Redirecting and Modulating Rationalizations of Tumor-Immanent Normative Functions in Castration-Resistant Prostate Cancer

  • M. Vogelhuber
  • S. Feyerabend
  • A. Stenzl
  • T. Suedhoff
  • M. Schulze
  • J. Huebner
  • R. Oberneder
  • W. Wieland
  • S. Mueller
  • F. Eichhorn
  • H. Heinzer
  • K. Schmidt
  • M. Baier
  • A. Ruebel
  • K. Birkholz
  • A. Bakhshandeh-Bath
  • R. Andreesen
  • A. Reichle
Chapter

Abstract

With a median survival period of approximately 19 months, therapeutic options for patients with castration-resistant prostate cancer (CRPC) remain limited. In a multicenter phase II trial, 65 patients with histologically confirmed CRPC continuously received a biomodulatory regimen during the 6-month core period for redirecting tumor-promoting normative notions, i.e. angiogenesis, inflammation, immune response and the osteoplastic process. Treatment comprised daily doses of imatinib mesylate, pioglitazone, etoricoxib, treosulfan, and dexamethasone. The primary endpoint was prostate-specific antigen (PSA) response, defined as a confirmed reduction in serum PSA of ≥  50  % in patients with a baseline value of ≥  5 ng/mL. Responders could enter an extension phase until disease progression or presence of intolerable toxicity. Mean PSA was 45.3 ng/mL at baseline, and 77  % of the patients had a PSA doubling time of <  3 months. Twenty three (37.7  %) out of the 61 evaluable patients were PSA responders, who showed a mean PSA decrease from 278.9 ± 784.1 ng/mL at baseline to 8.8 ± 11.6 ng/mL at the final visit (24 weeks or LOCF). The remaining 38 non-responders included 14 patients (23.0  %) with stable disease. In one center, 6 out of 16 patients showed nearly complete resolution of bone metastases. Out of the 947 adverse events observed, 57.6  % were suspected to be drug-related, 13.8  % led to dose adjustment or permanent discontinuation of the study medication, and 40.2  % required concomitant medication. Twenty seven patients experienced serious adverse events. This novel multi-targeted approach led to an impressive PSA response rate of 37.7  % in CRPC patients despite the fact that individual components had shown limited efficacy when applied on their own. The good PSA response rate and the manageable toxicity profile suggest that this combination may offer an alternative treatment option to present therapeutic regimens.

References

  1. 1.
    Osanto S, Van Poppel H (2012) Emerging novel therapies for advanced prostate cancer. Ther Adv Urol 4:3–12PubMedCrossRefGoogle Scholar
  2. 2.
    Ryan CJ, Smith MR, de Bono JS et al (2013) COU-AA-302 Investigators. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 368(2):138–48. doi: 10.1056/NEJMoa1209096. Epub 2012 Dec 10PubMedCrossRefGoogle Scholar
  3. 3.
    Logothetis CJ, Basch E, Molina A et al (2012) Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial. Lancet Oncol 13(12):1210–1217. doi: 10.1016/S1470–2045(12)70473-4. Epub 2012 Nov 9PubMedCrossRefGoogle Scholar
  4. 4.
    Reichle A, Vogt T (2008) Systems biology: a therapeutic target for tumor therapy. Cancer Microenviron 1:159–170PubMedCrossRefGoogle Scholar
  5. 5.
    Reichle A, Hildebrandt GC (2009) Principles of modular tumor therapy. Cancer Microenviron 2(Suppl 1):227–237PubMedCrossRefGoogle Scholar
  6. 6.
    Reichle A (2009) Tumor systems need to be rendered usable for a new action-theoretical abstraction: the starting point for novel therapeutic options. Curr Cancer Ther Rev 5:232–242CrossRefGoogle Scholar
  7. 7.
    Mimeault M, Johansson SL, Batra SK (2012) Pathobiological implications of the expression of EGFR, pAkt, NF-Φ#186;B and MIC-1 in prostate cancer stem cells and their progenies. PLoS ONE 7:e31919PubMedCrossRefGoogle Scholar
  8. 8.
    Azevedo A, Cunha V, Teixeira AL et al (2011) IL-6/IL-6R as a potential key signaling pathway in prostate cancer development. World J Clin Oncol 2:384–396PubMedCrossRefGoogle Scholar
  9. 9.
    Jain G, Cronauer MV, Schrader M et al (2012) NF-κB signaling in prostate cancer: a promising therapeutic target? World J Urol 30:303–310PubMedCrossRefGoogle Scholar
  10. 10.
    Huber ML, Haynes L, Parker C et al (2012) Interdisciplinary critique of sipuleucel-T as immunotherapy in castration-resistant prostate cancer. J Natl Cancer Inst 104:273–279PubMedCrossRefGoogle Scholar
  11. 11.
    Kantoff PW, Higano CS, Shore ND et al (2010) Sipuleucel-T immunotherapy for castration-resistant prostate cancer. New Engl J Med 363:411–422PubMedCrossRefGoogle Scholar
  12. 12.
    Tang S, Moore ML, Grayson JM et al (2012) Increased CD8 + T cell function following castration and immunization is countered by parallel expansion of regulatory T cells. Cancer Res 72:1975–1985PubMedCrossRefGoogle Scholar
  13. 13.
    Scher HI, Halabi S, Tannock I et al (2008) Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol 26:1148–1159PubMedCrossRefGoogle Scholar
  14. 14.
    Ustach CV, Huang W, Conley-LaComb MK et al (2010) A novel signaling axis of matriptase/PDGF-D/ß-PDGFR in human prostate cancer. Cancer Res 70:9631–9640PubMedCrossRefGoogle Scholar
  15. 15.
    Mathew P, Thall PF, Jones D et al (2004) Platelet-derived growth factor receptor inhibitor imatinib mesylate and docetaxel: a modular phase I trial in androgen-independent prostate cancer. J Clin Oncol 22:3323–3329PubMedCrossRefGoogle Scholar
  16. 16.
    Meyer S, Vogt T, Landthaler M et al (2010) Cyclooxygenase 2 (COX2) and peroxisome proliferator-activated receptor gamma (PPARG) are stage-dependent prognostic markers of malignant melanoma. In: Reichle A (ed) From molecular to modular tumor therapy. Springer, Berlin, pp 433–465CrossRefGoogle Scholar
  17. 17.
    Nakamura Y, Suzuki T, Sugawara A et al (2009) Peroxisome proliferator-activated receptor gamma in human prostate carcinoma. Pathol Int 59:288–293PubMedCrossRefGoogle Scholar
  18. 18.
    Lyles BE, Akinyeke TO, Moss PE et al (2009) Thiazolidinediones regulate expression of cell cycle proteins in human prostate cancer cells via PPARgamma-dependent and PPARgamma independent pathways. Cell Cycle 8:268–277PubMedCrossRefGoogle Scholar
  19. 19.
    Matsuyama M, Yoshimura R (2008) Peroxisome proliferator-activated receptor-gamma is a potent target for prevention and treatment in human prostate and testicular cancer. PPAR Res 2008:249849PubMedCrossRefGoogle Scholar
  20. 20.
    Smith MR, Manola J, Kaufman DS et al (2004) Rosiglitazone versus placebo for men with prostate carcinoma and a rising serum prostate-specific antigen level after radical prostatectomy and/or radiation therapy. Cancer 101:1569–1574PubMedCrossRefGoogle Scholar
  21. 21.
    Shockley KR, Lazarenko OP, Czernik PJ et al (2009) PPARgamma2 nuclear receptor controls multiple regulatory pathways of osteoblast differentiation from marrow mesenchymal stem cells. J Cell Biochem 106:232–246PubMedCrossRefGoogle Scholar
  22. 22.
    Storlie JA, Buckner JC, Wiseman GA et al (1995) Prostate specific antigen levels and clinical response to low dose dexamethasone for hormone-refractory metastatic prostate carcinoma. Cancer 76:96–100PubMedCrossRefGoogle Scholar
  23. 23.
    Nishimura K, Nonomura N, Yasunaga Y et al (2000) Low doses of oral dexamethasone for hormone-refractory prostate carcinoma. Cancer 89:2570–2576PubMedCrossRefGoogle Scholar
  24. 24.
    Khor LY, Bae K, Pollack A et al (2007) COX-2 expression predicts prostate-cancer outcome: analysis of data from the RTOG 92-02 trial. Lancet Oncol 8:912–920PubMedCrossRefGoogle Scholar
  25. 25.
    Meyer S, Vogt T, Landthaler M et al (2009) Cyclooxygenase 2 (COX2) and peroxisome proliferator-activated receptor gamma (PPARG) are stage-dependent prognostic markers of malignant melanoma. PPAR Res 2009:848645PubMedGoogle Scholar
  26. 26.
    Emmenegger U, Chow A, Bocci G (2010) The biomodulatory capacities of low-dose metronomic chemotherapy: complex modulation of the tumor microenvironment. In: Reichle A (ed) From molecular to modular tumor therapy. Springer, Berlin, pp 433–465Google Scholar
  27. 27.
    Feyerabend S, Feil G, Krug J et al (2007) Cytotoxic effects of treosulfan on prostate cancer cell lines. Anticancer Res 27(4B):2403–2408PubMedGoogle Scholar
  28. 28.
    Nelius T, Rinard K, Filleur S (2011) Oral/metronomic cyclophosphamide-based chemotherapy as option for patients with castration-refractory prostate cancer: review of the literature. Cancer Treat Rev 37:444–455PubMedCrossRefGoogle Scholar
  29. 29.
    Glode LM, Barqawi A, Crighton F et al (2003) Metronomic therapy with cyclophosphamide and dexamethasone for prostate carcinoma. Cancer 98:1643–1648PubMedCrossRefGoogle Scholar
  30. 30.
    Walter B, Rogenhofer S, Vogelhuber M (2010) Modular therapy approach in metastatic castration-refractory prostate cancer. World J Urol 28:745–750PubMedCrossRefGoogle Scholar
  31. 31.
    Heidenreich A, Aus G, Bolla M et al (2008) EAU guidelines on prostate cancer. Eur Urol 53:68–80PubMedCrossRefGoogle Scholar
  32. 32.
    Berthold DR, Pond GR, Soban F et al (2008) Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol 26:242–245PubMedCrossRefGoogle Scholar
  33. 33.
    Tannock IF, de Wit R, Berry WR et al (2004) Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351:1502–1512PubMedCrossRefGoogle Scholar
  34. 34.
    Petrylak DP, Tangen CM, Hussain MH et al (2004) Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 351:1513–1520PubMedCrossRefGoogle Scholar
  35. 35.
    Morant R, Bernhard J, Dietrich D et al (2004) Capecitabine in hormone-resistant metastatic prostatic carcinoma—a phase II trial. Br J Cancer 90:1312–1317PubMedCrossRefGoogle Scholar
  36. 36.
    Pitteri SJ, Kelly-Spratt KS, Gurley KE et al (2011) Tumor microenvironment-derived proteins dominate the plasma proteome response during breast cancer induction and progression. Cancer Res 71:5090–5100PubMedCrossRefGoogle Scholar
  37. 37.
    Paulitschke V, Kunstfeld R, Gerner C et al (2010) Secretome proteomics, a novel tool for Biomarkers discovery and for guiding biomodulatory therapy approaches. In: Reichle A (ed) From molecular to modular tumor therapy. Springer, Berlin, pp 405–431CrossRefGoogle Scholar
  38. 38.
    Bundscherer A, Hafner C (2010) Breathing new life into old drugs. Indication discovery by systems-directed therapy. In: Reichle A (ed) In from molecular to modular tumor therapy. Springer, BerlinGoogle Scholar
  39. 39.
    Oprea TI, Bauman JE, Bologa CG et al (2011) Drug repurposing from an academic perspective. Drug DiscovToday Ther Strateg 8(3–4):61–69CrossRefGoogle Scholar
  40. 40.
    Berry DA (2011) Adaptive clinical trials in oncology. Nat Rev Clin Oncol 9:199–207PubMedCrossRefGoogle Scholar
  41. 41.
    Reichle A, Hildebrandt GH (2010) The comparative uncovering of tumor systems biology by modularly targeting tumor-associated inflammation. In: Reichle A (ed) From molecular to modular tumor therapy. Springer, Berlin, pp 287–303CrossRefGoogle Scholar
  42. 42.
    Ashida S, Orloff MS, Bebek G et al (2012) Integrated analysis reveals critical genomic regions in prostate tumor microenvironment associated with clinicopathologic phenotypes. Clin Cancer Res 18:1578–1587PubMedCrossRefGoogle Scholar
  43. 43.
    Squire JA, Park PC, Yoshimoto M et al (2011) Prostate cancer as a model system for genetic diversity in tumors. Adv Cancer Res 112:183–216PubMedCrossRefGoogle Scholar
  44. 44.
    Gu G, Brothman AR (2011) Cytogenomic aberrations associated with prostate cancer. Cancer Genet 204:57–67PubMedCrossRefGoogle Scholar
  45. 45.
    Bellmunt J (2008) Chemotherapy for prostate cancer in senior adults: are we treating the elderly or the frail? Eur Urol 55:1310–1312PubMedCrossRefGoogle Scholar
  46. 46.
    Walter LC, Covinsky KE (2001) Cancer screening in elderly patients: a framework for individualized decision making. JAMA 285:2750–2756PubMedCrossRefGoogle Scholar
  47. 47.
    Koroukian SM, Murray P, Madigan E (2006) Comorbidity, disability, and geriatric syndromes in elderly cancer patients receiving home health care. J Clin Oncol 24:2304–2310PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • M. Vogelhuber
    • 1
  • S. Feyerabend
    • 2
  • A. Stenzl
    • 2
  • T. Suedhoff
    • 3
  • M. Schulze
    • 4
  • J. Huebner
    • 5
  • R. Oberneder
    • 6
  • W. Wieland
    • 7
  • S. Mueller
    • 8
  • F. Eichhorn
    • 9
  • H. Heinzer
    • 10
  • K. Schmidt
    • 11
  • M. Baier
    • 11
  • A. Ruebel
    • 11
  • K. Birkholz
    • 11
  • A. Bakhshandeh-Bath
    • 12
  • R. Andreesen
    • 1
  • A. Reichle
    • 1
  1. 1.Department of Hematology and OncologyUniversity Hospital RegensburgRegensburgGermany
  2. 2.Department of UrologyUniversity Hospital TuebingenTuebingenGermany
  3. 3.Department of Hematology and OncologyHospital PassauPassauGermany
  4. 4.Outpatient Center for Urology and OncologyMarkkleebergGermany
  5. 5.Department of OncologyJ. W. Goethe UniversityFrankfurtGermany
  6. 6.Department of UrologyHospital PlaneggPlaneggGermany
  7. 7.Department of UrologyHospital St. Josef, University RegensburgRegensburgGermany
  8. 8.Department of UrologyUniversity Hospital BonnBonnGermany
  9. 9.Outpatient CenterBad ReichenhallGermany
  10. 10.University Hospital Hamburg-EppendorfHamburgGermany
  11. 11.Novartis Pharma GmbHNuernbergGermany
  12. 12.Outpatient Center for Medical OncologyHamburgGermany

Personalised recommendations