Abstract
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.
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Breau RH, Blute ML (2010) Surgery for renal cell carcinoma metastases. Curr Opin Urol 20(5):375–381 (Review)
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):1255–1262
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)
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)
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 4503
Bhargava P, Robinson MO (2011) Development of second-generation VEGFR tyrosine kinase inhibitors: current status. Curr Oncol Rep 13(2):103–111
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):1856–1862
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):6567–6571
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 4615
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)
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_13
Huynh H, Ong RW, Li PY et al (2011) Targeting receptor tyrosine kinase pathways in hepatocellular carcinoma. Anticancer Agents Med Chem 11(6):560–575
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):49–59
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):3312–3318
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 8:349
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_27
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_17
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/s12032-011-9982-0
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_22
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 4560
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 1:87–98
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_21
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_20
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 4599
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):E1214
Reichle A, Hildebrandt GC (2008) Systems biology: a therapeutic target for tumor therapy. Cancer Microenviron 1(1):159–170
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_26
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_11
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_11
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_10
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.4052
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)
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):82–91
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)
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Reichle, A. (2013). Biomodulatory Therapy Approaches in Renal Clear Cell Carcinoma: A Perspective. In: Reichle, A. (eds) Evolution-adjusted Tumor Pathophysiology:. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-6866-6_7
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