Abstract
We hypothesized, that tumor systems-directed therapies might have the capability to therapeutically modulate and redirect the tumor systems’ stability, homeostasis, robustness, and normative notions. This therapeutic ‘top down’ strategy may provide novel targets for the control of metastatic tumor disease. We comparatively analyzed redirection and modulation of tumor-associated normative notions, particularly inflammatory, osteoblastic activities, ECOG status, and metastatic potential in parallel with response, time to response and duration of response induced by continuously administered biomodulatory treatment modules (module M: metronomic low-dose chemotherapy; module A: pioglitazone plus etoricoxib; module A+M; module A+M/+: plus second transcriptional modulator [interferon-alpha or dexamethasone +/− imatinib or dexamethasone plus lenalidomide]) in the metastatic stages of seven different histological tumor types (ten phase II trials, two of them randomized; 333 patients; 80 % systemically pre-treated). A series of (randomized) phase II studies demonstrated differentially modularized accessibility of tumor-associated normative notions, i.e., inflammation, ECOG status, osteoblastic metastases, and metastatic tumor spread for mediating objective tumor response. Biomodulatory treatment schedules may induce long-term disease stabilization followed by prolonged objective response (3–100 %), even continuous complete remission, despite poor or no monoactivity of the respective drugs. Progression-free survival data are comparable with those of reductionist-designed standard first-line therapies. The differential response patterns indicate the therapies’ systems biological activity. Clinical efficacy of ‘top-down’ therapy strategies (biomodulatory therapy elements administered as fixed modules) for metastatic cancer provide excellent opportunities to point to central problems of communication among ‘systems participators’ in tumors. Combined modularized therapies (1) help to detect multifaceted, situatively adapted rationalization processes available for ubiquitously occurring tumor-immanent normative notions, (2) may uncover novel regulatory systems in tumor biology (e.g., hubs), (3) pathologies within communication processes (e.g., inconsistencies, disturbances in intersystemic exchange processes) (4) are a basis for studying communicative rules mediating the ‘metabolism’ of tumor evolution, and (5) may pave the way for inducing biological memory in metastatic tumors.
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References
Bundscherer A, Reichle A, Hafner C, Meyer S, Vogt T (2009) Targeting the tumor stroma with peroxisome proliferator activated receptor (PPAR) agonists. Anticancer Agents Med Chem 9(7):816–821. (Review)
Hafner C, Reichle A, Vogt T (2005) New indications for established drugs: combined tumor-stroma-targeted cancer therapy with PPARgamma agonists, COX-2 inhibitors, mTOR antagonists and metronomic chemotherapy. Curr Cancer Drug Targets 5(6):393–419. (Review)
Gehrmann M, Brunner M, Pfister K, Reichle A, Kremmer E, Multhoff G (2004) Differential up-regulation of cytosolic and membrane-bound heat shock protein 70 in tumor cells by anti-inflammatory drugs. Clin Cancer Res 10(10):3354–3364
Gottfried E, Rogenhofer S, Waibel H, Kunz-Schughart LA, Reichle A, Wehrstein M, Peuker A, Peter K, Hartmannsgruber G, Andreesen R, Kreutz M (2011) Pioglitazone modulates tumor cell metabolism and proliferation in multicellular tumor spheroids. Cancer Chemother Pharmacol 67(1):117–126
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 7(1):87–98
Paulitschke V, Gruber S, Hofstätter E, Haudek-Prinz V, Klepeisz P, Schicher N, Jonak C, Petzelbauer P, Pehamberger H, Gerner C, Kunstfeld R (2012) Proteome analysis identified the PPARγ ligand 15d-PGJ2 as a novel drug inhibiting melanoma progression and interfering with tumor-stroma interaction. PLoS One 7(9):e46103
Reichle A, Hildebrandt GC (2008) Systems biology: a therapeutic target for tumor therapy. Cancer Microenviron 1(1):159–170
Reichle A, Vogelhuber M, Feyerabend S et al (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)
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
Meyer S, Vogt T, Landthaler M, Berand A, Reichle A, Bataille F, Marx AH, Menz A, Hartmann A, Kunz-Schughart LA, Wild PJ (2009) Cyclooxygenase 2 (COX2) and peroxisome proliferator-activated receptor gamma (PPARG) are stage-dependent prognostic markers of malignant melanoma. PPAR Res 2009:848645. (Epub 2009)
Reichle A, Vogt T, Coras B, Terheyden P, Neuber K, Trefzer U, Schultz E, Berand A, Bröcker EB, Landthaler M, Andreesen R (2007) Targeted combined anti-inflammatory and angiostatic therapy in advanced melanoma: a randomized phase II trial. Melanoma Res 17(6):360–364
Coras B, Hafner C, Reichle A, Hohenleutner U, Szeimies RM, Landthaler M, Vogt T (2004) Antiangiogenic therapy with pioglitazone, rofecoxib, and trofosfamide in a patient with endemic Kaposi sarcoma. Arch Dermatol 140(12):1504–1507
Reichle A, Bross K, Vogt T, Bataille F, Wild P, Berand A, Krause SW, Andreesen R (2004) Pioglitazone and rofecoxib combined with angiostatically scheduled trofosfamide in the treatment of far-advanced melanoma and soft tissue sarcoma. Cancer 101(10):2247–2256
Vogt T, Hafner C, Bross K, Bataille F, Jauch KW, Berand A, Landthaler M, Andreesen R, Reichle A (2003) Antiangiogenetic therapy with pioglitazone, rofecoxib, and metronomic trofosfamide in patients with advanced malignant vascular tumors. Cancer 98(10):2251–2256
Walter B, Rogenhofer S, Vogelhuber M, Berand A, Wieland WF, Andreesen R, Reichle A (2010) Modular therapy approach in metastatic castration-refractory prostate cancer. World J Urol 28(6):745–750
Hau P, Kunz-Schughart L, Bogdahn U, Baumgart U, Hirschmann B, Weimann E, Muhleisen H, Ruemmele P, Steinbrecher A, Reichle A (2007) Low-dose chemotherapy in combination with COX-2 inhibitors and PPAR-gamma agonists in recurrent high-grade gliomas—a phase II study. Oncology 73(1–2):21–25
Vogt T, Coras B, Hafner C, Landthaler M, Reichle A (2006) Antiangiogenic therapy in metastatic prostate carcinoma complicated by cutaneous lupus erythematodes. Lancet Oncol 7(8):695–697
Reichle A, Vogt T, Kunz-Schughart L, Bretschneider T, Bachthaler M, Bross K, Freund S, Andreesen R (2005) Anti-inflammatory and angiostatic therapy in chemorefractory multisystem Langerhans’ cell histiocytosis of adults. Br J Haematol 128(5):730–732. (No abstract available)
Reichle A, Hart C, Grube M, Andreesen R (2012) Anti-Inflammatory, immuno-modulatory and angiostatic treatment as third-line therapy for multiple myeloma (MM)—a combined treatment setting of lenalidomide with pioglitazone, dexamethasone and low-dose treosulfan (phase I/II) blood (ASH Annual Meeting Abstracts) 120:5029
Paulitschke V, Gruber S, Hofstätter E, Haudek-Prinz V, Klepeisz P, Schicher N, Jonak C, Petzelbauer P, Pehamberger H, Gerner C, Kunstfeld R (2012) Proteome analysis identified the PPARγ ligand 15d-PGJ2 as a novel drug inhibiting melanoma progression and interfering with tumor-stroma interaction. PLoS One 7(9):e46103
Emmenegger U et al (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, Berlin, pp 243–262. doi:10.1007/978–90-481–9531-2_11
Meyer S, Vogt T, Landthaler M, Bataille F, Reichle A, Marx A et al (2010) Cyclooxygenase2 (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: the tumor microenvironment, vol 3, part 6. Springer, Berlin, pp 443–65. doi:10.1007/978–90-481–9531-2_22
Reinhold SW, Reichle A, Leiminger S, Bergler T, Hoffmann U, Krüger B, Banas B , Krämer BK (2011) Renal function during rofecoxib therapy in patients with metastatic cancer: retrospective analysis of a prospective phase II trial. BMC Res Notes 4:2–6
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, Berlin, pp 287–303. doi:10.1007/978–90-481–9531-2_13
Grønbæk K, Müller-Tidow C, Perini G, Lehmann S, Bach Treppendahl M, Mills K, Plass C, Schlegelberger B (2012) European genomics and epigenomics study on MDS and AML (EuGESMA), COST action BM0801. A critical appraisal of tools available for monitoring epigenetic changes in clinical samples from patients with myeloid malignancies. Haematologica 97(9):1380–1388
Kanwal R, Gupta S (2012) Epigenetic modifications in cancer. Clin Genet 81(4):303–311
Nash PD (2012) Why modules matter. FEBS Lett 586(17):2572–2574
Haura EB (2012) From modules to medicine: how modular domains and their associated networks can enable personalized medicine. FEBS Lett 586(17):2580–2585
Pan CQ, Low BC (2012) Functional plasticity of the BNIP-2 and Cdc42GAP Homology (BCH) domain in cell signaling and cell dynamics. FEBS Lett 586(17):2674–2691
Joshua A Jadwin JA, Ogiue-Ikeda M, Machida K (2012) The application of modular protein domains in proteomics. FEBS Lett 586(17):2586–2596
Reichle A, Hildebrandt GC (2009) Principles of modular tumor therapy. Cancer Microenviron 2(Suppl 1):227–237
Reichle A (ed) (2010) From molecular to modular tumor therapy: the tumor microenvironment, vol 3. doi:10.1007/978–90-481–9531-2
Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D et al (2012) Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 366(10):883–892
Acknowledgements
This work was greatly facilitated by the use of previously published and publicly accessible research data, also by the systems-theoretical considerations of J Habermas. I would like to thank all colleagues who contributed to the multi-center trials.
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Reichle, A., Hildebrandt, G. (2013). Applied Systems Biology for the Control of Metastatic Cancer: Therapeutic Top-Down Strategy for Targeting the Tumors’ Normativity. In: Reichle, A. (eds) Evolution-adjusted Tumor Pathophysiology:. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-6866-6_2
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