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A comprehensive mechanistic basis of prostate cancer advancement & its personalized implementation-bridging the gap: present state and future prospect

  • Dipamoy Datta1
  • Md Aftabuddin2
  • Raja Kundu3
  • Mayank Baid4,5
  • Sanjoy Kumar Das6
  • Supriti Sarkar7
  • Suresh Bajoria8
  • Tapan Kumar Mandal9
  • Pragnadyuti Mandal10
  • Chandan Banerjee11
  • B Shiva Shankar5,12
  • Anish Banerjee13
  • Chinmay Kumar Panda14
  • Sougata Sarkar15
  • Nilkantha Garain16
  • Subrata Chakraborty17
  • Anirban Sinha18
  • Chaitali Banerjee19
  • Losiana Nayak20
  • Aniruddha Bagchi21
  • Subhadra Roy22
  • Kaushik Goswami23
  • Leena Kumari24

1Department of Biotechnology, Siksha Bhavana, Visva-Bharati, 731235 Santiniketan, India

2Department of Information Scientist, Maulana Abul Kalam Azad University of Technology, Haringhata, 741249 Simhat, India

3Computer Education Training Program, NICS Computer, 700032 Kolkata, India

4Department of Urology, S.V.S Marwari Hospital, 700014 Kolkata, India

5Department of Urology, AMRI Hospitals-Salt Lake, Salt Lake City, 700098 Kolkata, India

6Department of Oncology, S.V.S Marwari Hospital, 700014 Kolkata, India

7Department of Zoology, City College, 700009 Kolkata, India

8Department of Urology & Oncology, Rabindranath Tagore International Institute of Cardiac Sciences, 700099 Kolkata, India

9Department of Urology, Nil Ratan Sircar Medical College & Hospital, 700014 Kolkata, India

10Department of Pharmacology, Medical College, 700073 Kolkata, India

11Department of Radiotherapy, IPGMER and SSKM Hospital, 700020 Kolkata, India

12Department of Urology, North City Hospital, 700054 Kolkata, India

13Department of Radiotherapy, Medical College, 700073 Kolkata, India

14Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 700026 Kolkata, India

15Department of Clinical & Experimental Pharmacology, Calcutta School of Tropical Medicine, 700073 Kolkata, India

16Department of Information Technology, Jadavpur University, 700098 Kolkata, India

17Department of Pathology, Saroj Gupta Cancer Centre & Research Institute, 700063 Kolkata, India

18Department of Endocrinology, Medical College, 700073 Kolkata, India

19Department of Zoology, Vidyasagar College for Women, 700006 Kolkata, India

20Machine Intelligence Unit, Indian Statistical Institute, 700108 Kolkata, India

21Department of Pharmacology, IPGMER and SSKM Hospital, 700020 Kolkata, India

22Department of Zoology, Surendranath College, 700009 Kolkata, India

23Department of Computer Science, St. Xavier's College, 700016 Kolkata, India

24Department of Pharmaceutical Technology, Jadavpur University, 700032 Kolkata, India

DOI: 10.31083/jomh.2021.029

Submitted: 07 January 2021 Accepted: 06 February 2021

Online publish date: 12 April 2021

*Corresponding Author(s): Dipamoy Datta E-mail:

PDF (181.56 kB) Supplementary material


Despite significant achievements in prostate cancer mechanistic understanding and its targeted therapies, currently there exists several major challenges that mainly arises during the therapy of advanced prostate cancer. Present prostate cancer precision medicine strategy principally suffers from several practical concerns, particularly in point of therapeutic resistance, tumor heterogeneity, complex clinical & pathological behavior and an extensive genomic perturbation landscape.

Prostate Cancer Systems-Medicine Initiative is a global trans-disciplinary movement taken from corre-sponding scientific domains to critically determine the nature of this major existing challenges and its corresponding most possible solutions by systematically accumulating the present existing knowledge. Basically, it explains the importance of broad spectrum cancer hallmark based integrative approaches for development of combination therapy associated strategic measures for metastatic castration resistant prostate cancer. The major findings of this initiative can be summarized by identification of 136 therapeutic resistance mediators, 103 prostate cancer driver oncogenes and 8 progression pathways along with 5 terrain factors which centrally drives the basic events in prostate cancer pathogenesis, its further metastatic propagation and ultimate therapeutic resistance. In addition, it also attempts to summarize the critical features and basic challenging aspects of current therapeutic options.


Precision medicine; Therapy resistance; Cancer hallmarks; Terrain factors; Castration resistant prostate cancer (CRPC); Bone metastasis; Androgen receptor (AR)

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Dipamoy Datta,Md Aftabuddin,Raja Kundu,Mayank Baid,Sanjoy Kumar Das,Supriti Sarkar,Suresh Bajoria,Tapan Kumar Mandal,Pragnadyuti Mandal,Chandan Banerjee,B Shiva Shankar,Anish Banerjee,Chinmay Kumar Panda,Sougata Sarkar,Nilkantha Garain,Subrata Chakraborty,Anirban Sinha,Chaitali Banerjee,Losiana Nayak,Aniruddha Bagchi,Subhadra Roy,Kaushik Goswami,Leena Kumari. A comprehensive mechanistic basis of prostate cancer advancement & its personalized implementation-bridging the gap: present state and future prospect. Journal of Men's Health. 2021.doi:10.31083/jomh.2021.029.


[1] Wong MCS, Goggins WB, Wang HHX, Fung FDH, Leung C, Wong SYS, et al. Global incidence and mortality for prostate cancer: analysis of temporal patterns and trends in 36 countries. European Urology. 2018; 70: 862-874.

[2] Jain S, Saxena S, Kumar A. Epidemiology of prostate cancer in India. Meta Gene. 2014; 2: 596-605.

[3] Nevedomskaya E, Baumgart SJ, Haendler B. Recent advances in prostate cancer treatment and drug discovery. International Journal of Molecular Sciences. 2018; 19: 1359.

[4] Dellis A, Zagouri F, Liontos M, Mitropoulos D, Bamias A, Papatsoris AG, et al. Management of advanced prostate cancer: a systemic review of existing guidelines and recommendations. Cancer Treatment Reviews. 2019; 73: 54-61.

[5] Yoo S, Choi SY, You D, Kim C. New drugs in prostate cancer. Prostate International. 2016; 4: 37-42.

[6] Nussbaum N, George DJ, Abernethy AP, Dolan CM, Oestreicher N, Flanders S, et al. Patient experience in the treatment of metastatic castration-resistant prostate cancer: state of the science. Prostate Cancer and Prostatic Diseases. 2016; 19: 111-121.

[7] Shore N, Heidenreich A, Saad F. Predicting response and recognizing resistance: improving outcomes in patients with castration-resistant prostate cancer. Urology. 2017; 109: 6-18.

[8] Datta D, Aftabuddin M, Gupta DK, Raha S, Sen P. Human prostate cancer hallmarks map. Scientific Reports. 2016; 6: 30691.

[9] Huggins C, Stevens RE, Hodges CV. Studies on prostatic cancer: Ii. the effects of castration on advanced carcinoma of the prostate gland. Archives of Surgery. 1941; 43: 209-223.

[10] Crawford ED, Higano CS, Shore ND, Hussain M, Petrylak DP. Targeting patients with metastatic castration resistant prostate cancer: a comprehensive review of available therapies. Journal of Urology. 2015; 194: 1537-1547.

[11] Nuhn P, De Bono JS, Fizazi K, Freedland SJ, Grilli M, Kantoff PW, et al. Update on systemic prostate cancer therapies: management of metastatic castration-resistant prostate cancer in the era of precision oncology. European Urology. 2019; 75: 88-99.

[12] Nakazawa M, Paller C, Kyprianou N. Mechanisms of therapeutic resistance in prostate cancer. Current Oncology Reports. 2017; 19: 13.

[13] Chandrasekar T, Yang JC, Gao AC, Evans CP. Targeting molecular resistance in castration-resistant prostate cancer. BMC Medicine. 2015; 13: 206.

[14] Bumbaca B, Li W. Taxane resistance in castration-resistant prostate cancer: mechanisms and therapeutic strategies. Acta Pharmaceutica Sinica. B. 2018; 8: 518-529.

[15] Boudadi K, Antonarakis ES. Resistance to novel antiandrogen therapies in metastatic castration-resistant prostate cancer. Clinical Medicine Insights: Oncology. 2016; 10: 1-9.

[16] Dong L, Zieren RC, Xue W, de Reijke TM, Pienta KJ. Metastatic prostate cancer remains incurable, why? Asian Journal of Urology. 2019; 6: 26-41.

[17] Sathianathen NJ, Konety BR, Crook J, Saad F, Lawrentschuk N. Landmarks in prostate cancer. Nature Reviews Urology. 2018; 15: 627-642.

[18] Chi KN, Agarwal N, Bjartell A, Chung BH, Pereira de Santana Gomes AJ, Given R, et al. Apalutamide for metastatic, castration-sensitive prostate cancer. New England Journal of Medicine. 2019; 381: 13-24.

[19] Bastos DA, Antonarakis ES. Darolutamide for castration-resistant prostate cancer. OncoTargets and Therapy. 2019; 12: 8769-8777.

[20] de Bono J, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, et al. Olaparib for metastatic castration-resistant prostate cancer. New England Journal of Medicine. 2020; 382: 2091-2102.

[21] Suzman DL, Luber B, Schweizer MT, Nadal R, Antonarakis ES. Clinical activity of enzalutamide versus docetaxel in men with castration-resistant prostate cancer progressing after abiraterone. The Prostate. 2014; 74: 1278-1285.

[22] Hoshi S, Numahata K, Ono K, Yasuno N, Bilim V, Hoshi K, et al. Treatment sequence in castration-resistant prostate cancer: a retrospective study in the new anti-androgen era. Molecular and Clinical Oncology. 2017; 7: 601-603.

[23] Caffo O, Maines F, Kinspergher S, Veccia A, Messina C. Sequencing strategies in the new treatment landscape of prostate cancer. Future Oncology. 2019; 15: 2967-2982.

[24] Lorente D, Fizazi K, Sweeney C, de Bono JS. Optimal treatment sequence for metastatic castration-resistant prostate cancer. European Urology Focus. 2016; 2: 488-498.

[25] Azad AA, Eigl BJ, Murray RN, Kollmannsberger C, Chi KN. Efficacy of enzalutamide following abiraterone acetate in chemotherapy-naive metastatic castration-resistant prostate cancer patients. European Urology. 2015; 67: 23-29.

[26] Handle F, Prekovic S, Helsen C, Van den Broeck T, Smeets E, Moris L, et al. Drivers of AR indifferent anti-androgen resistance in prostate cancer cells. Scientific Reports. 2019; 9: 13786.

[27] Lombard AP, Liu C, Armstrong CM, Cucchiara V, Gu X, Lou W, et al. ABCB1 mediates cabazitaxel-docetaxel cross-resistance in advanced prostate cancer. Molecular Cancer Therapeutics. 2017; 16: 2257-2266.

[28] Maughan BL, Gschwend JE. Treatment sequencing of abiraterone acetate plus prednisone and enzalutamide in patients with metastatic castration-resistant prostate cancer. European Oncology & Haematol-ogy. 2019; 15: 92-97.

[29] Caffo O, Maines F, Kinspergher S, Veccia A, Messina C. To treat or not to treat: is it acceptable to avoid active therapies in advanced prostate cancer today? Expert Review of Anticancer Therapy. 2020; 1-12.

[30] Zhao J, Ning S, Lou W, Yang JC, Armstrong CM, Lombard AP, et al. Cross-resistance among next-generation antiandrogen drugs through the AKR1C3/AR-V7 axis in advanced prostate cancer. Molecular Cancer Therapeutics. 2020; 19: 1708-1718.

[31] Tonyali S, Haberal HB, Sogutdelen E. Toxicity, adverse events, and quality of life associated with the treatment of metastatic castration-resistant prostate cancer. Current Urology. 2017; 10: 169-173.

[32] Tomaszewski EL, Moise P, Krupnick RN, Downing J, Meyer M, Naidoo S, et al. Symptoms and impacts in non-metastatic castration-resistant prostate cancer: qualitative study findings. The Patient. 2017; 10: 567-578.

[33] Mullane SA, Van Allen EM. Precision medicine for advanced prostate cancer. Current Opinion in Urology. 2016; 26: 231-239.

[34] Wang J. Applying precision medicine approach to metastatic castra-tion resistant prostate cancer: urgent education need on genomic oncology. Journal of Molecular Oncology Research. 2018; 2: 1.

[35] Hwang C. Overcoming docetaxel resistance in prostate cancer: a perspective review. Therapeutic Advances in Medical Oncology. 2012; 4: 329-340.

[36] Sekino Y, Teishima J. Molecular mechanisms of docetaxel resistance in prostate cancer. Cancer Drug Resist. 2020; 3: 676-685.

[37] Li D, Zhao L, Zheng X, Lin P, Lin F, Li Y, et al. Sox2 is involved in paclitaxel resistance of the prostate cancer cell line PC-3 via the PI3K/Akt pathway. Molecular Medicine Reports. 2014; 10: 3169-3176.

[38] Shiota M, Itsumi M, Yokomizo A, Takeuchi A, Imada K, Kashiwagi E, et al. Targeting ribosomal S6 kinases/Y-box binding protein-1 signaling improves cellular sensitivity to taxane in prostate cancer. The Prostate. 2014; 74: 829-838.

[39] Hou X, Li Z, Huang W, Li J, Staiger C, Kuang S, et al. Plk1-dependent microtubule dynamics promotes androgen receptor signaling in prostate cancer. The Prostate. 2013; 73: 1352-1363.

[40] Chen L, Cao H, Feng Y. MiR-199a suppresses prostate cancer paclitaxel resistance by targeting YES1. World Journal of Urology. 2018; 36: 357-365.

[41] Shiota M, Zoubeidi A, Kumano M, Beraldi E, Naito S, Nelson CC, et al. Clusterin is a critical downstream mediator of stress-induced YB-1 transactivation in prostate cancer. Molecular Cancer Research. 2011; 9: 1755-1766.

[42] Kato T, Fujita Y, Nakane K, Kojima T, Nozawa Y, Deguchi T, et al. ETS1 promotes chemoresistance and invasion of paclitaxel-resistant, hormone-refractory PC3 prostate cancer cells by up-regulating MDR1 and MMP9 expression. Biochemical and Biophysical Research Communications. 2012; 417: 966-971.

[43] Wu Y, Hu L, Qin Z, Wang X. MicroRNA‑302a upregulation me-diates chemo‑resistance in prostate cancer cells. Molecular Medicine Reports. 2019; 19: 4433-4440.

[44] Tucci M, Zichi C, Buttigliero C, Vignani F, Scagliotti GV, Di Maio M. Enzalutamide-resistant castration-resistant prostate cancer: challenges and solutions. OncoTargets and Therapy. 2018; 11: 7353-7368.

[45] Culig Z. Molecular mechanisms of enzalutamide resistance in prostate cancer. Current Molecular Biology Reports. 2017; 3: 230-235.

[46] Li S, Fong K, Gritsina G, Zhang A, Zhao JC, Kim J, et al. Activation of MAPK signaling by CXCR7 leads to enzalutamide resistance in prostate cancer. Cancer Research. 2019; 79: 2580-2592.

[47] Thaper D, Vahid S, Kaur R, Kumar S, Nouruzi S, Bishop JL, et al. Galiellalactone inhibits the STAT3/AR signaling axis and suppresses Enzalutamide-resistant Prostate Cancer. Scientific Reports. 2018; 8: 17307.

[48] Kohli M, Ho Y, Hillman D, Van Etten J. Androgen receptor variant AR-V9 is coexpressed in AR-V7 in prostate cancer metastases and predicts Abiraterone resistance. Clinical Cancer Research. 2017; 23: 4704-4715.

[49] Sharp A, Coleman I, Yuan W, Sprenger C, Dolling D, Rodrigues DN, et al. Androgen receptor splice variant-7 expression emerges with castration resistance in prostate cancer. Journal of Clinical Investigation. 2019; 129: 192-208.

[50] Tosoian JJ, Antonarakis ES. Molecular heterogeneity of localized prostate cancer: more different than alike. Translational Cancer Research. 2017; 6: S47-S50.

[51] Van Etten JL, Dehm SM. Clonal origin and spread of metastatic prostate cancer. Endocrine-Related Cancer. 2016; 23: R207-R217.

[52] Shoag J, Barbieri CE. Clinical variability and molecular heterogeneity in prostate cancer. Asian Journal of Andrology. 2016; 18: 543-548.

[53] Arshad OA, Datta A. Towards targeted combinatorial therapy design for the treatment of castration-resistant prostate cancer. BMC Bioin-formatics. 2017; 18: 134.

[54] Iglesias-Gato D, Thysell E, Tyanova S, Crnalic S, Santos A, Lima TS, et al. The proteome of prostate cancer bone metastasis reveals heterogeneity with prognostic implications. Clinical Cancer Research. 2018; 24: 5433-5444.

[55] Robinson D, Van Allen EM, Wu Y, Schultz N, Lonigro RJ, Mosquera J, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015; 161: 1215-1228.

[56] Mateo J, Seed G, Bertan C, Rescigno P, Dolling D, Figueiredo I, et al. Genomics of lethal prostate cancer at diagnosis and castration resistance. Journal of Clinical Investigation. 2020; 130: 1743-1751.

[57] Gulley JL, Borre M, Vogelzang NJ, Ng S, Agarwal N, Parker CC, et al. Phase III Trial of PROSTVAC in asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. Journal of Clinical Oncology. 2019; 37: 1051-1061.

[58] Beer TM, Kwon ED, Drake CG, Fizazi K, Logothetis C. Random-ized, double-blind, phase III trial of ipilimumab versus placebo in asymptomatic or minimally symptomatic patients with metastatic chemotherapy-naïve castration-resistant prostate cancer. Journal of Clinical Oncology. 2017; 35: 40-47.

[59] Kumar-Sinha C, Chinnaiyan AM. Precision oncology in the age of integrative genomics. Nature Biotechnology. 2018; 36: 46-60.

[60] Rubin MA. Toward a prostate cancer precision medicine. Urologic Oncology. 2015; 33: 73-74.

[61] Ku S, Gleave ME, Beltran H. Towards precision oncology in advanced prostate cancer. Nature Reviews Urology. 2019; 16: 645-654.

[62] Al Hussein Al Awamlh B, Shoag JE. Genomics and risk stratification in high-risk prostate cancer. Nature Reviews Urology. 2019; 16: 641-642.

[63] Logothetis CJ, Gallick GE, Maity SN, Kim J, Aparicio A, Efstathiou E, et al. Molecular classification of prostate cancer progression: foundation for marker-driven treatment of prostate cancer. Cancer Discovery. 2013; 3: 849-861.

[64] Kaffenberger SD, Barbieri CE. Molecular subtyping of prostate cancer. Current Opinion in Urology. 2016; 26: 213-218.

[65] Hovelson DH, Tomlins SA. The role of next-generation sequencing in castration-resistant prostate cancer treatment. Cancer Journal. 2016; 22: 357-361.

[66] Bartucci M, Ferrari AC, Kim IY, Ploss A, Yarmush M, Sabaawy HE. Personalized medicine approaches in prostate cancer employing patient derived 3D organoids and humanized mice. Frontiers in Cell and Developmental Biology. 2016; 4: 64.

[67] Risbridger GP, Toivanen R, Taylor RA. Preclinical models of prostate cancer: patient-derived xenografts, organoids, and other explant models. Cold Spring Harbor Perspectives in Medicine. 2018; 8: a030536.

[68] Lam H, Nguyen HM, Corey E. Generation of prostate cancer patient-derived xenografts to investigate mechanisms of novel treatments and treatment resistance. Methods in Molecular Biology. 2018; 1786: 1-27.

[69] Pine AC, Fioretti FF, Brooke GN, Bevan CL. Advances in genetics: widening our understanding of prostate cancer. F1000Research. 2016; 5: pii: F1000 Faculty Rev-1512.

[70] Ikeda S, Elkin SK, Tomson BN, Carter JL, Kurzrock R. Next-generation sequencing of prostate cancer: genomic and pathway alterations, potential actionability patterns, and relative rate of use of clinical-grade testing. Cancer Biology & Therapy. 2019; 20: 219-226.

[71] Sartor O, Gillessen S. Treatment sequencing in metastatic castrate-resistant prostate cancer. Asian Journal of Andrology. 2014; 16: 426-431.

[72] Li Y, Malapati S, Lin YT, Patnaik A. An integrative approach for sequencing therapies in metastatic prostate cancer. American Journal of Hematology. 2017; 13, 26-31.

[73] Angeles AK, Bauer S, Ratz L, Klauck SM, Sültmann H. Genome-based classification and therapy of prostate cancer. Diagnostics. 2018; 8: 3.

[74] Hinkson IV, Davidsen TM, Klemm JD, Kerlavage AR, Kibbe WA, Chandramouliswaran I. A comprehensive infrastructure for big data in cancer research: accelerating cancer research and precision medicine. Frontiers in Cell and Developmental Biology. 2017; 5: 83.

[75] Fröhlich H, Balling R, Beerenwinkel N, Kohlbacher O, Kumar S, Lengauer T, et al. From hype to reality: data science enabling personalized medicine. BMC Medicine. 2018; 16: 150.

[76] Jin R, Sterling JA, Edwards JR, DeGraff DJ, Lee C, Park SI, et al. Activation of NF-kappa B signaling promotes growth of prostate cancer cells in bone. PLoS ONE. 2013; 8: e60983.

[77] Stankiewicz E, Mao X, Mangham DC, Xu L, Yeste-Velasco M, Fisher G, et al. Identification of FBXL4 as a metastasis associated gene in prostate cancer. Scientific Reports. 2017; 7: 5124.

[78] Geynisman DM, Plimack ER, Zibelman M. Second-generation andro-gen receptor-targeted therapies in nonmetastatic castration-resistant prostate cancer: effective early intervention or intervening too early?European Urology. 2016; 70: 971-973.

[79] Vela I, Chen Y. Prostate cancer organoids: a potential new tool for testing drug sensitivity. Expert Review of Anticancer Therapy. 2015; 15: 261-263.

[80] Beltran H, Rubin MA. New strategies in prostate cancer: translating genomics into the clinic. Clinical Cancer Research. 2013; 19: 517-523.

[81] Rubin MA, Demichelis F. The Genomics of Prostate Cancer: emerging understanding with technologic advances. Modern Pathology. 2018; 31: S1-S11.

[82] Barbieri CE, Bangma CH, Bjartell A, Catto JWF, Culig Z, Grönberg H, et al. The mutational landscape of prostate cancer. European Urology. 2013; 64: 567-576.

[83] Armenia J, Wankowicz SAM, Liu D, Gao J, Kundra R, Reznik E, et al. The long tail of oncogenic drivers in prostate cancer. Nature Genetics. 2019; 50: 645-651.

[84] Bryant G, Wang L, Mulholland DJ. Overcoming oncogenic mediated tumor immunity in prostate cancer. International Journal of Molecular Sciences. 2017; 18: 1542.

[85] Wedge DC, Gundem G, Mitchell T, Woodcock DJ. Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets. Nature Genetics. 2018; 50: 682-692.

[86] Roshan-Moniri M, Hsing M, Rennie PS, Cherkasov A, Cox ME. The future of prostate cancer precision medicine: anti-ERG therapies. Translational Cancer Research. 2017; 6: S1136-S1138.

[87] Adamo P, Ladomery MR. The oncogene ERG: a key factor in prostate cancer. Oncogene. 2015; 35: 403-414.

[88] Ayala G, Frolov A, Chatterjee D, He D, Hilsenbeck S, Ittmann M. Expression of ERG protein in prostate cancer: variability and biological correlates. Endocrine-Related Cancer. 2016; 22: 277-287.

[89] Chen Y, Lee M, Lucht A, Chou F, Huang W, Havighurst TC, et al. TMPRSS2, a serine protease expressed in the prostate on the apical surface of luminal epithelial cells and released into semen in prostasomes, is misregulated in prostate cancer cells. The American Journal of Pathology. 2010; 176: 2986-2996.

[90] Deplus R, Delliaux C, Marchand N, Flourens A, Vanpouille N, Leroy X, et al. TMPRSS2-ERG fusion promotes prostate cancer metastases in bone. Oncotarget. 2017; 8: 11827-11840.

[91] Lucas JM, Heinlein C, Kim T, Hernandez SA, Malik MS, True LD, et al. The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis. Cancer Discovery. 2014; 4: 1310-1325.

[92] Semaan L, Mander N, Cher ML, Chinni SR. TMPRSS2-ERG fusions confer efficacy of enzalutamide in an in vivo bone tumor growth model. BMC Cancer. 2019; 19: 972.

[93] Thaper D, Vahid S, Kaur R, Kumar S, Nouruzi S, Bishop JL, et al. Galiellalactone inhibits the STAT3/AR signaling axis and suppresses Enzalutamide-resistant prostate cancer. Scientific Reports. 2018; 8: 17307.

[94] Bishop JL, Thaper D, Zoubeidi A. The multifaceted roles of STAT3 signaling in the progression of prostate cancer. Cancers. 2014; 6: 829-859.

[95] Mohanty SK, Yagiz K, Pradhan D, Luthringer DJ, Amin MB, Alkan S, et al. STAT3 and STAT5a are potential therapeutic targets in castration-resistant prostate cancer. Oncotarget. 2017; 8: 85997-86010.

[96] Hu F, Zhao Y, Yu Y, Cui R. Docetaxel-mediated autophagy promotes chemoresistance in castration-resistant prostate cancer cells by inhibi-tion STAT3. Cancer Letters. 2018; 416: 24-30.

[97] Day KC, Lorenzatti Hiles G, Kozminsky M, Dawsey SJ, Paul A, Broses LJ, et al. HER2 and EGFR overexpression support metastatic progression of prostate cancer to bone. Cancer Research. 2017; 77: 74-85.

[98] DeHaan AM, Wolters NM, Keller ET, Ignatoski KMW. EGFR ligand switch in late stage prostate cancer contributes to changes in cell signaling and bone remodeling. The Prostate. 2009; 69: 528-537.

[99] Liu YL, Horning AM, Lieberman B. Spatial EGFR dynamics and metastatic phenotypes modulated by upregulated EphB2 and Src pathways in advanced prostate cancer. Cancers. 2019; 11: 1910.

[100] Mandel A, Larsson P, Sarwar M, Semenas J, Syed Khaja AS, Persson JL. The interplay between AR, EGF receptor and MMP-9 signaling pathways in invasive prostate cancer. Molecular Medicine. 2018; 24: 34.

[101] Miller DR, Ingersoll MA, Lin M. ErbB-2 signaling in advanced prostate cancer progression and potential therapy. Endocrine-Related Cancer. 2019; 26: R195-R209.

[102] Sharifi N, Salmaninejad A, Ferdosi S, Bajestani AN, Khaleghiyan M, Estiar MA, et al. HER2 gene amplification in patients with prostate cancer: evaluating a CISH-based method. Oncology Letters. 2016; 12: 4651-4658.

[103] Jathal MK, Steele TM, Siddiqui S, Mooso BA, D’Abronzo LS, Drake CM, et al. Dacomitinib, but not lapatinib, suppressed progression in castration-resistant prostate cancer models by preventing HER2 increase. British Journal of Cancer. 2019; 121: 237-248.

[104] Niyat M M. Prognostic value of HER2/neu expression in patients in prostate cancer. Reviews in Clinical Medicine. 2015; 2: 168-173.

[105] Pettersson A, Gerke T, Penney KL, Lis RT, Stack EC, Pértega-Gomes N, et al. MYC overexpression at the protein and mRNA level and cancer outcomes among men treated with radical prostatectomy for prostate cancer. Cancer Epidemiology Biomarkers & Prevention. 2018; 27: 201-207.

[106] Rebello RJ, Pearson RB, Hannan RD, Furic L. Therapeutic ap-proaches targeting MYC-driven prostate cancer. Genes. 2017; 8: 71.

[107] Sun C, Dobi A, Mohamed A, Li H, Thangapazham RL, Furusato B, et al. TMPRSS2-ERG fusion, a common genomic alteration in prostate cancer activates C-MYC and abrogates prostate epithelial differentiation. Oncogene. 2008; 27: 5348-5353.

[108] Dong H, Hu J, Wang L, Qi M, Lu N, Tan X, et al. SOX4 is activated by C-MYC in prostate cancer. Medical Oncology. 2019; 36: 92.

[109] Baena-Del Valle JA, Zheng Q, Esopi DM. MYC drives overexpression of telomerase RNA (hTR/TERC) in prostate cancer. Pathology. 2018; 244: 11-24.

[110] Allen-Petersen BL, Sears RC. Mission possible: advances in MYC therapeutic targeting in cancer. BioDrugs. 2019; 33: 539-553.

[111] Drake JM, Paull EO, Graham NA, Lee JK, Smith BA, Titz B, et al. Phosphoproteome integration reveals patient-specific networks in prostate cancer. Cell. 2016; 166: 1041-1054.

[112] Santos R, Ursu O, Gaulton A, Bento AP, Donadi RS, Bologa CG, et al. A comprehensive map of molecular drug targets. Nature Reviews Drug Discovery. 2017; 16: 19-34.

[113] Logothetis C, Morris MJ, Den R, Coleman RE. Current perspectives on bone metastases in castrate-resistant prostate cancer. Cancer and Metastasis Reviews. 2018; 37: 189-196.

[114] Bilusic M, Madan RA, Gulley JL. Immunotherapy of prostate cancer: facts and hopes. Clinical Cancer Research. 2017; 23: 6764-6770.

[115] Prokhnevska N, Emerson DA, Kissick HT, Redmond WL. Immuno-logical complexity of the prostate cancer microenvironment influences the response to immunotherapy. Advances in Experimental Medicine and Biology. 2019; 355: 121-147.

[116] Cordes LM, Gulley JL, Madan RA. Perspectives on the clinical development of immunotherapy in prostate cancer. Asian Journal of Andrology. 2018; 20: 253-259.

[117] Silvestri I, Cattarino S, Aglianò AM, Collalti G, Sciarra A. Beyond the immune suppression: the immunotherapy in prostate cancer. BioMed Research International. 2015; 2015: 794968.

[118] Sanaei M, Salimzadeh L, Bagheri N. Crosstalk between myeloid‐derived suppressor cells and the immune system in prostate cancer. Journal of Leukocyte Biology. 2020; 107: 43-56.

[119] Erlandsson A, Carlsson J, Lundholm M, Fält A, Andersson S, Andrén O, et al. M2 macrophages and regulatory T cells in lethal prostate cancer. The Prostate. 2019; 79: 363-369.

[120] Zhao E, Wang L, Dai J, Kryczek I, Wei S, Vatan L, et al. Regulatory T cells in the bone marrow microenvironment in patients with prostate cancer. Oncoimmunology. 2012; 1: 152-161.

[121] Calcinotto A, Spataro C, Zagato E, Di Mitri D, Gil V, Crespo M, et al. IL-23 secreted by myeloid cells drives castration-resistant prostate cancer. Nature. 2018; 559: 363-369.

[122] O’Donnell JS, Teng MWL, Smyth MJ. Cancer immunoediting and resistance to T cell-based immunotherapy. Nature Reviews. Clinical Oncology. 2019; 16: 151-167.

[123] Boettcher AN, Usman A, Morgans A, VanderWeele DJ, Sosman J, Wu JD. Past, current, and future of immunotherapies for prostate cancer. Frontiers in Oncology. 2019; 9: 884.

[124] Janiczek M, Szylberg Ł, Kasperska A, Kowalewski A, Parol M, Antosik P, et al. Immunotherapy as a promising treatment for prostate cancer: a systematic review. Journal of Immunology Research. 2017; 2017: 1-6.

[125] Yap TA, Smith AD, Ferraldeschi R, Al-Lazikani B, Workman P, de Bono JS. Drug discovery in advanced prostate cancer: translating biology into therapy. Nature Reviews Drug Discovery. 2016; 15: 699-718.

[126] Saad F, Sternberg CN, Mulders PFA, Niepel D, Tombal BF. The role of bisphosphonates or denosumab in light of the availability of new therapies for prostate cancer. Cancer Treatment Reviews. 2018; 68: 25-37.

[127] Finianos A, Aragon-Ching JB. Zoledronic acid for the treatment of prostate cancer. Expert Opinion on Pharmacotherapy. 2019; 20: 657-666.

[128] Wong SK, Mohamad NV, Giaze TR, Chin KY, Mohamed N, Ima-Nirwana S. Prostate cancer bone metastasis: the underlying mechanisms. International Journal of Molecular Sciences. 2019; 20: 2587.

[129] Spratt DE. Combination therapies in prostate cancer: proceed with caution. The Lancet Oncology. 2019; 20: 321-323.

[130] Qu S, Ci X, Xue H, Dong X, Hao J, Lin D, et al. Treatment with docetaxel in combination with Aneustat leads to potent inhibition of metastasis in a patient-derived xenograft model of advanced prostate cancer. British Journal of Cancer. 2018; 118: 802-812.

[131] Etheridge T, Damodaran S, Schultz A, Richards KA, Gawdzik J, Yang B, et al. Combination therapy with androgen deprivation for hormone sensitive prostate cancer: a new frontier. Asian Journal of Urology. 2019; 6: 57-64.

[132] Qiu Y, Xu J. Current opinion and mechanistic interpretation of combination therapy for castration-resistant prostate cancer. Asian Journal of Andrology. 2019; 21: 270.

[133] Sternberg CN. Improving survival for metastatic castrate-resistant prostate cancer: will combination therapy help us to move forward?European Urology. 2016; 70: 722-723.

[134] Wadosky KM, Koochekpour S. Therapeutic rationales, progresses, failures, and future directions for advanced prostate cancer. Interna-tional Journal of Biological Sciences. 2016; 12: 409-426.

[135] Pollard ME, Moskowitz AJ, Diefenbach MA, Hall SJ. Cost-effectiveness analysis of treatments for metastatic castration resistant prostate cancer. Asian Journal of Urology. 2017; 4: 37-43.

[136] Block KI, Gyllenhaal C, Lowe L, Amedei A, Amin ARMR, Amin A, et al. Designing a broad-spectrum integrative approach for cancer prevention and treatment. Seminars in Cancer Biology. 2015; 35: S276-S304.

[137] Bishayee A, Block K. A broad-spectrum integrative design for cancer prevention and therapy: the challenge ahead. Seminars in Cancer Biology. 2015; 35: S1-S4.

[138] Block KI, Block PB, Gyllenhaal C. Integrative Therapies in Cancer. Integrative Cancer Therapies. 2015; 14: 113-118.

[139] Vaishampayan UN. Sequences and combinations of multifaceted therapy in advanced prostate cancer. Current Opinion in Oncology. 2015; 27: 201-208.

[140] Krueger TE, Thorek DLJ, Meeker AK, Isaacs JT, Brennen WN. Tumor infiltrating mesenchymal stem cells: drivers of immunosup-pressive tumor microenvironment in prostate cancer? Prostate. 2019; 79(3): 320-330.

[141] Boettcher AN, Usman A, Morgans A, VanderWeele DJ. Past, current and future of immunotherapies in prostate cancer. Frontiers in Oncology. 2019; 9: 884.

[142] Rescigno P, Gurel B, Pereira R, Crespo M, Rekowski J, Rediti M, et al. Characterizing CDK12-Mutated Prostate Cancers. Clinical Cancer Research. 2021; 27: 566-574.

[143] Messina C, Cattrini C, Soldato D, Vallome G. BRCA mutations in prostate cancer: prognostic and predictive implications. Journal of Oncology. 2020; 2020: 4986365.

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