Abstract
Targeted therapy in hormone refractory prostate cancer (HRPC) is currently under evaluation in many trials. The effect of androgen deprivation therapy (ADT) on many targets in prostate cancer is incompletely known. For the first time, immunohistochemical expression of the platelet-derived growth factor receptor (PDGFR), epidermal growth factor receptor (EGFR), vascular endothelial growth factor C (VEGF-C), mammalian target of rapamycin (mToR), p70 ribosomal protein S6 kinase 1 (PS6K), human epidermal growth factor receptor 2 (c-erbB-2), and carbonic anhydrase IX (CA9) was evaluated in 44 patients with prostate carcinoma treated with or without ADT, at biopsy time and after radical prostatectomy. PDGFR, VEGF-C, mToR, and PS6K expression was significantly reduced (p = 0.002, p = 0.035, p = 0.025, and p = 0.033, respectively) after ADT, whereas expression of EGFR, c-erbB-2, and CA9 was not influenced by ADT. In conclusion, targeting PDGFR, VEGF-C, mToR, or PS6K after ADT should be considered with precaution, as those targets can severely be altered or functionally deregulated by ADT.
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Bono AV, Pagano F, Montironi R, Zattoni F, Manganelli A, Selvaggi FP, Comeri G, Fiaccavento G, Guazzieri S, Selli C, Lembo A, Cosciani-Cunico S, Potenzoni D, Muto G, Diamanti L, Santinelli A, Mazzucchelli R, Prayer-Galletti T (2001) Effect of complete androgen blockade on pathologic stage and resection margin status of prostate cancer: progress pathology report of the Italian PROSIT study. Urology 57(1):117–121. doi:10.1016/s0090-4295(00)00866-9
Gravina GL, Festuccia C, Galatioto GP, Muzi P, Angelucci A, Ronchi P, Costa AM, Bologna M, Vicentini C (2007) Surgical and biologic outcomes after neoadjuvant bicalutamide treatment in prostate cancer. Urology 70(4):728–733. doi:10.1016/j.urology.2007.05.024
Shelley M, Kumar S, Wilt T, Staffurth J, Coles B, Mason M (2009) A systematic review and meta-analysis of randomised trials of neo-adjuvant hormone therapy for localised and locally advanced prostate carcinoma. Cancer Treat Rev 35:9–17. doi:10.1016/j.ctrv.2008.08.002
Petrylak DP, Tangen CM, Hussain MHA, Lara PN, Jones JA, Taplin ME, Burch PA, Berry D, Moinpour C, Kohli M, Benson MC, Small EJ, Raghavan D, Crawford ED (2004) Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 351(15):1513–1520. doi:10.1056/NEJMoa041318
Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Théodore C, James ND, Turesson I, Rosenthal MA, Eisenberger MA, Investigators T (2004) Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351(15):1502–1512. doi:10.1056/NEJMoa040720
Dagher R, Li N, Abraham S, Rahman A, Sridhara R, Pazdur R (2004) Approval summary: Docetaxel in combination with prednisone for the treatment of androgen-independent hormone-refractory prostate cancer. Clin Cancer Res 10(24):8147–8151. doi:10.1158/1078-0432.CCR-04-1402
Nayyar R, Sharma N, Gupta NP (2009) Docetaxel-based chemotherapy with zoledronic acid and prednisone in hormone refractory prostate cancer: factors predicting response and survival. Int J Urol 16(9):726–731. doi:10.1111/j.1442-2042.2009.02351.x
Pirrotta MT, Bernardeschi P, Fiorentini G (2011) Targeted-therapy in advanced renal cell carcinoma. Curr Med Chem 18(11):1651–1657. doi:10.2174/092986711795471293
Wallerand H, Bernhard JC, Culine S, Ballanger P, Robert G, Reiter RE, Ferriere JM, Ravaud A (2011) Targeted therapies in non-muscle-invasive bladder cancer according to the signaling pathways. Urol Oncol 29(1):4–11. doi:10.1016/j.urolonc.2009.07.025
Di Lorenzo G, Tortora G, D’Armiento FP, De Rosa G, Staibano S, Autorino R, D’Armiento M, De Laurentiis M, De Placido S, Catalano G, Bianco AR, Ciardiello F (2002) Expression of epidermal growth factor receptor correlates with disease relapse and progression to androgen-independence in human prostate cancer. Clin Cancer Res 8(11):3438–3444
Hernes E, Fossa SD, Berner A, Otnes B, Nesland JM (2004) Expression of the epidermal growth factor receptor family in prostate carcinoma before and during androgen-independence. Br J Cancer 90(2):449–454. doi:10.1038/sj.bjc.6601536
Traish AM, Morgentaler A (2009) Epidermal growth factor receptor expression escapes androgen regulation in prostate cancer: a potential molecular switch for tumour growth. Br J Cancer 101(12):1949–1956. doi:10.1038/sj.bjc.6605376
Le Page C, Koumakpayi IH, Lessard L, Mes-Masson AM, Saad F (2005) EGFR and Her-2 regulate the constitutive activation of NF-kappaB in PC-3 prostate cancer cells. Prostate 65(2):130–140. doi:10.1002/pros.20234
Festuccia C, Gravina GL, Biordi L, D’ascenzo S, Dolo V, Ficorella C, Ricevuto E, Tombolini V (2009) Effects of EGFR tyrosine kinase inhibitor erlotinib in prostate cancer cells in vitro. Prostate 69(14):1529–1537. doi:10.1002/pros.20995
Sirotnak FM, Zakowski MF, Miller VA, Scher HI, Kris MG (2000) Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase. Clin Cancer Res 6(12):4885–4892
Small EJ, Fontana J, Tannir N, DiPaola RS, Wilding G, Rubin M, Iacona RB, Kabbinavar FF (2009) A phase II trial of gefitinib in patients with non-metastatic hormone-refractory prostate cancer. British Journal of Urology 100(4):765–769. doi:10.1111/j.1464-410X.2007.07121.x
Whang YE, Armstrong AJ, Rathmell WK, Godley PA, Kim WY, Pruthi RS, Wallen EM, Crane JM, Moore DT, Grigson G, Morris K, Watkins CP, George DJ (2011) A phase II study of lapatinib, a dual EGFR and HER-2 tyrosine kinase inhibitor, in patients with castration-resistant prostate cancer. Urol Oncol 31(1):82–86. doi:10.1016/j.urolonc.2010.09.018
Minner S, Jessen B, Stiedenroth L, Burandt E, Kollermann J, Mirlacher M, Erbersdobler A, Eichelberg C, Fisch M, Brummendorf TH, Bokemeyer C, Simon R, Steuber T, Graefen M, Huland H, Sauter G, Schlomm T (2010) Low level Her2 overexpression is associated with rapid tumor cell proliferation and poor prognosis in prostate cancer. Clin Cancer Res 16(5):1553–1560. doi:10.1158/1078-0432.CCR-09-2546
Ross JS, Sheehan CE, Hayner-Buchan AM, Ambros RA, Kallakury BV, Kaufman RP, Fisher HA, Rifkin MD, Muraca PJ (1997) Prognostic significance of HER-2/neu gene amplification status by fluorescence in situ hybridization of prostate carcinoma. Cancer 79(11):2162–2170. doi:10.1002/(SICI)1097-0142(19970601)79:11<2162::AID-CNCR14>3.0.CO;2-U
Signoretti S, Montironi R, Manola J, Altimari A, Tam C, Bubley G, Balk S, Thomas G, Kaplan I, Hlatky L, Hahnfeldt P, Kantoff P, Loda M (2000) Her-2-neu expression and progression toward androgen independence in human prostate cancer. J Natl Cancer Inst 92(23):1918–1925. doi:10.1093/jnci/92.23.1918
Rabindran SK, Discafani CM, Rosfjord EC, Baxter M, Floyd MB, Golas J, Hallett WA, Johnson BD, Nilakantan R, Overbeek E, Reich MF, Shen R, Shi X, Tsou HR, Wang YF, Wissner A (2004) Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res 64(11):3958–3965. doi:10.1158/0008-5472.CAN-03-2868
Nagasawa J, Mizokami A, Koshida K, Yoshida S, Naito K, Namiki M (2006) Novel HER2 selective tyrosine kinase inhibitor, TAK-165, inhibits bladder, kidney and androgen-independent prostate cancer in vitro and in vivo. Int J Urol 13(5):587–592. doi:10.1111/j.1442-2042.2006.01342.x
de Bono JS, Bellmunt J, Attard G, Droz JP, Miller K, Flechon A, Sternberg C, Parker C, Zugmaier G, Hersberger-Gimenez V, Cockey L, Mason M, Graham J (2007) Open-label phase II study evaluating the efficacy and safety of two doses of pertuzumab in castrate chemotherapy-naive patients with hormone-refractory prostate cancer. J Clin Oncol 25(3):257–262. doi:10.1200/JCO.2006.07.0888
Lara PN Jr, Chee KG, Longmate J, Ruel C, Meyers FJ, Gray CR, Edwards RG, Gumerlock PH, Twardowski P, Doroshow JH, Gandara DR (2004) Trastuzumab plus docetaxel in HER-2/neu-positive prostate carcinoma: final results from the California Cancer Consortium screening and phase II trial. Cancer 100(10):2125–2131. doi:10.1002/cncr.20228
Ziada A, Barqawi A, Glode LM, Varella-Garcia M, Crighton F, Majeski S, Rosenblum M, Kane M, Chen L, Crawford ED (2004) The use of trastuzumab in the treatment of hormone refractory prostate cancer; phase II trial. Prostate 60(4):332–337. doi:10.1002/pros.20065
Fudge K, Wang CY, Stearns ME (1994) Immunohistochemistry analysis of platelet-derived growth factor A and B chains and platelet-derived growth factor alpha and beta receptor expression in benign prostatic hyperplasias and Gleason-graded human prostate adenocarcinomas. Mod Pathol 7(5):549–554
George DJ (2002) Receptor tyrosine kinases as rational targets for prostate cancer treatment: platelet-derived growth factor receptor and imatinib mesylate. Urology 60(3 Suppl 1):115–121. doi:10.1016/S0090-4295(02)01589-3
Mathew P, Pisters LL, Wood CG, Papadopoulos JN, Williams DL, Thall PF, Wen S, Horne E, Oborn CJ, Langley R, Fidler IJ, Pettaway CA (2009) Neoadjuvant platelet derived growth factor receptor inhibitor therapy combined with docetaxel and androgen ablation for high risk localized prostate cancer. J Urol 181:81–87. doi:10.1016/j.juro.2008.09.006
Mathew P, Thall PF, Bucana CD, Oh WK, Morris MJ, Jones DM, Johnson MM, Wen S, Pagliaro LC, Tannir NM, Tu SM, Meluch AA, Smith L, Cohen L, Kim SJ, Troncoso P, Fidler IJ, Logothetis CJ (2007) Platelet-derived growth factor receptor inhibition and chemotherapy for castration-resistant prostate cancer with bone metastases. Clin Cancer Res 13(19):5816–5824. doi:10.1158/1078-0432.CCR-07-1269
Russell M, Jamieson W, Dolloff N, Fatatis A (2009) The a-receptor for platelet-derived growth factor as a target for antibody-mediated inhibition of skeletal metastases from prostate cancer cells. Oncogene 28:412–421. doi:10.1038/onc.2008.390
Brakenhielm E, Burton JB, Johnson M, Chavarria N, Morizono K, Chen I, Alitalo K, Wu L (2007) Modulating metastasis by a lymphangiogenic switch in prostate cancer. Int J Cancer 121(10):2153–2161. doi:10.1002/ijc.22900
Jennbacken K, Vallbo C, Wang W, Damber J-E (2005) Expression of vascular endothelial growth factor C (VEGF-C) and VEGF receptor-3 in human prostate cancer is associated with regional lymph node metastasis. Prostate 65(2):110–116. doi:10.1002/pros.20276
Weidner N, Carroll PR, Flax J, Blumenfeld W, Folkman J (1993) Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma. Am J Pathol 143(2):401–409
Burton JB, Priceman SJ, Sung JL, Brakenhielm E, An DS, Pytowski B, Alitalo K, Wu L (2008) Suppression of prostate cancer nodal and systemic metastasis by blockade of the lymphangiogenic axis. Cancer Res 68(19):7828–7837. doi:10.1158/0008-5472.CAN-08-1488
Ortholan C, Durivault J, Hannoun-Levi JM, Guyot M, Bourcier C, Ambrosetti D, Safe S, Pages G (2010) Bevacizumab/docetaxel association is more efficient than docetaxel alone in reducing breast and prostate cancer cell growth: a new paradigm for understanding the therapeutic effect of combined treatment. Eur J Cancer 46(16):3022–3036. doi:10.1016/j.ejca.2010.07.021
Di Lorenzo G, Figg WD, Fossa SD, Mirone V, Autorino R, Longo N, Imbimbo C, Perdona S, Giordano A, Giuliano M, Labianca R, De Placido S (2008) Combination of bevacizumab and docetaxel in docetaxel-pretreated hormone-refractory prostate cancer: a phase 2 study. Eur Urol 54(5):1089–1094. doi:10.1016/j.eururo.2008.01.082
Picus J, Halabi S, Kelly WK, Vogelzang NJ, Whang YE, Kaplan EB, Stadler WM, Small EJ (2011) A phase 2 study of estramustine, docetaxel, and bevacizumab in men with castrate-resistant prostate cancer: results from Cancer and Leukemia Group B Study 90006. Cancer 117(3):526–533. doi:10.1002/cncr.25421
Kelly WK, Halabi S, Carducci M, George D, Mahoney JF, Stadler WM, Morris M, Kantoff P, Monk JP, Kaplan E, Vogelzang NJ, Small EJ (2012) Randomized, double-blind, placebo-controlled phase III trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer: CALGB 90401. J Clin Oncol 30(13):1534–1540. doi:10.1200/JCO.2011.39.4767
Ning YM, Gulley JL, Arlen PM, Woo S, Steinberg SM, Wright JJ, Parnes HL, Trepel JB, Lee MJ, Kim YS, Sun H, Madan RA, Latham L, Jones E, Chen CC, Figg WD, Dahut WL (2010) Phase II trial of bevacizumab, thalidomide, docetaxel, and prednisone in patients with metastatic castration-resistant prostate cancer. J Clin Oncol 28(12):2070–2076. doi:10.1200/JCO.2009.25.4524
Dror Michaelson M, Regan MM, Oh WK, Kaufman DS, Olivier K, Michaelson SZ, Spicer B, Gurski C, Kantoff PW, Smith MR (2009) Phase II study of sunitinib in men with advanced prostate cancer. Ann Oncol 20(5):913–920. doi:10.1093/annonc/mdp111
Zurita AJ, George DJ, Shore ND, Liu G, Wilding G, Hutson TE, Kozloff M, Mathew P, Harmon CS, Wang SL, Chen I, Maneval EC, Logothetis CJ (2011) Sunitinib in combination with docetaxel and prednisone in chemotherapy-naive patients with metastatic, castration-resistant prostate cancer: a phase 1/2 clinical trial. Ann Oncol 23(3):688–694. doi:10.1093/annonc/mdr349
Evren S, Dermen A, Lockwood G, Fleshner N, Sweet J (2010) Immunohistochemical examination of the mTORC1 pathway in high grade prostatic intraepithelial neoplasia (HGPIN) and prostatic adenocarcinomas (PCa): a tissue microarray study (TMA). Prostate 70(13):1429–1436. doi:10.1002/pros.21178
Kobayashi T, Shimizu Y, Terada N, Yamasaki T, Nakamura E, Toda Y, Nishiyama H, Kamoto T, Ogawa O, Inoue T (2010) Regulation of androgen receptor transactivity and mTOR-S6 kinase pathway by Rheb in prostate cancer cell proliferation. Prostate 70(8):866–874. doi:10.1002/pros.21120
Wang Y, Mikhailova M, Bose S, Pan C-X, deVere White RW, Ghosh PM (2008) Regulation of androgen receptor transcriptional activity by rapamycin in prostate cancer cell proliferation and survival. Oncogene 27(56):7106–7117. doi:10.1038/onc.2008.318
Goc A, Al-Husein B, Kochuparambil ST, Liu J, Heston WW, Somanath PR (2011) PI3 kinase integrates Akt and MAP kinase signaling pathways in the regulation of prostate cancer. Int J Oncol 38(1):267–277. doi:10.3892/ijo_00000847
Rai JS, Henley MJ, Ratan HL (2010) Mammalian target of rapamycin: a new target in prostate cancer. Urol Oncol 28(2):134–138. doi:10.1016/j.urolonc.2009.03.023
Tostain J, Li G, Gentil-Perret A, Gigante M (2010) Carbonic anhydrase 9 in clear cell renal cell carcinoma: a marker for diagnosis, prognosis and treatment. Eur J Cancer 46(18):3141–3148. doi:10.1016/j.ejca.2010.07.020
Smyth LG, O’Hurley G, O’Grady A, Fitzpatrick JM, Kay E, Watson RW (2010) Carbonic anhydrase IX expression in prostate cancer. Prostate Cancer Prostatic Dis 13(2):178–181. doi:10.1038/pcan.2009.58
Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council Trial. The Medical Research Council Prostate Cancer Working Party Investigators Group (1997) Br J Urol 79(2):235–246. doi:10.1046/j.1464-410X.1997.d01-6840.x
Messing EM, Manola J, Sarosdy M, Wilding G, Crawford ED, Trump D (1999) Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med 341(24):1781–1788. doi:10.1056/NEJM199912093412401
Uehara H, Kim SJ, Karashima T, Shepherd DL, Fan D, Tsan R, Killion JJ, Logothetis C, Mathew P, Fidler IJ (2003) Effects of blocking platelet-derived growth factor-receptor signaling in a mouse model of experimental prostate cancer bone metastases. J Natl Cancer Inst 95(6):458–470. doi:10.1093/jnci/95.6.458
Tsurusaki T, Kanda S, Sakai H, Kanetake H, Saito Y, Alitalo K, Koji T (1999) Vascular endothelial growth factor-C expression in human prostatic carcinoma and its relationship to lymph node metastasis. Br J Cancer 80(1–2):309–313. doi:10.1038/sj.bjc.6690356
Wedel S, Hudak L, Seibel J-M, Juengel E, Tsaur I, Haferkamp A, Blaheta RA (2011) Combined targeting of the VEGFr/EGFr and the mammalian target of rapamycin (mTOR) signaling pathway delays cell cycle progression and alters adhesion behavior of prostate carcinoma cells. Cancer Lett 301(1):17–28. doi:10.1016/j.canlet.2010.11.003
Fox WD, Higgins B, Maiese KM, Drobnjak M, Cordon-Cardo C, Scher HI, Agus DB (2002) Antibody to vascular endothelial growth factor slows growth of an androgen-independent xenograft model of prostate cancer. Clin Cancer Res 8(10):3226–3231
Ghosh PM, Malik SN, Bedolla RG, Wang Y, Mikhailova M, Prihoda TJ, Troyer DA, Kreisberg JI (2005) Signal transduction pathways in androgen-dependent and -independent prostate cancer cell proliferation. Endocr Relat Cancer 12(1):119–134. doi:10.1677/erc.1.00835
Antonarakis ES, Carducci MA, Eisenberger MA (2010) Novel targeted therapeutics for metastatic castration-resistant prostate cancer. Cancer Lett 291(1):1–13. doi:10.1016/j.canlet.2009.08.012
Mofid B, Jalali Nodushan M, Rakhsha A, Zeinali L, Mirzaei H (2007) Relation between HER-2 gene expression and Gleason score in patients with prostate cancer. Urol J 4(2):101–104. doi:10.1016/S1569-9056(08)60724-1
Shi Y, Brands FH, Chatterjee S, Feng AC, Groshen S, Schewe J, Lieskovsky G, Cote RJ (2001) Her-2/neu expression in prostate cancer: high level of expression associated with exposure to hormone therapy and androgen independent disease. J Urol 166(4):1514–1519
Neto AS, Tobias-Machado M, Wroclawski ML, Fonseca FL, Teixeira GK, Amarante RD, Wroclawski ER, Del Giglio A (2010) Her-2/neu expression in prostate adenocarcinoma: a systematic review and meta-analysis. J Urol 184(3):842–850. doi:10.1016/j.juro.2010.04.077
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Kozakowski, N., Hartmann, C., Klingler, H.C. et al. Immunohistochemical expression of PDGFR, VEGF-C, and proteins of the mToR pathway before and after androgen deprivation therapy in prostate carcinoma: significant decrease after treatment. Targ Oncol 9, 359–366 (2014). https://doi.org/10.1007/s11523-013-0298-1
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DOI: https://doi.org/10.1007/s11523-013-0298-1