaclitaxel treatments Nov;38(11):6271–9 negative Breast Cancer andPancreatic Cancer Cells. Anticancer Res. 2018 Viability, Colony-forming Activity, andCell Migration inHuman Triple- Fu S,Lin J. Blocking Interleukin-6 andInterleukin-8 Signaling Inhibits Cell Cancer. J Natl Cancer Inst. 2018Nov 20 nofin/Vitamin C: A Novel Drug Combination Targeting Triple-Negative Breast Hatem E, Azzi S,El Banna N,He T, Heneman-Masurel A, Vernis L,et al. Aura- 15 May L1 antibody for treatment of triple-negative breast cancer. Int J Cancer. 2019 cooperation between auranofin, athioredoxin reductase inhibitor andanti-PD- Raninga PV, Lee AC, Sinha D, Shih Y-Y, Mittal D, Makhale A, et al. Therapeutic pathway. J Cell Biochem. 2018Sep 6. naling pathways inbreast cancer stem-like cells via inhibitionof themevalonate statins antagonistically alter themajor epithelial-to-mesenchymal transition sig- Koohestanimobarhan S,Salami S,Imeni V, Mohammadi Z,Bayat O. Lipophilic Oncol Rep. 2014Oct;32(4):1727–33 suppresses transcriptional activity of humanestrogen andandrogen receptor. Mafuvadze B,Liang Y, Hyder SM.Cholesterol synthesis inhibitor RO 48-8071 Res. 2014Feb 14;16(1):R20 kopf-1 isregulated by themevalonate pathway inbreast cancer. Breast Cancer Rachner TD, Göbel A, Thiele S,Rauner M,Benad-Mehner P, Hadji P, et al.Dick ing both neoplasticandmicroenvironment cells. Sci Rep. 2016 Jan 5;6:18673 pirin andatenolol enhance metformin activity againstbreast cancer by target- Talarico G,Orecchioni S,Dallaglio K,Reggiani F, Mancuso P, Calleri A, et al. As- Cancer. J Natl Cancer Inst. 2018Nov 20. nofin/Vitamin C: A Novel Drug Combination Targeting Triple-Negative Breast Hatem E, Azzi S,El Banna N,He T, Heneman-Masurel A, Vernis L,et al. Aura- pathways. Oncol Rep. 2017 Apr;37(4):2177–84. growth by increasing H2O2accumulation andactivating caspase-3andp38 with vitamin Candmethotrexate inhibitstriple-negative breast cancer cell Wu C-W, LiuH-C, Yu Y-L, Hung Y-T, Wei C-W, Yiang G-T. Combined treatment (continued) 19 -

Review ecancer 2020, 14:1071; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1071 Table S2.Preclinical references for repurposing of drugsfor TNBC by ReDO DB. Celecoxib Carglumic acid Calcitriol orrhea primary dysmen- AS, acute pain, RA, JRA, OA, thase deficiency glutamate syn- mia inN-acetyl Hyperammonae ciency Vitamin Ddefi- - - Cyclooxygenase inhibitor activator Carbamoyl phosphate synthase Vitamin Dreceptor agonist – – – – – – – – – – – with autophagy inhibitors. Cancer Lett. 2012Dec 1;325(1):63–71 pharmacological aggravators of endoplasmicreticulum stress are combined erential killingof triple-negative breast cancer cells in vitro andin vivo when Thomas S,Sharma N,Golden EB,ChoH, Agarwal P, Gaffney KJ, et al.Pref cells. Ultrastruct Pathol. 2018 Jun;42(3):289–94 on theproliferation andultrastructural changes of MDA-MB-231 breast cancer Ma Q, Gao Y, Wei D-F, Jiang N-H,Ding L,He X,et al. The effects of celecoxib Res. 2015;5(12):3560–9 tosis andsuppresses cancer cell proliferation in vitro andin vivo. Am J Cancer Chen C-T, Chen Y-C, Yamaguchi H,Hung M-C.Carglumic acidpromotes apop Jan;32(1):249–57 breast cancer cells by CDH1-promoter demethylation. Anticancer Res. 2012 dihydroxyvitamin D3induces denovo E-cadherin expression intriple-negative Lopes N,Carvalho J, Durães C,Sousa B,Gomes M,Costa JL, et al.1Alpha,25- Feb;35(2):805–10 D metabolizing enzymesintriple-negative breast cancer. Anticancer Res. 2015 Richards SE, Weierstahl KA,Kelts JL. Vitamin Deffect ongrowth and vitamin Res Treat.2016;157(1):77–90 gen receptor-targeted therapy for triple-negative breast cancer. Breast Cancer Thakkar A, Wang B,Picon-Ruiz M,Buchwald P, Ince TA. Vitamin Dandandro- negative breast cancer. J Steroid Biochem Mol Biol. 2017;173:122–9 compounds inhibitcancer stem-like cells andinduce differentiation intriple Shan NL, Wahler J, Lee HJ, Bak MJ, Gupta SD, Maehr H,et al. Vitamin D tive breast tumor. Biomed Pharmacother. 2017Oct;94:21–6 Combined calcitriolandmenadionereduces experimental murinetriplenega Bohl L,Guizzardi S,Rodríguez V, Hinrichsen L,Rozados V, Cremonezzi D, et al. 2018;177:135–9 D-resistant triple-negative 4T1breast cancer. J Steroid Biochem Mol Biol. hybrid vitamin Dreceptor agonist/histone deacetylase inhibitors in vitamin Bijian K,Kaldre D, Wang T-T, Su J, Bouttier M,Boucher A, et al.Efficacy of ERK pathway. Onco Targets Ther. 2019;12:721–32 of 1,25-(OH)2D3 againsthumanbreast cancer cell linesby targeting Ras/MEK/ Zheng W, CaoL,Ouyang L,Zhang Q, Duan B,Zhou W, et al. Anticancer activity kines IL-1β and Breast Cancer Cells through aMechanism Involving theProinflammatory Cyto- S, Soca-Chafre G,et al.CalcitriolInhibits theProliferation of Triple-Negative Martínez-Reza I,Díaz L,Barrera D, Segovia-Mendoza M,Pedraza-Sánchez (continued) TNF-α. J Immunol Res. 2019;2019:6384278 - - - 20

Review ecancer 2020, 14:1071; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1071 Table S2.Preclinical references for repurposing of drugsfor TNBC by ReDO DB. Chloroquine estinal Amebiasis Malaria, Extraint- Antimalarial agent – – – – – – – – – – – – – in HCC1806 breast cancer cells. Adv Med Sci. 2019Mar;64(1):202–9 tinate complex andautophagy modulation ondoxorubicin-induced cytotoxicity Abdel-Mohsen MA, Abdel Malak CA,El-Shafey ES.Influence of copper (I)nico- 82 negative MDA-MB-231 breast cancer cells. Int J Mol Med. 2014 Jul;34(1):276– gemcitabine-induced autophagy associated with apoptosis inhibitionintriple- Chen M,He M,Song Y, ChenL,XiaoP, Wan X,et al. The cytoprotective role of triple-negative breast cancers. Autophagy. 2014;10(12):2122–42 autophagy asanew meansof improving chemotherapy efficiency inhigh-LC3B Lefort S, Joffre C,Kieffer Y, Givel A-M, Bourachot B,Zago G,et al.Inhibition of with autophagy inhibitors. Cancer Lett. 2012Dec 1;325(1):63–71 pharmacological aggravators of endoplasmicreticulum stress are combined erential killingof triple-negative breast cancer cells in vitro andin vivo when Thomas S,Sharma N,Golden EB,ChoH, Agarwal P, Gaffney KJ, et al.Pref Cancer Res. 2018Nov 27;37(1):286 overcome resistance to doxorubicin intriplenegative breast cancer. J ExpClin GEFA-E, et al.Increasing intratumor Salaroglio IC,Gazzano E, Abdullrahman A, Mungo E,Castella B, Abd-Elrahman cancer cells. Cell Death Dis. 2014Dec 11;5:e1563 cytotoxicity induced by recombinant humanarginase intriple-negative breast Wang Z,Shi X,Li Y, Fan J, Zeng X,XianZ,et al.Blocking autophagy enhanced Stem Cells. 2014Sep;32(9):2309–23 quine eliminates cancer stem cells through deregulation of Jak2 andDNMT1. Choi DS,Blanco E,Kim Y-S, Rodriguez AA, Zhao H,Huang TH-M, et al.Chloro- isorhamnetin andchloroquine. J ExpClinCancer Res. 2019May 28;38(1):225. mitochondrial fissionandapoptosis intriple-negative breast cancer cells by and mitochondrial translocation of CaMKII contributes to Drp1-dependent Hu J, Zhang Y, Jiang X, Zhang H,Gao Z,Li Y, et al.ROS-mediated activation CancerTher. 2012 Apr;11(4):973–83. exerts superior efficacy againsttriple-negative humanbreast cancer cells. Mol Combination of pan-histone deacetylase inhibitor andautophagy inhibitor Rao R,Balusu R,Fiskus W, Mudunuru U, Venkannagari S,ChauhanL,et al. (MDA-MB-231) cells. Food Chem Toxicol. 2017May;103:1–17. anticancer properties of Antrodia salmoneaintriple-negative breast cancer Inhibition of ROS production, autophagy or apoptosis signaling reversed the Chang C-T, Korivi M,Huang H-C, Thiyagarajan V, LinK-Y, Huang P-J, et al. breast cancer. Oncol Lett. 2013Dec;6(6):1665–72 roquine hastumor-inhibitory andtumor-promoting effects intriple-negative Tuomela J, Sandholm J, Kauppila JH, Lehenkari P, Harris KW, Selander KS.Chlo Cancer. 201610;16:361 formation isprevented by chloroquine inapre-irradiated mousemodel.BMC al. Stimulation of triplenegative breast cancer cell migration andmetastases Bouchard G, Therriault H,Geha S,Bérubé-Lauzière Y, Bujold R,Saucier C,et Cancer Lett. 201601;376(2):249–58 cancer by inducingmitochondrial damage andimpairingDNA break repair. tophagy inhibitor chloroquine targets cancer stem cells intriplenegative breast Liang DH,ChoiDS,Ensor JE, Kaipparettu BA, Bass BL,Chang JC. The au- (continued) C/EBP-β LIP andnitricoxide levels - 21 -

Review ecancer 2020, 14:1071; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1071 Table S2.Preclinical references for repurposing of drugsfor TNBC by ReDO DB. Dipyridamole Digoxin Digitoxin Deferiprone Deferasirox Danazol Colchicine Clotrimazole Ciprofloxacin Cholecalciferol zine Chlorproma- ment Valve Replace - laxis Post-Cardiac bolism Prophy- Thromboem atrial fibrillation Heart failure, cardiogenic shock atrial flutter, PAT, atrial fibrillation, Congestive HF, thalassemia major Iron overload in iron overload toxication, chronic Acute iron in- tary angioedema disease, heredi- fibrocystic breast Endometriosis, Gout Fungal infections Antibiotic ciency Vitamin Ddefi- hiccups vomiting, anxiety, ders, nauseaand Psychotic disor - - Phosphodiesterase inhibitor ATPase inhibitor ATPase inhibitor Chelating agent Chelating agent tor agonist antagonist|progesterone recep- Estrogen receptor Microtubule inhibitor ligand inhibitor|imidazoline receptor Cytochrome P450 Bacterial DNA gyrase inhibitor Dopamine receptor antagonist – – – – – – – – –Beberok – – Metastasis. 2013 Jan;30(1):47–68Metastasis. et al.Dipyridamole prevents triple-negative breast-cancer progression. ClinExp Spano D, Marshall J-C, Marino N,De Martino D, Romano A, Scoppettuolo MN, Proc Natl Acad Sci USA. 2014Dec 16;111(50):E5429-5438 factors are required for chemotherapy resistance of breast cancer stem cells. Samanta D, Gilkes DM,Chaturvedi P, XiangL,Semenza GL.Hypoxia-inducible Jun;39(6):1010428317705331 receptor-positive andtriple-negative breast cancer cells. Tumour Biol. 2017 al. Anti-tumorigenic effects of anovel digitoxin derivative onboth estrogen Kulkarni YM, Yakisich JS, Azad N, Venkatadri R,Kaushik V, O’Doherty G,et peroxide. Food Chem Toxicol. 2018 Aug;118:154–67 by theiron-dependent generation of reactive oxygen speciesfrom hydrogen Myricetin-induced apoptosis of triple-negative breast cancer cells ismediated Knickle A, Fernando W, Greenshields AL, Rupasinghe HPV, Hoskin DW. breast cancers. J Pathol. 2018Sep;246(1):103–14 iron chelator deferasirox synergises with chemotherapy to treat triple-negative Tury S, Assayag F, Bonin F, Chateau-Joubert S,Servely J-L, Vacher S,et al. The cancer cells. ChemBiol Drug Des. 2017;89(6):953–63 to causePKC translocation, cell cycle dysregulation, andapoptosis inbreast Deka SJ, Roy A, Ramakrishnan V, Manna D, Trivedi V. Danazol haspotential 2017 31;7(1):10298. resistant cancer cells by inhibitingtubulinactivity Rep. andMRP1function.Sci Novel quinolonechalcones targeting colchicine-binding pocket killmultidrug- Lindamulage IK, Vu H-Y, Karthikeyan C,Knockleby J, Lee Y-F, Trivedi P, et al. 2016;11(4):e0154471. Mesenchymal Transition in Triple-Negative Breast Cancer Cells. PLoS ONE. sium ChannelsSuppresses Cell Proliferation, Migration andtheEpithelial- Zhang P, Yang X, Yin Q, Yi J, Shen W, Zhao L,et al.Inhibition of SK4Potas- 8 MB-231 cells via thep53/Bax/Bcl-2 signalingpathway. Int J Oncol. 2018Mar floxacin triggers theapoptosis of humantriple-negative breast cancer MDA- 802. of Triple-Negative Breast Cancer. AAPS PharmSciTech. 2018Feb;19(2):792– lecalciferol-PEG Conjugate Based Nanomicelles of Doxorubicin for Treatment Kutlehria S,Behl G,Patel K,Doddapaneni R, Vhora I,Chowdhury N,et al.Cho- Sep;37(9):1237–5 cell death intriple-negative humanbreast cancer. Acta Pharmacol Sin. 2016 of HJ-PI01asanovel Pim-2 inhibitor that induces apoptosis andautophagic Zhao Y-Q, Yin Y-Q, Liu J, Wang G-H,Huang J, Zhu L-J, et al.Characterization (continued) A, Wrześniok D, Rok J, Rzepka Z,Respondek M,Buszman E.Cipro- 22

Review ecancer 2020, 14:1071; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1071 Table S2.Preclinical references for repurposing of drugsfor TNBC by ReDO DB. Fingolimod Fenofibrate Fasudil Esomeprazole Dutasteride Doxycycline Disulfiram Multiple Sclerosis Hyperlipidemia Vasodilator Antacid hyperplasia Benign prostatic talmic infection urinary tract/oph- Respiratory/ ism Chronic alcohol- phosphate receptor agonist Immunosuppressant|sphingosine PPAR receptor agonist Rho associated kinaseinhibitor ATPase inhibitor 5 alphareductase inhibitor Metalloproteinase inhibitor inhibitor|TRPV agonist inhibitor|DNA methyltransferase Aldehyde dehydrogenase – – – – – – – – – – – – – esis. 2015 Jun 8;4:e156 ERα expression andenhances hormonaltherapy phorylated prodrug FTY720isahistone deacetylase inhibitor that reactivates Hait NC, Avni D, Yamada A, Nagahashi M, Aoyagi T, Aoki H,et al. The phos- Oct;165(3):531–43 and inhibitsmetastatic breast tumour growth. Breast Cancer Res Treat. 2017 docetaxel nanoparticletherapy overcomes FTY720-induced lymphopenia Alshaker H, Wang Q, Srivats S,Chao Y, Cooper C,Pchejetski D. New FTY720- 4;19(1):90. mal growth factor receptor kinaseblockade.Breast Cancer Res. 2017 Aug of basal-like breast cancer growth by FTY720incombination with epider Martin JL, Julovi SM,LinMZ,deSilva HC,Boyle FM,Baxter RC. Inhibition Cancer. 2014Feb 16;14:96. sis of Li T, Zhang Q, Zhang J, Yang G,Shao Z,Luo J, et al.Fenofibrate induces apopto- 20;7(1):13723. cell migration of MDA-MB 231humanbreast cancer cells. Sci Rep. 2017 inhibition with Fasudil induces beta-catenin nuclear translocation andinhibits Guerra FS, Oliveira RG de,Fraga CAM,MermelsteinFernandes CDS, PD. ROCK Pharm Pharm Sci. 2014;17(3):439–46 adjunct treatment for triple-negative breast cancers. An introductory study. J Goh W, Sleptsova-Freidrich I,Petrovic N.Use of proton pumpinhibitors as Endocrinol. 2015Feb;31(2):160–4. sensitive to chemotherapy anti-androgen drugdutasteride renders triplenegative breast cancer cells more von Wahlde M-K,Hülsewig C,Ruckert C,Götte M,KieselL,Bernemann C. The Jun;39(6):3041–7. aldehyde dehydrogenase‑positive breast cancer stem cells. Oncol Rep. 2018 Lin C-C,Lo M-C,Moody RR,Stevers NO, Tinsley SL,Sun D. Doxycycline targets 18;9(1):236. Delay Tumor Recurrence in Tumor Initiating Cell-Rich TNBC. Sci Rep. 2019 Jan BKM120 inCombination with Chemotherapy Impede Tumor Progression and Wu L,Meng F, Dong L,Block CJ, Mitchell AV, Wu J, et al.Disulfiram and 2013 Oct 1;109(7):1876–85. acquired paclitaxel-resistant triple-negative breast cancer cells. Br J Cancer. targets cancer stem-like cells andreverses resistance andcross-resistance in Liu P, Kumar IS,Brown S,Kannappan V, Tawari PE, Tang JZ, et al.Disulfiram Cycle. 2013Sep 15;12(18):3013–24. negative breast cancer cells: interaction with IQmotif-containing factors. Cell throughput screen identifies disulfiram asapotential therapeutic for triple- Robinson TJW, Pai M,Liu JC, Vizeacoumar F, Sun T, Egan SE,et al.High- cells. Biochem Biophys Res Commun. 2017May 13;486(4):1069–76. cancer stem-like properties and STAT3 signaling in triple-negative breast cancer Kim Y-J, Kim JY, Lee N,Oh E,Sung D, Cho T-M, et al.Disulfiram suppresses tion. Cancer Lett. 201701;386:151–60. suppresses lungcolonization intriple-negative breast cancer via calpainactiva- Kim JY, Lee N,Kim Y-J, Cho Y, An H,Oh E,et al.Disulfiram induces anoikisand triple-negative breast cancer (continued)

via inhibitionof cells via activation of HIF-1α-/VEGF-signaling. Gynecol for breast cancer. Oncogen- NF-κB pathway. BMC - 23

Review ecancer 2020, 14:1071; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1071 Table S2.Preclinical references for repurposing of drugsfor TNBC by ReDO DB. Leflunomide Ivermectin Indomethacin roquine Hydroxychlo- Hydralazine Ganciclovir Fluvastatin Fluoxetine Flubendazole Arthritis Parasitic infection Analgesia Malaria Hypertension Anti-viral Hyperlipidemia Depression Parasitic infection receptor inhibitor inhibitor|PDGFR tyrosine kinase Dihydroorotate dehydrogenase D Benzodiazepine receptor agonist Cyclooxygenase inhibitor Vasodilator DNA polymerase inhibitor HMGCR inhibitor inhibitor (SSRI) Selective serotonin reuptake Tubulin polymerisation inhibitor – – – – – – – – – – – – – 2014 Jul 9;14:498. 2014 Jul omeprazole inhibitsbreast cancer cell invasion andmetastasis. BMCCancer. Jin U-H,Lee S-O, Pfent C,Safe S. The arylhydrocarbon receptor ligand Cancer. Cancer Discov. 2017;7(4):391–9. Pyrimidine Synthesis Is aMetabolic Vulnerability in Triple-Negative Breast Brown KK,Spinelli JB, Asara JM, Toker A. Adaptive Reprogramming of De Novo gy in Triple-Negative BreastCancer. Mol Cancer Ther. 2015 Aug;14(8):1824–36 Inhibition of SIN3Corepressor with Avermectins as aNovel Therapeutic Strate- Kwon Y-J, Petrie K,Leibovitch BA, Zeng L,Mezei M,Howell L,et al.Selective 2017 05;114(49):13030–5. survival inestrogen receptor-negative breast cancer. Proc Natl Acad Sci USA. al. Coexpression of NOS2andCOX2 accelerates tumor growth andreduces Basudhar D, Glynn SA, Greer M,Somasundaram V, No JH, Scheiblin DA, et Cancer Res. 2014 Jun 15;20(12):3159–73 in anthracycline-sensitive and-resistant triple-negative breast cancer. Clin Autophagy inhibitionaugments theanticancer effects of epirubicintreatment Chittaranjan S,Bortnik S,Dragowska WH, Xu J, Abeysundara N,Leung A, et al. Dec;91(3):768–74 sis by zolidinedione andhydralazine suppresses proliferation andinduces apopto- Jiang Y, Huang Y, ChengC,Lu W, Zhang Y, Liu X,et al.Combination of thia- breast cancer therapy. Nanomedicine (Lond). 2018;13(9):1051–66 tic genes by PEGylated-PLGA/PIE nanoparticlesfor enhanced triplenegative Ultrasound-guided delivery of thymidine kinase-nitroreductase dualtherapeu Devulapally R,Lee T, Barghava-Shah A, Sekar TV, Foygel K,Bachawal SV, et al. xenografted inathymic mice. PLoS ONE.2014;9(5):e97151 the growth of humanMDA-MB-231 triplenegative breast cancer tumors plex nanoparticles via thebloodstream andGCV Treatment specifically inhibit D, Gompel A, Forgez P, et al.Suicide HSVtk gene delivery by neurotensin-poly Castillo-Rodríguez RA, Arango-Rodríguez ML,Escobedo L,Hernandez-Baltazar vention of triplenegative breast cancer. Breast Cancer Res. 201811;20(1):150. isomiR-140-3p-regulated mevalonic acidpathway asapotential target for pre - Bhardwaj A, Singh H, Trinidad CM, Albarracin CT, Hunt KK,Bedrosian I. The breast cancer. World J ClinOncol. 2015Dec 10;6(6):299–311 duces cytotoxic endoplasmicreticulum stress andautophagy intriplenegative Bowie M,Pilie P, Wulfkuhle J, Lem S,Hoffman A, Desai S,et al.Fluoxetine in- cancer. Cell Prolif. 2018 Apr;51(2):e12402. cell death via eEF2K-AMPK-mTOR-ULK complex axisintriplenegative breast Sun D, Zhu L,Zhao Y, Jiang Y, ChenL, Yu Y, et al.Fluoxetine induces autophagic in breast cancer. Mol Biosyst. 2015Nov;11(11):2860–6. discovery of apotential Atg4B agonist (Flubendazole) that induces autophagy Zhang L,Guo M,Li J, Zheng Y, Zhang S,Xie T, et al.Systems biology-based J Cancer. 201815;143(8):1978–93 anti-metastatic effects intriple-negative breast cancer via STAT3 inhibition.Int Oh E,Kim Y-J, An H,Sung D, Cho T-M, Farrand L,et al.Flubendazole elicits (continued) PPARγ up-expression inMDA-MB-231 cells. ExpMol Pathol. 2011 - 24 -

Review ecancer 2020, 14:1071; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1071 Table S2.Preclinical references for repurposing of drugsfor TNBC by ReDO DB. Melatonin Mebendazole Maraviroc Lovastatin Losartan Insomnia Parasitic infection Anti-retroviral Hyperlipidemia Hypertension oxide synthase inhibitor Melatonin receptor agonist|nitric Tubulin polymerisation inhibitor nist CC chemokinereceptor antago- HMGCR inhibitor Angiotensin receptor antagonist – – – – – – – – – – – – 30;9(1):966 actions of melatonin inabreast cancer xenograft model.Sci Rep. 2019 Jan O, Fukumasu H,et al.RNA-Seq transcriptome analysis shows anti-tumor Jardim-Perassi BV, Alexandre PA, Sonehara NM,dePaula-Junior R,Reis Júnior of breast cancer. PLoS ONE.2014;9(1):e85311 et al.Effect of melatonin ontumor growth andangiogenesis inxenograft model Jardim-Perassi BV, Arbab AS, Ferreira LC, Borin TF, Varma NRS,Iskander ASM, and Angiogenic Factors inBreast Cancer. Microrna. 2019;8(3):237–47 TF, et al. Therapeutic Potential of Melatonin intheRegulation of MiR-148a-3p Lacerda JZ, Ferreira LC, Lopes BC, Aristizábal-Pachón AF, Bajgelman MC,Borin – breast cancer cell invasiveness. Oncol Lett. 2017 Aug;14(2):2511–6 Kim T-H, ChoS-G.Melatonin-induced KiSS1 expression inhibits triple-negative Radiat Oncol Biol Phys. 2019 Jan 1;103(1):195–207 dazole Potentiates Radiation Therapy in Triple-Negative Breast Cancer. Int J Zhang L,Bochkur Dratver M, Yazal T, Dong K,Nguyen A, Yu G,et al.Meben- sis. Breast Cancer Res. 201814;20(1):54. for synergistic inhibitionof triple-negative breast cancer growth andmetasta in K,Pandey NB,Popel AS. Simultaneous blockadeof IL-6 andCCL5 signaling expression, cancer stemcells, and hypoxia.Syst BMC Biol. 2017 Jul11;11(1):68 negative breast cancer: theinterplay between chemokinereceptor CCR5 Norton K-A, Wallace T, Pandey NB,Popel AS. An agent-based modelof triple- pathway. J Cell Biochem. 2018Sep 6 naling pathways inbreast cancer stem-like cells via inhibitionof themevalonate statins antagonistically alter themajor epithelial-to-mesenchymal transition sig- Koohestanimobarhan S,Salami S,Imeni V, Mohammadi Z,Bayat O. Lipophilic breast cancer cells. Oncotarget. 2017Mar 14;8(11):17833–48 ysosome maturation stimulates LBH589-induced cell death intriple-negative Lin Z,Zhang Z, Jiang X,Kou X,Bao Y, LiuH,et al.Mevastatin blockadeof autol- ACS Appl Mater Interfaces. 2018Sep 5;10(35):29385–97. metastatic Efficacy of Cocktail Chemotherapy on Triple-negative Breast Cancer. into Camptothecin-Floxuridine Conjugate Nanocapsules for Enhancing Anti- Zhang N,LiangX,Gao C,ChenM,Zhou Y, Krueger CJ, et al.Loading Lovastatin 28;10(8):7022–30 To Improve Therapeutic Efficacy. ACS Appl Mater Interfaces. 2018Feb hybrids for Efficient Inhibition of Triple-Negative Breast Cancer Stem Cells Song L, Tao X,LinL,ChenC, Yao H,He G,et al.Cerasomal Lovastatin Nano - cancer. Biomaterials. 2017Nov;144:60–72 chemotherapy ininhibitinggrowth andlungmetastasis of triplenegative breast ated fibroblasts with losartan-loadedinjectablepeptide hydrogel to potentiate Hu C,LiuX,Ran W, Meng J, Zhai Y, Zhang P, et al.Regulating cancer associ- 1;208:131–8 by targeting miR-152-3p: In vivo andin vitro studies.Life Sci. 2018Sep al. Melatonin restrains angiogenic factors intriple-negative breast cancer Marques JHM, Mota AL, Oliveira JG, Lacerda JZ, Stefani JP, Ferreira LC, et (continued)

- 25

Review ecancer 2020, 14:1071; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1071 Table S2.Preclinical references for repurposing of drugsfor TNBC by ReDO DB. Metformin Diabetes Insulin sensitizer – – – – – – – – – – – – – – ing growth factor cancer cells involves oxidative stress generation, DNA damage, andtransform- Mechanism of metformin actioninMCF-7 andMDA-MB-231 humanbreast Marinello PC,daSilva TNX, Panis C,Neves AF, Machado KL,Borges FH,et al. ing both neoplasticandmicroenvironment cells. Sci Rep. 2016 Jan 5;6:18673. pirin andatenolol enhance metformin activity againstbreast cancer by target- Talarico G,Orecchioni S,Dallaglio K,Reggiani F, Mancuso P, Calleri A, et al. As- 2016;15(8):1046–59. mesenchymal stem-like/claudin-low triple negative breast cancer. Cell Cycle. attenuates transforming growth factor Wahdan-Alaswad R,Harrell JC, Fan Z,Edgerton SM,LiuB, Thor AD. Metformin sis indifferent breast cancer models.Oncotarget. 2017 Jan 10;8(2):2874–89. formin andpropranolol combination prevents cancer progression andmetasta Rico M,Baglioni M,Bondarenko M,Laluce NC,Rozados V, André N,et al.Met- 89. in Triple Negative Breast Cancer inaMurine Model. J Cancer. 2017;8(2):178– Zentella-Dehesa A, Cortés-González C,et al. Targeting Metabolic Remodeling García-Castillo V, López-Urrutia E, Villanueva-Sánchez O, Ávila-Rodríguez MÁ, expression. Breast Cancer Res Treat. 2017 Jun;163(3):435–47. tive breast cancer to proapoptotic TRAIL receptor agonists by suppressing XIAP Strekalova E,Malin D, Rajanala H,Cryns VL. Metformin sensitizes triple-nega tumors. Oncol Rep. 2017 Apr;37(4):2418–24. cells with pharmacologic dosesof 2-deoxy-D-glucose andmetformin: Starving Wokoun U, Hellriegel M,Emons G,Gründker C.Co-treatment of breast cancer Discov. 2017;3:17010. triple-negative breast cancer stem cells by targeting KLF5for degradation. Cell Shi P, Liu W, Tala null, Wang H,LiF, Zhang H,et al.Metformin suppresses cancer subtypes. Invest New Drugs. 2018;36(5):782–96. clinical effects of metformin andaspirinonthecell linesof different breast Amaral MEA,Nery LR,Leite CE,de Azevedo Junior WF, CamposMM.Pre- MB-231) breast cancer cells. Biomed Pharmacother. 2018 Jun;102:94–101. gen andprogesterone receptor-positive (MCF-7) andtriple-negative (MDA- Amaral I,Silva C,Correia-Branco A, Martel F. Effect of metformin onestro- 2018;4(1). Glucose Metabolism in Triple Negative Breast Cancer. J Oncol Transl Res. Wahdan-Alaswad RS,Edgerton SM,Salem HS, Thor AD. Metformin Targets vention of triplenegative breast cancer. Breast Cancer Res. 201811;20(1):150. isomiR-140-3p-regulated mevalonic acidpathway asapotential target for pre - Bhardwaj A, Singh H, Trinidad CM, Albarracin CT, Hunt KK,Bedrosian I. The Triple Negative Breast Cancer Cells. Biomolecules. 201908;9(1). Represses the Anti-Proliferative andPro-Apoptotic Effect of Metformin in Varghese S,Samuel SM, Varghese E,Kubatka P, Büsselberg D. High Glucose – in thepresence of iron chelators. Oncotarget. 2019May 28;10(37):3518–32 ergistic inhibitionof tumor cell proliferation by metformin andmito-metformin Cheng G,Zielonka J, Hardy M,Ouari O, Chitambar CR,DwinellMB,et al.Syn- ulation intriple-negative breast cancer. Am J Cancer Res. 2019;9(4):800–15 PARP inhibitors-induced epithelial-mesenchymal transition andPD-L1upreg- Han Y, LiC-W, Hsu J-M, Hsu JL, ChanL-C, Tan X,et al.Metformin reverses (continued) β1induction. Tumour beta (TGF-β) mediated oncogenesis in Biol. 2016 Apr;37(4):5337–46. - 26 -

Review ecancer 2020, 14:1071; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1071 Table S2.Preclinical references for repurposing of drugsfor TNBC by ReDO DB. Nimodipine Nicotinamide Niclosamide Nelfinavir Montelukast Minocycline Mifepristone Methimazole Hypertension moprevention Skin cancer che- Niacin Deficiency, Parasitic infection Anti-retroviral Allergies Antibiotic Abortifacient Hyperthyroidism Calcium channelblocker Protein synthesis stimulant inhibitor DNA replication inhibitor|STAT HIV protease inhibitor Leukotriene receptor antagonist inhibitor Bacterial 30Sribosomalsubunit tor antagonist antagonist|progesterone recep - Glucocorticoid receptor Antithyroid agent – – – – – – – – – – – – 2014 Jul 9;14:498. 2014 Jul omeprazole inhibitsbreast cancer cell invasion andmetastasis. BMCCancer. Jin U-H,Lee S-O, Pfent C,Safe S. The arylhydrocarbon receptor ligand triple negative breast cancer. Sci Rep. 201714;7(1):3466. modification induced by nicotinamide usingmulti-omicnetwork analyses in Kim JY, Lee H, Woo J, Yue W, KimK,ChoiS,et al.Reconstruction of pathway Ind Pharm. 2019Feb;45(2):304–13. inhibitor to improve itsactivity intriplenegative breast cancer cells. Drug Dev thineedi K.Formulation-optimisation of solidlipidnanocarrier system of STAT3 Pindiprolu SKSS,Chintamaneni PK,Krishnamurthy PT, Ratna Sree Ganapa- 2018;37(39):5292–304. in breast cancer andovercome of radioresistance with niclosamide.Oncogene. Bcl-2 andreduction of reactive oxygen species(ROS) promote radioresistance Lu L,Dong J, Wang L,XiaQ, Zhang D, KimH,et al. Activation of STAT3 and tant triple-negative breast cancer. Tumour Biol. 2016 Jul;37(7):9825–35. inhibits epithelial-mesenchymal transition andtumor growth incisplatin-resis - Liu J, ChenX, Ward T, Pegram M,Shen K.Combined niclosamide with cisplatin inhibition of triple-negative breast cancer cells to ionizingradiation inassociation with the Yin L,Gao Y, Zhang X, Wang J, Ding D, Zhang Y, et al.Niclosamide sensitizes with autophagy inhibitors. Cancer Lett. 2012Dec 1;325(1):63–71. pharmacological aggravators of endoplasmicreticulum stress are combined erential killingof triple-negative breast cancer cells in vitro andin vivo when Thomas S,Sharma N,Golden EB,ChoH, Agarwal P, Gaffney KJ, et al.Pref 27;19(3):833–7. ity in Triple Negative Breast Cancer Cells. Asian Pac J Cancer Prev. 2018Mar Vivithanaporn P. Leukotriene Receptor Antagonists Inhibit Mitogenic Activ Suknuntha K, Yubolphan R,Krueaprasertkul K,Srihirun S,Sibmooh N, col Pathol. 2016Oct;68(9):505–15. chemotherapy inaxenograft modelof triple-negative breast cancer. Exp Toxi- putative neuroprotectant, co-administered with doxorubicin-cyclophosphamide HimmelLustbergLE, DeVries MB, AC, PoiKulpChen C-S, M, Minocycline,SK. a Clin Cancer Res. 2013Nov 15;19(22):6163–72. ticoid receptor antagonism asanovel therapy for triple-negative breast cancer. Skor MN, Wonder EL,Kocherginsky M,Goyal A, Hall BA, Cai Y, et al.Glucocor Expression.2016;6(4):533–44. Theranostics. Basal Triple-Negative Breast Cancer Stem Cells by Down-regulating KLF5 Liu R,Shi P, Nie Z,LiangH,Zhou Z,Chen W, et al.Mifepristone Suppresses 15;803:130–7. expression by triplenegative breast cancer cells. Eur J Pharmacol. 2017May Phenylmethimazole andathiazole derivative of phenylmethimazole inhibitIL-6 Noori MS,O’Brien JD, ChampaZJ, Deosarkar SP, Lanier OL,Qi C,et al. (continued)

Wnt/β-catenin signaling.Oncotarget. 2016 Jul 5;7(27):42126–38. - - 27 -

Review ecancer 2020, 14:1071; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1071 Table S2.Preclinical references for repurposing of drugsfor TNBC by ReDO DB. Pentamidine Penfluridol Orlistat Omeprazole Omega 3 Noscapine Parasitic infection ders Psychotic disor Obesity Antacid Hyperlipidemia Anti-tussive - Anti-pneumocystis agent T-type calciumchannelblocker Lipase inhibitor ATPase inhibitor tion inhibitor antagonist|tubulin polymerisa Bradykinin receptor - – – – – – – – – – Res. 2016;185(5):549–62 ticle Radiosensitization by Pentamidine in Triple Negative Breast Cancer. Radiat Her S,Cui L,Bristow RG, Allen C.Dual Action Enhancement of Gold Nanopar ing Integrin Signaling Axis. Cancer Res. 2016Feb 15;76(4):877–90. presses Metastatic Tumor Growth in Triple-Negative Breast Cancer by Inhibit- Ranjan A, Gupta P, Srivastava SK.Penfluridol: An Antipsychotic Agent Sup breast cancer therapy. Nanomedicine (Lond). 2016Feb;11(3):235–47. antisense-miRNA-loaded PLGA-PEG nanoparticlesfor enhanced triplenegative Bhargava-Shah A, Foygel K,Devulapally R,Paulmurugan R.Orlistat and Cancer Ther. 2016Feb;15(2):221–31 of Orlistat asaRepurposed Drug against Triple-Negative Breast Cancer. Mol et al.Folate Receptor-Targeted Polymeric Micellar Nanocarriers for Delivery Paulmurugan R,Bhethanabotla R,Mishra K,Devulapally R,Foygel K,Sekar TV, 9;14:498. 2014 Jul omeprazole inhibitsbreast cancer cell invasion andmetastasis. BMCCancer. Jin U-H,Lee S-O, Pfent C,Safe S. The arylhydrocarbon receptor ligand – triple-negative breast cancer cells. Sci Rep. 201831;8(1):1952. JAF, et al.Omega-3 docosahexaenoic acidinduces pyroptosis cell death in Pizato N,Luzete BC,Kiffer LFMV, Corrêa LH,deOliveira Santos I, Assumpção cancer. Sci Rep. 2017Nov 20;7(1):15824. by noscapinechemo-sensitization indocetaxel resistant triplenegative breast Doddapaneni R,Patel K,Chowdhury N,Singh M.Reversal of drug-resistance 2011 Mar 15;6(3):e17733. in combination with Doxorubicin intriplenegative breast cancer. PLoS ONE. Chougule MB,Patel AR, Jackson T, Singh M. Antitumor activity of Noscapine negative breast cancer. ExpCell Res. 201601;346(1):65–73. tion enhances docetaxel anticancer activity andnanocarrier uptake intriple Doddapaneni R,Patel K,Chowdhury N,Singh M.Noscapine chemosensitiza – cholesterol efflux. Oncogene. 2019;38(12):2135–50. preclinical modelsof triple-negative breast cancer by disrupting cellular pentaenoic acidincombination with EPHA2inhibitionshows efficacy in Torres-Adorno AM, Vitrac H,Qi Y, Tan L,Levental KR,Fan Y-Y, et al.Eicosa- – ness. Nutrients. 2019May 28;11(6). esis andLipophagy inBreast Cancer Cells: theImpact inCancer Aggressive- et al.Omega 3-DHA andDelta-Tocotrienol Modulate Lipid Droplet Biogen- Pizato N,Kiffer LFMV, Luzete BC, Assumpção JAF, Correa LH,Melo HABde, – Dev Biol Anim. 2015Feb;51(2):121–7 proliferation intriplenegative over luminalbreast cancer cells. In Vitro Cell al. Oxidized derivative of docosahexaenoic acidpreferentially inhibitcell Pogash TJ, El-Bayoumy K, Amin S,Gowda K,deCicco RL,Barton M,et (continued) 2015;46(6):2649–55. breast cancer cells through upregulation of cytokeratin-1. Int J Oncol. Chénais B.Docosahexaenoic acidinhibitstheinvasion of MDA-MB-231 Blanckaert V, Kerviel V, Lépinay A, Joubert-Durigneux V, Hondermarck H,

- - - 28

Review ecancer 2020, 14:1071; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1071 Table S2.Preclinical references for repurposing of drugsfor TNBC by ReDO DB. Riluzole amine Pyrimeth- Propranolol Pirfenidone Pentoxifylline ALS Parasitic infection Hypertension Anti-fibrotic disease Peripheral artery Glutamate inhibitor tor Dihydrofolate reductase inhibi Adrenergic receptor antagonist TGF beta receptor inhibitor Phosphodiesterase inhibitor - – – – – –Xie – – – –Qi X, – – – 19. triple-negative breast cancer. Breast Cancer Res Treat. 2017 Nov;166(2):407– Riluzole synergizes with paclitaxel to inhibitcell growth andinduce apoptosis in Speyer CL,Bukhsh MA, Jafry WS, Sexton RE,Bandyopadhyay S,Gorski DH. 2016;157(2):217–28. pendent of metabotropic glutamate receptor-1. Breast Cancer Res Treat. et al.Riluzole mediates anti-tumor properties inbreast cancer cells inde- Speyer CL,Nassar MA,Hachem AH, Bukhsh MA, Jafry WS, KhansaRM, cancer. Breast Cancer Res Treat. 2012 Apr;132(2):565–73. glutamate receptor-1: apotential therapeutic target for thetreatment of breast Speyer CL,Smith JS, Banda M,DeVries JA, Mekani T, Gorski DH.Metabotropic 2018;20(5):489–98. TNFRSF1A Egusquiaguirre SP, Yeh JE, Walker SR,LiuS,Frank DA. The STAT3 Target Gene Oncol Rep. 2019 Jan;41(1):341–50. and thedrugresponse isaffected by ADRB2 single‑nucleotide polymorphisms. viability of breast cancer cells by regulating theERK/COX 2011 Oct;2(10):797–809. of chemotherapy agents: implication inbreast cancer treatment. Oncotarget. Propranolol potentiates theanti-angiogenic effects andanti-tumor efficacy Pasquier E,Ciccolini J, Carre M,Giacometti S,Fanciullino R,Pouchy C,et al. Jun;35(6):3135–42. tases: of Choy C,Raytis JL, Smith DD, Duenas M,Neman J, Jandial R,et al.Inhibition sis indifferent breast cancer models.Oncotarget. 2017 Jan 10;8(2):2874–89. formin andpropranolol combination prevents cancer progression andmetasta Rico M,Baglioni M,Bondarenko M,Laluce NC,Rozados V, André N,et al.Met- Cell Expansion.Stem Cells. 2015Sep;33(9):2738–47. Target for Triple-Negative Breast Cancer by Stimulation of Cancer Stem-Like 13;7(50):82889–901 blasts asatreatment intriple-negative breast cancer. Oncotarget. 2016Dec Takai K,Le A, Weaver VM, Werb Z. Targeting thecancer-associated fibro- 4;9(34):23462–81. multiple modelsystems andisnot apreventive target. Oncotarget. 2018May Limited fibrosis accompanies triple-negative breast cancer metastasis in Brooks D, Zimmer A, Wakefield L,Lyle LT, Difilippantonio S, Tucci FC, et al. 2018 Apr;52(4):1246–54 apoptosis of triple-negative MDA-MB-231 breast cancer cells. Int J Oncol. B, et al.Synergistic promoting effects of pentoxifylline andsimvastatin onthe Castellanos-Esparza YC, Wu S,Huang L,Buquet C,Shen R,Sanchez-Gonzalez β2-adrenergic receptor W-Y, He R-H,Zhang (continued) Yin N,Ma S,Lepp The potential benefit of Modulates theNF-κB Pathway A, J, He reduces triple-negative breast cancer Tang perioperative β-blockade.Oncol Rep. 2016 Y-J, J, Jing Wan Z,Zhou C-F, et al.β‑blockers inhibitthe W, et al.p38γMAPKIs a inBreast Cancer ‑2 signalingpathway Cells. Neoplasia. brain metas- Therapeutic 29 -

Review ecancer 2020, 14:1071; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1071 Table S2.Preclinical references for repurposing of drugsfor TNBC by ReDO DB. bonate Sodium Bicar Simvastatin - griping pains Relief of wind and Hyperlipidemia HMGCR inhibitor – – – – – – postmastectomy radiation. Stem Cells Transl Med. 2014 Jul;3(7):849-56. improved localcontrol ininflammatory breast cancer patients treated with differentiated andstem-like breast cancer cell linesandisassociated with sensitizes W, Hortobágyi GN,Buchholz TA, Ueno NT, Woodward WA. Simvastatin radio- – – – – regulation of FOXO3a. Breast Cancer Res Treat. 2015Dec;154(3):495-508 triple-negative breast cancer metastasis inpre-clinical modelsthrough vents Hittelman W, Diehl M,Levental I,Ueno NT, Woodward WA. Simvastatin pre- Finetti P, Birnbaum D, Van Laere S,Diagaradjan P, Ruffell B, Trenton NJ, ChuK, – – cellular uptake of doxorubicin. J Control Release. 2019Feb 28;296:1–13. Sodium bicarbonate nanoparticles modulate thetumor pH andenhance the Abumanhal-Masarweh H,Koren L,Zinger A, Yaari Z,Krinsky N,Kaneti G,et al. pathway. J Cell Biochem. 2018Sep 6; naling pathways inbreast cancer stem-like cells via inhibitionof themevalonate statins antagonistically alter themajor epithelial-to-mesenchymal transition sig- Koohestanimobarhan S,Salami S,Imeni V, Mohammadi Z,Bayat O. Lipophilic 2013 Sep 20;439(2):275–9. breast cancer (TNBC)cells via PI3Kpathway. Biochem Biophys Res Commun. Park YH, Jung HH, Ahn JS, Im Y-H. Statin induces inhibitionof triplenegative dant defence mechanisms.FEBS J. 2014 Aug;281(16):3719–38. involves attenuation of iron transport: intermediacy of nitricoxide andantioxi- R, et al.Statin-induced inhibitionof breast cancer proliferation andinvasion Kanugula AK, Gollavilli PN, Vasamsetti SB,Karnewar S,Gopoju R,Ummanni cin. Oncogene. 2018;37(36):4979–93. signaling regulates thebreast tumor cell response to simvastatin anddoxorubi- Abdoul-AzizeBuquet S, PicquenotH, C, Li J-M, Vannier J-P. Integrationof Ca2+ 2018 Apr;52(4):1246–54. apoptosis of triple-negative MDA-MB-231 breast cancer cells. Int J Oncol. B, et al.Synergistic promoting effects of pentoxifylline and simvastatin onthe Castellanos-Esparza YC, Wu S,Huang L,Buquet C,Shen R,Sanchez-Gonzalez Lacerda L,Reddy JP, LiuD, Larson R,LiL,Masuda H,Brewer T, Debeb BG,Xu 2018;12(4):423–40. negative breast cancer inboth mesenchymal andepithelialstates. Mol Oncol. of Wnt and Yes-associated protein signalingretards thegrowth of triple- Sulaiman A, McGarry S,LiL, Jia D, Ooi S, Addison C,et al.Dual inhibition Sci Rep. 201608;6:33035 expressing triple-negative breast cancer cells by restoring DUSP4deficiency. Jung HH,Lee S-H,Kim J-Y, Ahn JS, Park YH, Im Y-H. Statins affect ETS1-over Sci. 2018Oct;109(10):3272–84. heat shockprotein 90inhibitor againsttriple-negative breast cancer. Cancer Kou X, Jiang X,LiuH, Wang X,Sun F, Han J, et al.Simvastatin functionsasa Wolfe AR, Debeb BG,Lacerda L,Larson R,Bambhroliya A, Huang X,Bertucci F, Rab7 prenylation. Eur J Pharmacol. 2017Oct 15;813:161–71. have synergistic effects ontriple-negative breast cancer cells via abrogating Kou X, Yang Y, Jiang X,LiuH,Sun F, Wang X,et al. Vorinostat andSimvastatin (continued) - 30

Review ecancer 2020, 14:1071; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1071 Table S2.Preclinical references for repurposing of drugsfor TNBC by ReDO DB. Trifluoperazine Tocilizumab Tigecycline Thioridazine Sulfasalazine ders Psychotic disor arthritis Rheumatoid Infections ders Psychotic disor Crohn's Disease. colitis; active thritis; ulcerative Rheumatoid ar - - - Dopamine receptor antagonist inhibitor Bacterial 30Sribosomalsubunit Dopamine receptor antagonist Cyclooxygenase inhibitor – – – – – – – – – – Oncotarget. 2016 Jul 5;7(27):42110–25. tion of FOXO3 suppresses triple-negative breast cancer in vitro andin vivo. Park S-H,Chung YM, Ma J, Yang Q, Berek JS, Hu MC-T. Pharmacological activa- negative breast cancer cells. J Cell Biochem. 2018;119(7):6216–30. tagonist enhances DR5-mediated apoptotic signalingin TRA-8 resistant triple Fancy RM,KimH,Napier T, Buchsbaum DJ, Zinn KR,Song Y. Calmodulinan 2018 Sep 26;9(10):1006. and brain metastasis by inducingG0/G1 arrest andapoptosis. Cell Death Dis. perazine hydrochloride suppresses triple-negative breast cancer tumor growth Feng Z,Xia Y, Gao T, Xu F, Lei Q, Peng C,et al. The antipsychotic agent trifluo breast cancer. Oncotarget. 2019Mar 12;10(21):2055–67. for aclassof antipsychotics to reduce growth andmetastasis of triple-negative B, et al. AXL knockdown gene signature reveals adrugrepurposing opportunity Goyette M-A,Cusseddu R,Elkholi I, Abu-Thuraia A, El-Hachem N,Haibe-Kains 2019 18;18(1):42. and M2macrophage polarization intriple-negative breast cancer. Mol Cancer. miR-34a/IL-6/IL-6R signalingaxispromotes EMT progression, cancer stemness Weng Y-S, Tseng H-Y, Chen Y-A, Shen P-C, Al Haq AT, ChenL-M, et al.MCT-1/ sis. Breast Cancer Res. 201814;20(1):54. for synergistic inhibitionof triple-negative breast cancer growth andmetasta Jin K,Pandey NB,Popel AS. Simultaneous blockadeof IL-6 andCCL5 signaling Invest. 201603;126(10):3739–57 in triple-negative breast cancer induces mitochondrial protein translation. J Clin Jones RA,Robinson TJ, Liu JC, Shrestha M, Voisin V, Ju Y, et al.RB1deficiency breast cancer. Oncotarget. 2019Mar 12;10(21):2055–67 for aclassof antipsychotics to reduce growth andmetastasis of triple-negative B, et al. AXL knockdown gene signature reveals adrugrepurposing opportunity Goyette M-A,Cusseddu R,Elkholi I, Abu-Thuraia A, El-Hachem N,Haibe-Kains independent of DRD2. J Biol Chem.201812;293(41):15977–90. cancer cells via DRD2-dependent STAT3 inhibition,butinduces aG1arrest Tegowski M,Fan C,Baldwin AS. Thioridazine inhibitsself-renewal inbreast – 15;7(11):11756–69. oncoprotein intriple-negative breast cancer cells. Oncotarget. 2016Mar tional interactions of thecystine/glutamate antiporter, CD44v andMUC1-C Hasegawa M, Takahashi H,Rajabi H, Alam M,Suzuki Y, Yin L,et al.Func 14;24(4):450–65 triple-negative breast tumor therapeutic target. Cancer Cell. 2013Oct Glutamine sensitivity analysis identifies thexCT antiporter asacommon Timmerman LA,Holton T, Yuneva M,Louie RJ, Padró M,Daemen A, et al. (continued) - - - - 31

Review ecancer 2020, 14:1071; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1071 Table S2.Preclinical references for repurposing of drugsfor TNBC by ReDO DB. Warfarin Verteporfin Verapamil Valproic acid lism. pulmonary embo- thrombosis and oflism, venous systemic embo Prophylaxis of degeneration related macular Exudative age- angina pectoris Hypertension, Epilepsy - Vitamin Kantagonist Photosensitising agent Calcium channelblocker HDAC inhibitor – – – – – – – – – – triple negative breast cancer cells. Oncotarget. 2019Mar 19;10(23):2292–305 Beaudin S,Kokabee L, Welsh J. Divergent effects of vitamins K1andK2on 17;8(58):98495–508 the DNA damage response andcell survival pathways. Oncotarget. 2017Nov YAP1 inhibitionradiosensitizes triplenegative breast cancer cells by targeting Andrade D, Mehta M,Griffith J, Panneerselvam J, Srivastava A, Kim T-D, et al. 13;19(8):3361–70 glycol) Triblock Micelles for Cancer Therapy. Biomacromolecules. 2018 Verteporfin-Loaded Poly(ethylene glycol)-Poly(beta-amino ester)-Poly(ethylene Kim J, Shamul JG, Shah SR,Shin A, Lee BJ, Quinones-Hinojosa A, et al. sistance. Cancer Sci. 2019Feb;110(2):561–7. associated protein 1intriple-negative breast cancer with taxol-based chemore- Li Y, Wang S, Wei X,Zhang S,Song Z,ChenX,et al.Role of inhibitor of yes- 2017;118(5):1239–48 tizes Human Breast Cancer Cells to Proteasome Inhibitors. J Cell Biochem. Deshmukh RR,KimS,Elghoul Y, Dou QP. P-Glycoprotein Inhibition Sensi- Oct;14(10):2321–31 Dictate Synthetic Lethality with PARP1 Inhibition. Mol Cancer Ther. 2015 sion of Key DNA Damage Repair Genes after Epigenetic-Induced BRCAness Wiegmans AP, Yap P-Y, Ward A, Lim YC, KhannaKK.Differences inExpres- phosphate pathway metabolism. Oncotarget. 2016May 10;7(19):28329–39 Histone deacetylase inhibitor-induced cancer stem cells exhibit highpentose Debeb BG,Lacerda L,Larson R, Wolfe AR, Krishnamurthy S,Reuben JM, et al. Enzyme Inhib Med Chem.2016;31(sup3):140–9 anti-proliferative activity inHeLa, rhabdomyosarcoma and breast cancer cells. J pentanamide, a valproic acidaryl derivative designedinsilico with improved García-Sánchez JR, Pérez-González OA, et al.N-(2-hydroxyphenyl)-2-propyl- Prestegui-Martel B,Bermúdez-Lugo JA, Chávez-Blanco A, Dueñas-González A, deacetylase inhibitors. J Cell Biochem. 2018;119(4):3417–28 the anticancer properties of anovel valproic acidprodrug to leadinghistone Tarasenko N,Chekroun-Setti H,Nudelman A, Rephaeli A. Comparison of Jul 26;9(8):815. negative breast cancer andsuppresses cancer stem cells. Cell Death Dis. 2018 Co-inhibition of Sulaiman A, McGarry S,LamKM,El-Sahli S,Chambers J, Kaczmarek S,et al. (continued) mTORC1, HDAC andESR1αretards thegrowth of triple- 32

Review ecancer 2020, 14:1071; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1071 Table S2.Preclinical references for repurposing of drugsfor TNBC by ReDO DB. acid Zoledronic metastases pain from bone malignancy, treat hypercalcemia of tures andtreat skeletal frac prophylaxis of Osteoporosis, - Bone resorption inhibitor – – – – – – – through Endoplasmic Reticulum Stress. Nutr Cancer. 2016 Jun;68(4):679–88. Molecular Iodine CauseSynergistic Cell Death in Triple Negative Breast Cancer Tripathi R,Singh P, Singh A, Chagtoo M,KhanS, Tiwari S,et al.Zoledronate and 2017;12(9):e0185566 of Zoledronic acidinhormonesensitive breast cancer cells in vitro. PLoS ONE. Gamper J, et al.Estradiol impairs theantiproliferative andproapoptotic effect Gschwantler-Kaulich D, Weingartshofer S,Grunt TW, Mairhofer M, Tan Y, zoledronic acid.Cancer Cell Int. 2012Nov 22;12(1):48. breast cancer cell proliferation inrepeated andnon-repeated treatment with Ibrahim T, Mercatali L,Sacanna E, Tesei A, CarloniS,Ulivi P, et al.Inhibition of breast cancer cell lines.Int J Oncol. 2013 Apr;42(4):1263–70 in combination with zoledronic acid:a synergistic effect intriple-negative Ibrahim T, Liverani C,Mercatali L,Sacanna E,Zanoni M,Fabbri F, et al.Cisplatin cells through inactivation of epithelial-mesenchymal transition andinhibitsself-renewal of breast cancer Schech AJ, Kazi AA, Gilani RA,Brodie AH. Zoledronic acidreverses the 2017 Oct 13;8(48):84248–57 tumor-associated macrophages intriplenegative breast cancer. Oncotarget. tumor effects of metronomic useof novel liposomalzoledronic aciddepletes Cai X-J, Wang Z,Cao J-W, Ni J-J, Xu Y-Y, Yao J, et al. Anti-angiogenic andanti- 2019 Feb 26;19(1):176. interaction between breast cancer cells andregulatory T-cells. BMCCancer. Liu H, Wang S-H,ChenS-C,C-Y, Lin T-M. Zoledronic acidblocksthe (continued) NF-κB. Mol Cancer

Ther. 2013 Jul;12(7):1356–66 33

Review