Overcoming Drug Resistance in Advanced Prostate Cancer by Drug Repurposing
Abstract
:1. Introduction
1.1. Prostate Cancer
1.2. Therapy Resistance in Prostate Cancer
1.3. Molecular Landscape in Prostate Cancer
2. Repurposing Approved Drugs in Cancer
2.1. Introduction to Drug Repurposing
2.2. A Computational Approach for Drug Repurposing
2.2.1. Network-Based Drug Repurposing
2.2.2. Profile-Based Drug Repurposing
2.2.3. Data-Based Drug Repurposing
2.3. Drug Repurposing Approach in Cancer
3. Drug Repurposing in Prostate Cancer
3.1. Clinical Challenges in Prostate Cancer
3.2. Drugs Repurposed in Prostate Cancer: From Benchside to Bedside
Ref. | Drug | Original Indication | PCa Cell Lines Targeted | In Vivo Studies | Mode(s) of Action | Effect(s) |
---|---|---|---|---|---|---|
[137] | Propranolol | Anti-hypertensive | - | - |
|
|
[138] | Digoxin | Anti-arrhythmic |
| |||
[138,139] | Ouabain | Anti-arrhythmic | PPC-1 | Male SCID |
| |
[140] | Aspirin | Anti-inflammatory | LNCaP |
|
| |
[141] | Celecoxib | Anti-inflammatory | LNCaP & androgen-nonresponsive PC-3 | LNCaP in bovine brain extracts |
|
|
[142] | dexamethasone | Anti-inflammatory | DU145 PCa cells |
|
| |
[143,144,145] | Simvastatin | Anti-hyperlipidimic | PC3, 22Rv1, DU145, DU145R80, LNCaP prostate cancer cell lines and EPN normal prostate epithelial cells | DU145R80, 22Rv1 parental and docetaxel resistant cells in xenografts |
|
|
[146,147,148] | Metformin | Anti-diabetic |
|
| ||
[149] | Glipizide | Anti-diabetic | PC-3, 22Rv1 and DU145 PC | TRAMP transgenic mouse model |
|
|
[150] | Mebendazole | Anti-helminthic | LNCaP |
|
| |
[151] | Niclosamide | Anti-helminthic | LNCaP, VCaP, CWR22Rv1, PC3 and HEK293 | CWR22Rv1 cells in SCID mice |
|
|
[152,153] | Nelfinavir | Anti-retroviral | DU145 and PC3 cell lines |
|
| |
[154] | CMT-3 | Anti-microbial | Many lines | xenografts of PC-3 tumors |
|
|
[155] | Zoledronic acid | Bisphosphonate | LuCaP 23.1, a PSA-producing human CaP xenograft | LuCaP 23.1, a PSA-producing human CaP xenograft |
|
|
[156] | Valproic acid | Anti-epileptic | AR-positive (LNCaP and C4-2) and AR-negative (DU145 and PC3) | LNCaP, C4-2, and DU145 Xenograft models |
|
|
[157] | Mifepristone | Anti-progestational steroid |
|
|
3.2.1. Anti-Hypertensives and Anti-Arrhythmic Drugs
3.2.2. NSAIDS, Anti-Inflammatory Drugs and Aspirin
3.2.3. Anti-Hyperlipidemic Drugs
3.2.4. Anti-Diabetic Drugs
3.2.5. Anti-Helminthic Drugs
3.2.6. Anti-Retroviral Drugs
3.2.7. Anti-Microbial Drugs
3.2.8. Anti-Malarial Drugs
3.2.9. Others
4. Clinical Trials of Drugs Repurposed in PCa
5. Conclusions and Future Directions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Drug Category | Clinical Trial Title | Number ClinicalTrials.gov ID | Phase | Study Start Date | Estimated Enrollment | Status | Intervention |
---|---|---|---|---|---|---|---|
Anti-diabetic | Metformin Hydrochloride as First-Line Therapy in Treating Patients with Locally Advanced or Metastatic PCa | NCT01243385 | II | 1 December 2010 | 44 | Completed | Metformin |
Anti-diabetic | Castration Compared to Castration Plus Metformin as First Line Treatment for Patients with Advanced PCa | NCT01620593 | II | 1 April 2011 | 41 | Completed | Metformin |
Anti-diabetic | Prevention of Metabolic Syndrome and Increased Weight Using Metformin Concurrent to ADT and Radiotherapy for Locally Advanced PCa | NCT01996696 | II | 1 September 2014 | 104 | Recruiting | Metformin |
Anti-diabetic | Repurposing Metformin as Anticancer Drug in Advanced PCa (Mansmed) | NCT03137186 | II | 1 January 2017 | 120 | Unknown | Metformin |
Anti-diabetic | Study of Metformin Plus Oligomeric Procyanidin Complex for Pharmacologic Manipulation of AGE Levels in PCa Patients | NCT03465345 | Ib | 1 July 2018 | 0 | Withdrawn | Metformin + oligomeric procyanidin complex |
Anti-diabetic | Drug-Drug Interaction of SHR3680 with Digoxin, Rosuvastatin Calcium and Metformin Hydrochloride | NCT04621669 | I | 1 November 2020 | 18 | Not yet recruiting | Metformin hydrochloride + SHR3680 + digoxin + rosuvastatin |
Anti-hyperlipidemic | Impact of Adjuvant Statin Therapy in Patients who Underwent Radical Prostatectomy for Locally Advanced PCa | NCT01759836 | II | 1 October 2012 | 354 | Unknown | Atorvastatin vs. placebo |
Anti-parasitic | Low, Intermediate, or High Dose Suramin in Treating Patients with Hormone-Refractory PCa | NCT00002723 | III | 1 January 1996 | 390 | Completed | Suramin |
Anti-parasitic | Combination Chemotherapy with Suramin Plus Doxorubicin in Treating Patients with Advanced Solid Tumors | NCT00003038 | I | 1 October 1997 | 20 | Completed | Doxorubicin + suramin |
Anti-parasitic | Akt Inhibitor MK2206 and Hydroxychloroquine in Treating Patients with Advanced Solid Tumors, Melanoma, Prostate or Kidney Cancer | NCT01480154 | I | 1 November 2011 | 62 | Active, not recruiting | Hydroxycloroquine + Akt inhibitor MK2206 |
Anti-helminthic | Enzalutamide and Niclosamide in Treating Patients with Recurrent or Metastatic CRPC | NCT03123978 | I | 1 January 2017 | 12 | Recruiting | Enzalutamide + niclosamide |
Anti-helminthic | Niclosamide and Enzalutamide in Treating Patients With CRPC | NCT02532114 | I | 1 December 2015 | 5 | Completed | Niclosamide + enzalutamide |
Anti-fungal | Hormonal Therapy and Chemotherapy Followed by Prostatectomy in Patients with PCa | NCT02494713 | II | 1 October 2015 | 4 | Terminated | Degarelix + Doxorubicin + Ketoconazole + Docetaxel + Estramusine |
Anti-fungal | Hormone Therapy Plus Chemotherapy as Initial Treatment for Local Failures or Advanced PCa | NCT02560051 | II | 1 November 2015 | 19 | Terminated | Doxorubicin + ketoconazole + docetaxel + estramustine |
Antiviral | A Study of Aplidin (Plitidepsin) in Subjects with Advanced PCa | NCT00780975 | II | 1 February 2005 | 8 | Terminated | Plitidepsin |
NSAID | Dexamethasone, Aspirin, and Diethylstilbestrol in Treating Patients with Locally Advanced or Metastatic PCa | NCT00316927 | III | 1 December 2002 | 260 | Completed | Dexamethasone + aspirin vs. dexamethasone + diethylstilbestrol + aspirin |
Steroid | Combination of Docetaxel + Estramustine + Hydrocortisone Versus Docetaxel + Prednisone in Patients with Advanced PCa (PROSTATA) | NCT00705822 | III | 1 August 2006 | 54 | Terminated | Docetaxel + prednisone vs. docetaxel + estramusine + hydrocortisone |
Steroid | Docetaxel, Prednisone, and Vatalanib in Treating Patients with Advanced PCa | NCT00293371 | I/II | 1 September 2006 | 6 | Terminated | Docetaxel + prednisone + vatalanib |
Steroid | A Safety and Efficacy Study of Abiraterone Acetate in Participants with Advanced PCa who Failed ADT and Docetaxel-Based Chemotherapy | NCT00474383 | II | 1 November 2006 | 47 | Completed | Abiraterone acetate + glucocorticoid |
Steroid | An Open-Label Study of YM155 + Docetaxel in Subjects with Advanced Hormone Refractory PCa and Other Solid Tumors | NCT00514267 | I/II | 1 May 2007 | 32 | Completed | YM 155 + docetaxel + prednisone vs. YM 155 + docetaxel |
Steroid | An Efficacy and Safety Study of Abiraterone Acetate and Prednisone in Participants with PCa Who Failed ADT and Docetaxel-Based Chemotherapy | NCT00485303 | II | 1 June 2007 | 58 | Completed | Abiraterone acetate + prednisone |
Steroid | AMG 386 and Abiraterone for Advanced PCa | NCT01553188 | II | 1 February 2012 | 36 | Completed | Abiraterone + prednisone vs. abiraterone + prednisone + AMG |
Steroid | Cabozantinib Plus Docetaxel and Prednisone for Advanced PCa | NCT01683994 | I | 1 September 2012 | 49 | Completed | Carbozantinib + docetaxel + prednisone |
Steroid | Reducing Dexamethasone Around Docetaxel Infusion (REDEX) | NCT02776436 | I | 1 January 2016 | 46 | Active, not recruiting | Dexamethasone |
Steroid | Cognitive Effects of AR Directed Therapies for Advanced PCa | NCT03016741 | IV | 1 March 2017 | 100 | Recruiting | GnRH agonist/antagonist + prednisone + abiraterone acetate vs. GnRH agonist/antagonist + enzalutamide |
Steroid | Intermittent ADT for Stage IV Castration Sensitive PCa | NCT03511196 | 1b | 1 September 2018 | 17 | Active, not recruiting | ADT + abiraterone + prednisone |
Steroid | A Study of Nivolumab or Placebo in Combination with Docetaxel in Men with Advanced CRPC (CheckMate 7DX) | NCT04100018 | III | 1 February 2020 | 984 | Recruiting | Nivolumab + prednisone + docetaxel vs. placebo |
Immunosuppressive drug | Sirolimus Before Surgery in Treating Patients with Advanced Localized PCa | NCT00311623 | I/II | 1 August 2006 | 32 | Completed | No intervention vs. low dose rapamycin vs high dose rapamycin |
Synthetic vitamin D analogue | Paricalcitol in Treating Patients with Advanced PCa and Bone Metastases | NCT00634582 | II | 1 January 2009 | 2 | Terminated | Paricalcitol |
Vitamin D analogue | Effect of CTAP101 Capsules on Ca/iPTH in Advanced Breast/PCa Patients Treated with Denosumab/Zoledronic Acid | NCT02274623 | I | 1 December 2014 | 33 | Completed | CTAP101 capsules (vitamin D analogue) |
Vitamin D | Changes in Bone Mineral Density and Fracture Risk in Patients Receiving ADT for PCa | NCT00536653 | N/A * | 1 October 1999 | 618 | Completed | Bicalutamide + calcium/vitamin D supplementation vs. LHRH agonists + calcium/vitamin D supplementation |
Bisphosphonate | Study of Zoledronic Acid for Patients with Hormone-sensitive Bone Metastases from PCa | NCT00242567 | III | 1 December 2005 | 522 | Completed | Zoledronic acid |
Bisphosphonate | Zoledronate in Preventing Osteoporosis and Bone Fractures in Patients with Locally Advanced Nonmetastatic PCa Undergoing Radiation Therapy and Hormone Therapy | NCT00329797 | III | 1 March 2006 | 109 | Completed | Calcium + zoledronic acid + radiation therapy + LHRH + vitamin D vs. calcium + radiation therapy + LHRH + vitamin D |
Bisphosphonate | Study of Denosumab vs. Zoledronic Acid to Treat Bone Metastases in Subjects with Advanced Cancer or Multiple Myeloma. | NCT00330759 | III | 1 June 2006 | 1779 | Completed | Denosumab + zoledronic acid |
Somatostatin analogue | Effects of Octreotide Acetate on Circulating Levels of Chromogranin A in Advanced PCa Patients | NCT00166725 | II | 1 February 2004 | 40 | Completed | Octreotide acetate |
Anticoagulant | Standard Therapy with or Without Dalteparin in Treating Patients with Advanced Breast, Lung, Colorectal, or PCa | NCT00003674 | III | 1 December 1998 | 141 | Completed | Dalteparin |
Anticoagulant | Effects of Nadroparin in Patients with Lung, Pancreas or PCa | NCT00312013 | III | 1 May 2006 | 503 | Completed | Nadroparin |
Synthetic retinoid | Fenretinide In Treating Patients with Advanced or Metastatic Hormone-Refractory Prostate Cancer | NCT00077402 | II | 1 February 2004 | 50 | Completed | Fenretinide |
Other | Preoperative Thalidomide Followed by Radical Retropubic Prostatectomy in Select Patients with Locally Advanced PCa | NCT00038181 | II | 5 October 2000 | 18 | Completed | Thalidomide preoperatively |
Other | Trial of Docetaxel-Samarium in Patients with Hormone-Refractory Advanced PCa | NCT00126230 | II | 1 January 2004 | 55 | Terminated | Docetaxel-samarium |
Other | Samarium-153 With Neoadjuvant Hormonal and Radiation Therapy for Locally Advanced PCa | NCT00328614 | I | 1 March 2003 | 32 | Completed | Samarium + hormonal and radiation therapy |
Other | Study of Chitosan for Pharmacologic Manipulation of AGE Levels in PCa Patients | NCT03712371 | Ib/2 | 1 January 2019 | 45 | Recruiting | Chitosan |
Other | Study of Pharmacologic Manipulation of AGE Levels in PCa Patients Receiving ADT | NCT02946996 | II | 1 December 2016 | 45 | Recruiting | AGE |
Other | A Phase I/II Trial of 2-Deoxyglucose (2DG) for the Treatment of Advanced and Hormone Refractory PCa | NCT00633087 | I/II | 1 March 2011 | 12 | Terminated | 2-deoxyglucose |
Other | Omega-3 Fatty Acids in Treating Patients with Advanced PCa | NCT00996749 | 1 May 2011 | 0 | Withdrawn | Omega-3 PUFA supplementation | |
Other | Hyperpolarized C-13 Pyruvate as a Biomarker in Patients with Advanced Solid Tumor Malignancies | NCT02913131 | I/II | 1 October 2016 | 20 | Terminated | Pyruvate |
Other | Nanoparticle Albumin-Bound Rapamycin in Treating Patients with Advanced Cancer with mTOR Mutations | NCT02646319 | I | 1 January 2016 | 2 | completed | Rapamycin |
Other | Enzalutamide/Leuprolide ± Abiraterone/Pred in PCa | NCT02268175 | II | 1 October 2014 | 75 | Active, not recruiting | Enzalutamide + leuprolife + abiraterone acetate + prednisone vs. enzalutamide + leuprolide |
Other | Study to Compare the Effects of Repeated Doses of an Investigational New Drug and a Placebo on Appetite in Advanced PCa and Anorexia | NCT04803305 | I | 1 May 2021 | 40 | Recruiting | PF-06946860 |
Other | Study of XL102 as Single-Agent and Combination Therapy in Subjects with Solid Tumors | NCT04726332 | I | 1 February 2021 | 298 | Recruiting | XL102 + fulvestrant + abiraterone + prednisone |
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Bahmad, H.F.; Demus, T.; Moubarak, M.M.; Daher, D.; Alvarez Moreno, J.C.; Polit, F.; Lopez, O.; Merhe, A.; Abou-Kheir, W.; Nieder, A.M.; et al. Overcoming Drug Resistance in Advanced Prostate Cancer by Drug Repurposing. Med. Sci. 2022, 10, 15. https://doi.org/10.3390/medsci10010015
Bahmad HF, Demus T, Moubarak MM, Daher D, Alvarez Moreno JC, Polit F, Lopez O, Merhe A, Abou-Kheir W, Nieder AM, et al. Overcoming Drug Resistance in Advanced Prostate Cancer by Drug Repurposing. Medical Sciences. 2022; 10(1):15. https://doi.org/10.3390/medsci10010015
Chicago/Turabian StyleBahmad, Hisham F., Timothy Demus, Maya M. Moubarak, Darine Daher, Juan Carlos Alvarez Moreno, Francesca Polit, Olga Lopez, Ali Merhe, Wassim Abou-Kheir, Alan M. Nieder, and et al. 2022. "Overcoming Drug Resistance in Advanced Prostate Cancer by Drug Repurposing" Medical Sciences 10, no. 1: 15. https://doi.org/10.3390/medsci10010015
APA StyleBahmad, H. F., Demus, T., Moubarak, M. M., Daher, D., Alvarez Moreno, J. C., Polit, F., Lopez, O., Merhe, A., Abou-Kheir, W., Nieder, A. M., Poppiti, R., & Omarzai, Y. (2022). Overcoming Drug Resistance in Advanced Prostate Cancer by Drug Repurposing. Medical Sciences, 10(1), 15. https://doi.org/10.3390/medsci10010015