Biomodulatory Therapy Approaches in Renal Clear Cell Carcinoma: A Perspective

  • Albrecht Reichle


The remarkable efficacy of multi-targeted biomodulatory therapies may be exemplarily shown in renal clear cell carcinoma (RCCC), particularly the biomodulatory activity of VEGFR-tyrosine kinase inhibitors and transcriptional modulators (pioglitazone and interferon-alpha). Biomodulation remodels tumor-immanent normative notions by therapeutically implementing non-normative boundary conditions in such a way that tumor control becomes possible. Normative notions in a tumor are morphological structures that are not only built differently in an evolutionary context, but are also evolutionarily constrained action norms, such as the hallmarks of cancer, and multifaceted patterns of inherent decision maxims, i.e., hubs and nodes. The biomodulatory activity of VEGFR-tyrosine kinase inhibitors is underlined (1) by different mechanisms of action dependent on the type of tumor (hepatocellular carcinoma, RCCC, de novo and relapsed acute myelocytic leukemia), (2) by profiles of side effects related to the type of tumor, and (3) by efficacy dependent on the metastatic organ site. The specific activity of transcriptional modulators in RCCC has been shown in recent phase II trials by the combined administration of pioglitazone and interferon-alpha. Established biomodulatory first-line therapies in RCCC need to be supplemented by further biomodulatory therapeutic principles for circumventing the following two dilemmas: The difficult combination of VEGFR-tyrosine kinase inhibitors with other classic targeted therapies because of cumulative toxicities, and the inefficacy of VEGFR-tyrosine kinase inhibitors in patients with bone (about 30 %) and brain (4–48 %) metastases from RCCC. As shown in clinical trials, multi-targeted biomodulatory therapy approaches have in principle the ability to induce continuous complete remission in metastatic renal clear cell carcinoma at a low rate of side effects.


Acute Myelocytic Leukemia Metastatic Renal Cell Carcinoma Renal Clear Cell Carcinoma Transcriptional Modulator Histological Tumor Type 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Breau RH, Blute ML (2010) Surgery for renal cell carcinoma metastases. Curr Opin Urol 20(5):375–381 (Review)PubMedCrossRefGoogle Scholar
  2. 2.
    Chapin BF, Delacroix SE Jr, Wood CG (2011) Renal cell carcinoma: what the surgeon and treating physician need to know. AJR Am J Roentgenol 196(6):1255–1262PubMedCrossRefGoogle Scholar
  3. 3.
    Sun M, Shariat SF, Cheng C et al (2011) Prognostic factors and predictive models in renal cell carcinoma: a contemporary review. Eur Urol (Epub ahead of print)Google Scholar
  4. 4.
    Patard JJ, Pignot G, Escudier B et al (2011) ICUD-EAU international consultation on kidney cancer 2010: treatment of metastatic disease. Eur Urol (Epub ahead of print)Google Scholar
  5. 5.
    Rini BI, Escudier B, Tomczak P et al (2011) Axitinib versus sorafenib as second-line therapy for metastatic renal cell carcinoma (mRCC): results of phase III AXIS trial. Category: J Clin Oncol 29(suppl):abstr 4503Google Scholar
  6. 6.
    Bhargava P, Robinson MO (2011) Development of second-generation VEGFR tyrosine kinase inhibitors: current status. Curr Oncol Rep 13(2):103–111PubMedCrossRefGoogle Scholar
  7. 7.
    Ravandi F, Cortes JE, Jones D et al (2010) Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. J Clin Oncol 28(11):1856–1862PubMedCrossRefGoogle Scholar
  8. 8.
    Metzelder S, Wang Y, Wollmer E et al (2009) Compassionate use of sorafenib in FLT3- ITD-positive acute myeloid leukemia: sustained regression before and after allogeneic stem cell transplantation. Blood 113(26):6567–6571PubMedCrossRefGoogle Scholar
  9. 9.
    Molina AM, Jia X, Ginsberg MS et al (2011) Memorial Sloan-Kettering Cancer Center, New York, NY. Long-term response to sunitinib for metastatic renal cell carcinoma (mRCC) patients treated on clinical trials at Memorial Sloan-Kettering Cancer Center. J Clin Oncol 29(suppl):abstr 4615Google Scholar
  10. 10.
    Remon J, Lianes P, Martínez S (2011) Brain metastases from renal cell carcinoma. Should we change the current standard? Cancer Treat Rev (Epub ahead of print)Google Scholar
  11. 11.
    Reichle A, Hildebrandt GC (2010) The comparative uncovering of tumor systems biology by modularly targeting tumor-associated inflammation. In: From molecular to modular tumor therapy: the tumor microenvironment, vol 3, part 4. Springer, pp 287–303. doi:10.1007/978-90-481-9531-2_13Google Scholar
  12. 12.
    Huynh H, Ong RW, Li PY et al (2011) Targeting receptor tyrosine kinase pathways in hepatocellular carcinoma. Anticancer Agents Med Chem 11(6):560–575PubMedCrossRefGoogle Scholar
  13. 13.
    Duignan IJ, Corcoran E, Pennello A et al (2011) Pleiotropic stromal effects of vascular endothelial growth factor receptor 2 antibody therapy in renal cell carcinoma models. Neoplasia 13(1):49–59PubMedGoogle Scholar
  14. 14.
    Escudier B, Eisen T, Stadler WM et al (2009) Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol 27(20):3312–3318PubMedCrossRefGoogle Scholar
  15. 15.
    Hoffmann K, Glimm H, Radeleff B et al (2008) Prospective, randomized, double-blind, multi-center, phase III clinical study on transarterial chemoembolization (TACE) combined with Sorafenib versus TACE plus placebo in patients with hepatocellular cancer before liver transplantation—HeiLivCa [ISRCTN24081794]. BMC Cancer 8:349PubMedCrossRefGoogle Scholar
  16. 16.
    Reichle A, Hildebrandt GC (2010) From molecular to modular, from theme-dependent to evolution-adjusted tumor therapy. In: From molecular to modular tumor therapy: The tumor microenvironment, vol 3, part 9. Springer, pp 545–556. doi:10.1007/978-90-481-9531-2_27Google Scholar
  17. 17.
    Walter B, Schrettenbrunner I, Vogelhuber M et al (2010) C-reactive protein as a secretome-derived biomarker for predicting response to biomodulatory therapy in metastatic renal clear cell carcinoma. In: From molecular to modular tumor therapy: the tumor microenvironment, vol 3, part 5. Springer, pp 353–366. doi:10.1007/978-90-481-9531-2_17Google Scholar
  18. 18.
    Walter B, Schrettenbrunner I, Vogelhuber M, Grassinger J, Bross K, Wilke J, Suedhoff T, Berand A, Wieland WF, Rogenhofer S, Andreesen R, Reichle A (2012) Pioglitazone, etoricoxib, interferon-α, and metronomic capecitabine for metastatic renal cell carcinoma: final results of a prospective phase II trial. Med Oncol 29(2):799–805. doi: 10.1007/s12032-011-9982-0PubMedCrossRefGoogle Scholar
  19. 19.
    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: From molecular to modular tumor therapy: the tumor microenvironment, vol 3, part 6. Springer, pp 433–465. doi: 10.1007/978-90-481-9531-2_22Google Scholar
  20. 20.
    Heng DYC, Xie W, Harshman LC, Bjarnason GA, Vaishampayan UN, Lebert J, Wood L, Donskov F, Tan M, Rha SY, Wells C, Wang Y, Kollmannsberger CK, Rini BI, Choueiri TK (2011) External validation of the International Metastatic Renal Cell Carcinoma (mRCC) Database Consortium prognostic model and comparison to four other models in the era of targeted therapy. J Clin Oncol 29 (suppl):abstr 4560Google Scholar
  21. 21.
    Reichle A, Grassinger J, Bross K, Wilke J, Suedhoff T, Walter B, Wieland WF, Berand A, Andreesen R (2007) C-reactive protein in patients with metastatic clear cell renal carcinoma: an important biomarker for tumor-associated inflammation. Biomark Insights 1:87–98PubMedGoogle Scholar
  22. 22.
    Paulitschke V et al (2010) Secretome proteomics, a novel tool for biomarkers discovery and for guiding biomodulatory therapy approaches. In: From molecular to modular tumor therapy: the tumor microenvironment, vol 3, part 6. Springer, pp 405 431. doi:10.1007/978-90-481-9531-2_21Google Scholar
  23. 23.
    Kiessling F, Lederle W (2010) Early detection of systems response: molecular and functional imaging of angiogenesis. In: From molecular to modular tumor therapy: the tumor microenvironment, vol 3, part 6. Springer, pp 385–403. doi: 10.1007/978-90-481-9531-2_20Google Scholar
  24. 24.
    Reichle A, Vogelhuber M, Feyerabend S, Suedhoff T, Schulz M, Huebner J, Oberneder R, Baier M, Ruebel A, Birkholz K, Bakhshandeh-Bath A, Andreesen R (2011) A phase II study of imatinib with pioglitazone, etoricoxib, dexamethasone, and low-dose treosulfan: combined anti-inflammatory, immunomodulatory, and angiostatic treatment in patients (pts) with castration-refractory prostate cancer (CRPC). J Clin Oncol 29 (suppl):abstr 4599Google Scholar
  25. 25.
    Goel S, Fukumura D, Jain RK (2012) Normalization of the tumor vasculature through oncogenic inhibition: an emerging paradigm in tumor biology. Proc Natl Acad Sci USA 109(20):E1214PubMedCrossRefGoogle Scholar
  26. 26.
    Reichle A, Hildebrandt GC (2008) Systems biology: a therapeutic target for tumor therapy. Cancer Microenviron 1(1):159–170PubMedCrossRefGoogle Scholar
  27. 27.
    Reichle A, Hildebrandt GC (2010) To be an object in a biological system. The necessity of a formal-pragmatic communication theory. In: From molecular to modular tumor therapy: the tumor microenvironment, vol 3, part 9. Springer, pp 537–544. doi: 10.1007/978-90-481-9531-2_26Google Scholar
  28. 28.
    Emmenegger U, Chow A, Bocci G (2010) The biomodulatory capacities of low-dose metronomic chemotherapy: complex modulation of the tumor microenvironment. In: From molecular to modular tumor therapy: the tumor microenvironment, vol 3, part 3. Springer, pp 243–262. doi: 10.1007/978-90-481-9531-2_11Google Scholar
  29. 29.
    Bundscherer A, Hafner H (2010) Breathing new life into old drugs: indication discovery by systems directed therapy. In: From molecular to modular tumor therapy: the tumor microenvironment, vol 3, part 3. Springer, pp 483–503. doi:10.1007/978-90-481-9531-2_11Google Scholar
  30. 30.
    Beck Ilse ME, Haegemann G, De Bosscher K (2010) Molecular cross-talk between nuclear receptors and nuclear factor-NFkappaB. In: From molecular to modular tumor therapy: the tumor nicroenvironment, vol 3, part 3. pp 191–242. doi:10.1007/978-90-481-9531-2_10Google Scholar
  31. 31.
    Chung AS, Kowanetz M, Wu X, Zhuang G, Ngu H, Finkle D, Komuves L, Peale F, Ferrara N (2012) Differential drug class-specific metastatic effects following treatment with a panel of angiogenesis inhibitors. J Pathol. doi: 10.1002/path.4052Google Scholar
  32. 32.
    Hollebecque A, Massard C, Soria JC (2012) Vascular disrupting agents: a delicate balance between efficacy and side effects. Curr Opin Oncol 24(3):305–315 (Review)PubMedCrossRefGoogle Scholar
  33. 33.
    Van der Veldt AA, Lubberink M, Bahce I, Walraven M, de Boer MP, Greuter HN, Hendrikse NH, Eriksson J, Windhorst AD, Postmus PE, Verheul HM, Serné EH, Lammertsma AA, Smit EF (2012) Rapid decrease in delivery of chemotherapy to tumors after anti-VEGF therapy: implications for scheduling of anti-angiogenic drugs. Cancer Cell 21(1):82–91PubMedCrossRefGoogle Scholar
  34. 34.
    Serve H et al (2013) Sorafenib in combination with intensive chemotherapy in elderly patients with acute myeloid leukemia: results from a randomized, placebo-controlled trial. J Clin Oncol (in press)Google Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  1. 1.Department Hematology/OncologyUniversity Hospital RegensburgRegensburgGermany

Personalised recommendations