Skip to main content

Advertisement

SpringerLink
Log in

Growth factor and signaling pathways and their relevance to prostate cancer therapeutics

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

Treatments that target the androgen axis represent an effective strategy for patients with advanced prostate cancer, but the disease remains incurable and new therapeutic approaches are necessary. Significant advances have recently occurred in our understanding of the growth factor and signaling pathways that are active in prostate cancer. In conjunction with this, many new targeted therapies with sound preclinical rationale have entered clinical development and are being tested in men with castration-resistant prostate cancer. Some of the most relevant pathways currently being exploited for therapeutic gain are HGF/c-Met signaling, the PI3K/AKT/mTOR pathway, Hedgehog signaling, the endothelin axis, Src kinase signaling, the IGF pathway, and angiogenesis. Here, we summarize the biological basis for the use of selected targeted agents and the results from available clinical trials of these drugs in men with prostate cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Siegel, R., Naishadham, D., & Jemal, A. (2013). Cancer statistics, 2013. CA: A Cancer Journal for Clinicians, 63(1), 11–30.

    Google Scholar 

  2. Semenza, G. L. (2003). Targeting HIF-1 for cancer therapy. Nature Reviews Cancer, 3(10), 721–732.

    Article  CAS  PubMed  Google Scholar 

  3. Ferrer, F. A., Miller, L. J., Andrawis, R. I., Kurtzman, S. H., Albertsen, P. C., et al. (1997). Vascular endothelial growth factor (VEGF) expression in human prostate cancer: in situ and in vitro expression of VEGF by human prostate cancer cells. The Journal of Urology, 157(6), 2329–2333.

    Article  CAS  PubMed  Google Scholar 

  4. Ferrer, F. A., Miller, L. J., Lindquist, R., Kowalczyk, P., Laudone, V. P., et al. (1999). Expression of vascular endothelial growth factor receptors in human prostate cancer. Urology, 54(3), 567–572.

    Article  CAS  PubMed  Google Scholar 

  5. Kelly, W. K., Halabi, S., Carducci, M., George, D., Mahoney, J. F., et al. (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. Journal of Clinical Oncology, 30(13), 1534–1540.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Sandler, A., Gray, R., Perry, M. C., Brahmer, J., Schiller, J. H., et al. (2006). Paclitaxel-carboplatin alone or with bevacizumab for non-small cell lung cancer. New England Journal of Medicine, 355(24), 2542–2550.

    Article  CAS  PubMed  Google Scholar 

  7. Tannock I., Fizazi K., Ivanov S., Karlsson C., Flechon A., et al. (2013). Aflibercept versus placebo in combination with docetaxel/prednisone for first-line treatment of men with metastatic castration-resistant prostate cancer: Results from the multinational phase III trial (VENICE). Journal of Clinical Oncology, 31 (6 Suppl.), Abstract 13.

    Google Scholar 

  8. Ou Y., Michaelson M.D., Sengelov L., Saad F., Houede N., et al. (2011). Randomized, placebo-controlled, phase III trial of sunitinib in combination with prednisone versus prednisone alone in men with progressive metastatic castration-resistant prostate cancer. Journal of Clinical Oncology, 29 (15 Suppl.), Abstract 4515.

    Google Scholar 

  9. Aragon-Ching, J. B., Jain, L., Gulley, J. L., Arlen, P. M., Wright, J. J., et al. (2009). Final analysis of a phase II trial using sorafenib for metastatic castration-resistant prostate cancer. BJU International, 103(12), 1636–1640.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Beardsley, E. K., Hotte, S. J., North, S., Ellard, S. L., Winquist, E., et al. (2012). A phase II study of sorafenib in combination with bicalutamide in patients with chemotherapy-naïve castration resistant prostate cancer. Investigational New Drugs, 30(4), 1652–1659.

    Article  CAS  PubMed  Google Scholar 

  11. Dahut, W. L., Madan, R. A., Karakunnel, J. J., Adelberg, D., Gulley, J. L., et al. (2013). Phase II trial of cediranib in patients with metastatic castration-resistant prostate cancer. British Journal of Urology International, 111(8), 1269–1280.

    Article  CAS  Google Scholar 

  12. Heath E.I., Mannuel H.D., Liu G., Lara P., Monk J.P., et al. (2013). Randomized phase II trial of docetaxel and prednisone with or without AZD2171, in chemotherapy-naïve, metastatic castrate-resistant prostate cancer. Journal of Clinical Oncology, 31 (6 Suppl.), Abstract 38.

    Google Scholar 

  13. Paravar, T., & Lee, D. J. (2008). Thalidomide: mechanisms of action. International Reviews of Immunology, 27(3), 111–135.

    Article  CAS  PubMed  Google Scholar 

  14. Garcia J.A., Elson P., Tyler A., Triozzi P., Dreicer R. (2013). Sargramostim (GM-CSF) and lenalidomide in castration-resistant prostate cancer: results from a phase I-II clinical trial. Urologic Oncology, in press.

  15. Garcia J.A., Triozzi P., Elson P., Cooney M.M., Tyler A, et al. (2008). Clinical activity of ketoconazole and lenalidomide in castrate progressive prostate carcinoma: preliminary results of a phase II trial. Journal of Clinical Oncology, 26 (15 Suppl.), Abstract 5143.

    Google Scholar 

  16. Petrylak D.P., Fizazi K., Sternberg C.N., et al. (2012). A phase III study to evaluate the efficacy and safety of docetaxel and prednisone with or without lenalidomide in patients with castrate-resistant prostate cancer: The MAINSAIL trial. Meeting of the European Society of Medical Oncology, Vienna, Austria, September 28-October2, 2012, Abstract LBA24.

  17. Isaacs, J. T. (2010). The long and winding road for the development of tasquinimod as an oral second-generation quinolone-3-carboxamide antiangiogenic drug for the treatment of prostate cancer. Expert Opinion on Investigational Drugs, 19(10), 1235–1243.

    Article  CAS  PubMed  Google Scholar 

  18. Pili, R., Haggman, M., Stadler, W. M., Gingrich, J. R., Assikis, V. J., et al. (2011). Phase II randomized, double-blind, placebo-controlled study of tasquinimod in men with minimally symptomatic metastatic castrate-resistant prostate cancer. Journal of Clinical Oncology, 29(30), 4022–4028.

    Article  CAS  PubMed  Google Scholar 

  19. Fagiani, E., & Christofori, C. (2013). Angiopoietins in angiogenesis. Cancer Letters, 328(1), 18–26.

    Article  CAS  PubMed  Google Scholar 

  20. Lind, A. J., Wikstrom, P., Granfors, T., Egevad, L., Stattin, P., et al. (2005). Angiopoietin 2 expression is related to histological grade, vascular density, metastases, and outcome in prostate cancer. The Prostate, 62(4), 394–399.

    Article  PubMed  Google Scholar 

  21. Herbst, R. S., Hong, D., Chap, L., Kurzrock, R., Jackson, E., et al. (2009). Safety, pharmacokinetics, and antitumor activity of AMG 386, a selective angiopoietin inhibitor, in adult patients with advanced solid tumors. Journal of Clinical Oncology, 27(21), 3557–3565.

    Article  CAS  PubMed  Google Scholar 

  22. Trusolino, L., Bertotti, A., & Comoglio, P. M. (2010). MET signaling: principles and functions in development, organ regeneration and cancer. Nature Reviews Molecular Cell Biology, 11(12), 834–848.

    Article  CAS  PubMed  Google Scholar 

  23. Scagliotti G.V., Novello S., & von Pawel J. (2013). The emerging role of MET/HGF inhibitors in oncology. Cancer Treatment Reviews, 39(7), 793-801.

    Google Scholar 

  24. Peters, S., & Adjei, A. A. (2012). MET: a promising anticancer therapeutic target. Nature Reviews. Clinical Oncology, 9(6), 314–326.

    Article  CAS  PubMed  Google Scholar 

  25. Jeffers, M., Schmidt, L., Nakaigawa, N., Webb, C. P., Weirich, G., et al. (1997). Activating mutations for the met tyrosine kinase receptor in human cancer. Proceedings of the National Academy of Sciences of the United States of America, 94(21), 445–450.

    Article  Google Scholar 

  26. Knudsen, B. S., & Edlund, M. (2004). Prostate cancer and the Met hepatocyte growth factor receptor. Advances in Cancer Research, 91, 31–67.

    Article  CAS  PubMed  Google Scholar 

  27. Knudsen, B. S., Gmyrek, G. A., Inra, J., Scherr, D. S., Vaughan, E. D., et al. (2002). High expression of the Met receptor in prostate cancer metastasis to bone. Urology, 60(6), 1113–1117.

    Article  PubMed  Google Scholar 

  28. Verras, M., Lee, J., Xue, H., Li, T., Wang, Y., et al. (2007). The androgen receptor negatively regulates the expression of c-Met: implications for a novel mechanism of prostate cancer progression. Cancer Research, 67(3), 697–975.

    Article  Google Scholar 

  29. Ryan, C. J., Rosenthal, M., Ng, S., Alumkal, J., Picus, J., et al. (2013). Targeted MET inhibition in castration-resistant prostate cancer: a randomized phase II study and biomarker analysis with rilotumumab plus mitoxantrone and prednisone. Clinical Cancer Research, 19(1), 215–224.

    Article  CAS  PubMed  Google Scholar 

  30. Kurzrock, R., Sherman, S. I., Ball, D. W., Forastiere, A. A., Cohen, R. B., et al. (2011). Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. Journal of Clinical Oncology, 29(19), 2660–2666.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Smith, D. C., Smith, M. R., Sweeney, C., Elfiky, A. A., Logothetis, C., et al. (2013). Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. Journal of Clinical Oncology, 31(4), 412–419.

    Article  CAS  PubMed  Google Scholar 

  32. Yap, T. A., Olmos, D., Brunetto, A. T., Tunariu, N., Barriuso, J., et al. (2011). Phase I trial of a selective c-Met inhibitor ARQ197 incorporating proof of mechanism pharmacodynamic studies. Journal of Clinical Oncology, 29(10), 1271–1279.

    Article  CAS  PubMed  Google Scholar 

  33. Engelman, J. A. (2009). Targeting PI3K signaling in cancer; opportunities, challenges and limitations. Nature Reviews Cancer, 9(8), 550–562.

    Article  CAS  PubMed  Google Scholar 

  34. Courtney, K. D., Corcoran, R. B., & Engelman, J. A. (2010). The PI3K pathway as drug target in human cancer. Journal of Clinical Oncology, 28(6), 1075–1083.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Dancey, J. (2010). mTOR signaling and drug development in cancer. Nature Reviews. Clinical Oncology, 7(4), 209–219.

    Article  CAS  PubMed  Google Scholar 

  36. Taylor, B. S., Schultz, N., Hieronymus, H., Gopalan, A., Xiao, Y., et al. (2010). Integrative genomic profiling of human prostate cancer. Cancer Cell, 18(1), 11–22.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Amato, R. J., Jac, J., Mohammad, T., & Saxena, S. (2008). Pilot study of rapamycin in patients with hormone-refractory prostate cancer. Clinical Genitourinary Cancer, 6(2), 97–102.

    Article  CAS  PubMed  Google Scholar 

  38. Armstrong A.J., Shen T., Halabi S., Kemeny G., Bitting R.L., et al. (2013). A phase II trial of temsirolimus in men with castration-resistant metastatic prostate cancer. Journal of Clinical Oncology, 31 (6 Suppl.), Abstract 105.

    Google Scholar 

  39. Nakabayashi, M., Werner, L., Courtney, K. D., Buckel, G., Oh, W. K., et al. (2012). Phase II trial of RAD001 and bicalutamide for castration-resistant prostate cancer. BJU International, 110(11), 1729–1735.

    Article  CAS  PubMed  Google Scholar 

  40. Grunwald, V., DeGraffenried, L., Russel, D., Friedrichs, W. E., Ray, R. B., et al. (2002). Inhibitors of mTOR reverse doxorubicin resistance conferred by PTEN status in prostate cancer cells. Cancer Research, 62(21), 6141–6145.

    CAS  PubMed  Google Scholar 

  41. Duran I., Montagut C., Calvo E., Galtes S., Navarrete A., et al. (2012). Overcoming docetaxel resistance in advanced castration-resistant prostate cancer (CRPC): A phase I/II trial of the combination of temsirolimus and docetaxel. Journal of Clinical Oncology, 30 (5 Suppl.), Abstract 250.

    Google Scholar 

  42. Carver, B. S., Chapinski, C., Wongvipat, J., Hieronymus, H., Chen, Y., et al. (2011). Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell, 19(5), 575–586.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Maira, S. M., Stauffer, F., Brueggen, J., Furet, P., Schnell, C., et al. (2008). Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Molecular Cancer Therapeutics, 7(7), 1851–1863.

    Article  CAS  PubMed  Google Scholar 

  44. Burris H., Rodon J., Sharma S., Herbst R.S., Tabernero J., et al. (2010). First-in-human phase I study of the oral PI3K inhibitor BEZ235 in patients with advanced solid tumors. Journal of Clinical Oncology, 28 (15 Suppl.), Abstract 3005.

    Google Scholar 

  45. Posadas, E. M., Gulley, J., Arlen, P. M., Trout, A., Parnes, H. L., et al. (2005). A phase II study of perifosine in androgen independent prostate cancer. Cancer Biology & Therapy, 4(10), 1133–1137.

    Article  CAS  Google Scholar 

  46. Chee, K. G., Longmate, J., Quinn, D. I., Chatta, G., Pinski, J., et al. (2007). The AKT inhibitor perifosine in biochemically recurrent prostate cancer: a phase II California/Pittsburgh cancer consortium trial. Clinical Genitourinary Cancer, 5(7), 433–437.

    Article  CAS  PubMed  Google Scholar 

  47. Yap, T. A., Yan, L., Patnaik, A., Fearen, I., Olmos, D., et al. (2011). First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors. Journal of Clinical Oncology, 29(35), 4688–4695.

    Article  CAS  PubMed  Google Scholar 

  48. Bendell, J. C., Rodon, J., Burris, H. A., de Jonge, M., Verweij, J., et al. (2012). Phase I, dose-escalation study of BKM120, an oral pan-class I PI3K inhibitor, in patients with advanced solid tumors. Journal of Clinical Oncology, 30(3), 282–290.

    Article  CAS  PubMed  Google Scholar 

  49. Hong, D. S., Bowles, D. W., Falchook, G. S., Messersmith, W. A., George, G. C., et al. (2012). A multicenter phase I trial of PX-866, an oral irreversible phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors. Clinical Cancer Research, 18(15), 4173–4182.

    Article  CAS  PubMed  Google Scholar 

  50. Rubin, L. L., & de Sauvage, F. J. (2006). Targeting the hedgehog pathway in cancer. Nature Reviews Drug Discovery, 5(12), 1026–1033.

    Article  CAS  PubMed  Google Scholar 

  51. Kim, T. J., Lee, J. Y., Hwang, T. K., Kang, C. S., & Choi, Y. J. (2011). Hedgehog signaling protein expression and its association with prognostic parameters in prostate cancer: a retrospective study from the viewpoint of new 2010 anatomic stage/prognostic groups. Journal of Surgical Oncology, 104(5), 472–479.

    Article  CAS  PubMed  Google Scholar 

  52. Chen, M., Carkner, R., & Buttyan, R. (2011). The hedgehog/Gli signaling paradigm in prostate cancer. Expert Review of Endocrinology and Metabolism, 6(3), 453–467.

    Article  PubMed Central  PubMed  Google Scholar 

  53. Ibuki, N., Ghaffari, M., Pandey, M., Iu, I., Fazli, L., et al. (2013). TAK-441, a novel investigational smoothened antagonist, delays castration-resistant progression in prostate cancer by disrupting paracrine hedgehog signaling. International Journal of Cancer, 133(8), 1955–1966.

    Article  CAS  Google Scholar 

  54. Kim, J., Tang, J. Y., Gong, R., Kim, J., Lee, J. J., et al. (2010). Itraconazole, a commonly used antifungal that inhibits hedgehog pathway activity and cancer growth. Cancer Cell, 17(4), 388–399.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. Aftab, B. T., Dombromilskaya, I., Liu, J. O., & Rudin, C. M. (2011). Itraconazole inhibits angiogenesis and tumor growth in non-small cell lung cancer. Cancer Research, 71(21), 6764–6772.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  56. Antonarakis, E. S., Heath, E. I., Smith, D. C., Rathkopf, D., Blackford, A. L., et al. (2013). Repurposing itraconazole as a treatment for advanced prostate cancer: a noncomparative randomized phase II trial in men with metastatic castration-resistant prostate cancer. The Oncologist, 18(2), 163–173.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. Wheeler, D. L., Iida, M., & Dunn, E. F. (2009). The role of Src in solid tumors. The Oncologist, 14(7), 667–678.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Park, S. I., Zhang, J., Phillips, K. A., Araujo, J. C., Najjar, A. M., et al. (2008). Targeting Src family kinases inhibits growth and lymph node metastases of prostate cancer in an orthotopic nude mouse model. Cancer Research, 68(9), 3323–3333.

    Article  CAS  PubMed  Google Scholar 

  59. Yu, E. Y., Wilding, G., Posadas, E., Gross, M., Culine, S., et al. (2009). Phase II study of dasatinib in patients with metastatic castration-resistant prostate cancer. Clinical Cancer Research, 15(23), 7421–7428.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  60. Araujo, J. C., Mathew, P., Armstrong, A. J., Braud, E. L., Posadas, E., et al. (2012). Dasatinib combined with docetaxel for castration-resistant prostate cancer: results from a phase 1-2 study. Cancer, 118(1), 63–71.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  61. Araujo J.C., Trudel G.C., Saad F., Armstrong A.J., Yu E.Y., et al. (2013). Overall survival and safety of dasatinib/docetaxel versus docetaxel in patients with metastatic castration-resistant prostate cancer: results from the randomized phase III READY trial. Journal of Clinical Oncology, 31 (6 Suppl.), Abstract LBA8.

  62. Lara, P. N., Longmate, J., Evans, C. P., Quinn, D. I., Twardowski, P., et al. (2009). A phase II trial of the Src-kinase inhibitor AZD0530 in patients with advanced castration-resistant prostate cancer: a California Cancer Consortium study. Anti-Cancer Drugs, 20(3), 179–184.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  63. Antonarakis E.S., Heath E.I., Posadas E.M., Harrison M.R., Bruce J.Y., et al. (2013). A phase 2 study of KX2-391, an oral inhibitor of Src kinase and tubulin polymerization, in men with bone-metastatic castration-resistant prostate cancer. Cancer Chemotherapy and Pharmacology, 71(4), 883–892.

    Google Scholar 

  64. Nelson, J., Bagnato, A., Battinstini, B., & Nisen, P. (2003). The endothelin axis: emerging role in cancer. Nature Reviews Cancer, 3(2), 110–116.

    Article  CAS  PubMed  Google Scholar 

  65. Fizazi, K. S., Higano, C. S., Nelson, J. B., Gleave, M., Miller, K., et al. (2013). Phase III, randomized, placebo-controlled study of docetaxel in combination with zibotentan in patients with metastatic castration-resistant prostate cancer. Journal of Clinical Oncology, 31(14), 1740–1747.

    Article  CAS  PubMed  Google Scholar 

  66. Nelson, J. B., Fizazi, K., Miller, K., Higano, C., Moul, J. W., et al. (2012). Phase 3, randomized, placebo-controlled study of zibotentan (ZD4054) in patients with castration-resistant prostate cancer metastatic to bone. Cancer, 118(22), 5709–5718.

    Article  CAS  PubMed  Google Scholar 

  67. Miller, K., Moul, J. W., Gleave, M., Fizazi, K., Nelson, J. B., et al. (2013). Phase III, randomized, placebo-controlled study of once-daily oral zibotentan (ZD4054) in patients with non-metastatic castration resistant prostate cancer. Prostate Cancer and Prostatic Diseases, 16(2), 187–192.

    Article  CAS  PubMed  Google Scholar 

  68. Nelson, J. B., Love, W., Chin, J. L., Saad, F., Schulman, C. C., et al. (2008). Phase 3, randomized, controlled trial of atrasentan in patients with non-metastatic, hormone-refractory prostate cancer. Cancer, 113(9), 2478–2487.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  69. Quinn D.I., Tangen C.M., Hussain M., Lara P., Goldkorn A., et al. (2012). SWOG S0421: Phase III study of docetaxel and atrasentan versus docetaxel and placebo for men with advanced castrate resistant prostate cancer. Journal of Clinical Oncology, 30 (15 Suppl.), Abstract 4511.

    Google Scholar 

  70. Carducci, M. A., Saad, F., Abrahamsson, P. A., Dearnaley, D. P., Schulman, C. C., et al. (2007). A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer. Cancer, 110(9), 1959–1966.

    Article  CAS  PubMed  Google Scholar 

  71. Pollak, M. (2008). Insulin and insulin-like growth factor signaling in neoplasia. Nature Reviews Cancer, 8(12), 915–928.

    Article  CAS  PubMed  Google Scholar 

  72. Arcaro, A. (2013). Targeting the insulin-like growth factor-1 receptor in human cancer. Frontiers in Pharmacology, 4, 1–8.

    Article  Google Scholar 

  73. Renehan, A. G., Zwahlen, M., Minder, C., O’Dwyer, S. T., Shalet, S. M., et al. (2004). Insulin-like growth factor (IGF)-1, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet, 363(9418), 1346–1353.

    Article  CAS  PubMed  Google Scholar 

  74. Price, A. J., Allen, N. E., Appelby, P. N., Crowe, F. L., Travis, R. C., et al. (2012). Insulin-like growth factor-1 concentration and risk of prostate cancer: results from the European Prospective Investigation into Cancer and Nutrition. Cancer Epidemiology, Biomarkers & Prevention, 21(9), 1531–1541.

    Article  CAS  Google Scholar 

  75. Krueckl, S. L., Sikes, R. A., Edlund, N. M., Bell, R. H., Hurado-Coll, A., et al. (2004). Increased insulin-like growth factor I receptor expression and signaling are components of androgen-independent progression in a lineage-derived prostate cancer progression model. Cancer Research, 64(23), 8620–8629.

    Article  CAS  PubMed  Google Scholar 

  76. Wu, J. D., Odman, A., Higgins, L. M., Haugk, K., Vessella, R., et al. (2005). In vivo effects of the human type I insulin-like growth factor receptor antibody A12 on androgen-dependent and androgen-independent xenograft human prostate tumors. Clinical Cancer Research, 11(8), 3065–3074.

    Article  CAS  PubMed  Google Scholar 

  77. O’Reilly, K. E., Rojo, F., She, Q., Solit, D., Mills, G. B., et al. (2006). mTOR inhibition induces upstream tyrosine kinase signaling and activates AKT. Cancer Research, 66(3), 1500–1508.

    Article  PubMed Central  PubMed  Google Scholar 

  78. Higano C., Alumkal J., Ryan C.J., Yu E.Y., Beer T.M., et al. (2009). A phase II study evaluating the efficacy and safety of single agent IMC A12, a monoclonal antibody, against the insulin-like growth factor-1 receptor, as monotherapy in patients with metastatic, asymptomatic castration-resistant prostate cancer. Journal of Clinical Oncology, 27 (15 Suppl.), Abstract 5142.

    Google Scholar 

  79. Hussain M., Rathkopf D.E., Lui G., Armstrong A.J., Kelly W.K., et al. (2012). A phase II randomized study of cixutumumab or ramucirumab plus mitoxantrone and prednisone in patients with metastatic castrate-resistant prostate cancer following disease progression on docetaxel therapy. Journal of Clinical Oncology, 30 (5 Suppl.), Abstract 97.

    Google Scholar 

  80. Garcia J.A., Elson P., Cooney M.M, Tyler A.J., Rezash V., et al. (2013). A phase II study of linsitinib (OSI-906) in patients with asymptomatic or mildly symptomatic (non-opioid requiring) metastatic castrate resistant prostate cancer (CRPC). Journal of Clinical Oncology, 31 (6 Suppl.), Abstract 197.

    Google Scholar 

Download references

Disclosures

The authors have no relevant conflicts of interest related to this work.

Author information

Authors and Affiliations

  1. Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA

    Jocelyn L. Wozney

  2. Prostate Cancer Research Program, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, CRB1-1 M45, 1650 Orleans St., Baltimore, MD, 21231, USA

    Emmanuel S. Antonarakis

Authors
  1. Jocelyn L. Wozney
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Emmanuel S. Antonarakis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Emmanuel S. Antonarakis.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wozney, J.L., Antonarakis, E.S. Growth factor and signaling pathways and their relevance to prostate cancer therapeutics. Cancer Metastasis Rev 33, 581–594 (2014). https://doi.org/10.1007/s10555-013-9475-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-013-9475-z

Keywords

Search

Navigation