Keywords

Introduction

Tumor-related activities that seem to be operationally induced by the diversity of tumor-immanent normative notions and their multifaceted evolutionary confined rationalization processes, such as normative functions (i.e. inflammation, neoangiogenesis, Warburg effect, immune response, extracellular matrix remodelling, cell proliferation rate, apoptosis, coagulation effects), normative structures and decision maxims (hubs), present itself from a systems perspective as an enhancement of complexity. So far, tumor systems have been assumed to defy experimental therapeutic access from inside, in a comprehensive and reconstructive way that means, in a communication-derived systems view, and to only comply with reductionist knowledge with regard to biochemical pathways (Fig. 2.1).

Fig. 2.1
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The commonly used ‘bottom-up’ strategy regards as sufficient the availability of targets in cellular tumor compartments without identifying validity and denotation of targeted, presumably tumor-promoting systems participators. The communicatively cross-linked ‘background’, which may be functionally specified due to varying numbers of chromosomal or molecular-genetic aberrations, remains therapeutically unrecognized

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We hypothesized, that tumor systems-directed therapies might have the capability to use aggregated action effects of tumor-immanent normative notions, as adjustable sizes to therapeutically modulate and redirect the tumor systems’ stability, homeostasis, robustness, and normative notions, and that this therapeutic ‘top down’ strategy may provide novel targets for the control of metastatic tumor disease in contrast to currently provided ‘bottom-up’ strategies including the classic ‘targeted’ therapy approaches: Combined modularized therapy approaches have been designed to study the operative accessibility of tumor-immanent normative notions for tumor control (therapeutic implementation of ‘non-normative’ boundary conditions into the tumor systems world) by ubiquitously available, non-oncogene addicted, but differentially distributed targets among tumor and stroma cells [1–6] (Fig. 2.2, Tables 2.1, 2.2).

Fig. 2.2
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Tumors allow experimental therapeutic access from inside in a comprehensive and reconstructive way (systems view) via modular (biomodulatory) therapy approaches and may be described as evolutionary developing systems. Modular therapies evolve the informative background, which redeems validity and denotation of tumor-associated objects. Therapeutically accessible pathologies may derive from the decoupling of functional cellular and systems ‘world’ and can be targeted by modular therapy approaches

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Table 2.1 During progression from the organ-confined stage to the clinical metastatic stage tumors acquire asynchronously multifold chromosomal and molecular-genetic aberrations. Applied systems biology in metastatic tumors may meet this therapeutic challenge by targeting the tumor’s normativity, thereby, targeting tumor and stroma cells simultaneously and equally
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Table 2.2 The ‘Top-down’ approach allows redirecting and modulating the communicative ‘background’, which mediates validity and denotation of tumorpromoting systems participators and organizes the constitution of rationalizations for maintaining tumor-immanent rationalizations. The ‘background’ is modularly arranged and therapeutically accessible with primarily multi-track, modularized therapy elements
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Materials and Methods

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 (Table 2.4, 2.5) (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 different types of tumors (ten phase II trials, two of them randomized; 354 patients; 80 % systemically pre-treated; metastatic melanoma (two trials, one randomized), (angio-) sarcoma, renal clear cell carcinoma (two trials), glioblastoma, castration-resistant prostate cancer (two trials on CRPC), gastric cancer (randomized phase II trial), multi-systems Langerhans’ cell histiocytosis, and multiple myeloma in third-line) (Tables 2.3, 2.6) [7–22].

Table 2.3 For studying the capacity of combined modularized tumor therapies to redirect the tumors’ normativity, we selected tumors as normative model systems, i.e., tumors with predominant pro-angiogenic component, with strong pro-inflammatory component, and tumors with pro-inflammatory characteristics in the metastatic stage
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Table 2.4 Metronomic low-dose chemotherapies and mechanisms of action
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Table 2.5 Targeting the tumor systems biology: Combined transcriptional modulation of ubiquitously available targets
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Table 2.6 The table gives an overview about the performed combined modularized therapy approaches. In three trial designs we used combined transcriptional modulation (castration-resistant prostate cancer, multiple myeloma and renal clear cell carcinoma)
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Further, we analyzed the follow-up of patients discontinuing study medication due to medical indications, and who achieved objective response to module A+M/+ combined with a second transcriptional modulator (dexamethasone), besides metronomically administered imatinib (400 mg once daily) in CRPC (phase I/II trial for CRPC, first-line therapy) or lenalidomide (10 or 15 mg once daily) in multiple myeloma (third-line therapy for MM, phase I, on-going phase II trial) (Chap. 19).

Results

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 (Table 2.7). 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 (Figs. 2.3, 2.4 and 2.5).

Fig. 2.3
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Tumors represent pivotal evolution models, as the communicative ‘background’ of tumor-promoting systems objects is highly variable due to the varying numbers of chromosomal or molecular-genetic aberrations, which individualize a tumor disease to a high degree. But likewise, rationalizations of tumor-immanent normative notions are individualized and differentially accessible by modularized therapy approaches

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Fig. 2.4
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Induction of long-term tumor response or continuous complete remission in metastatic tumors indicates that tumor-promoting rationalizations at the metastatic sites are uniquely constituted within an individual tumor disease and are efficacious targets for combined modularized tumor therapies to overcome cytogenetic heterogeneity in tumor cells

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Fig. 2.5
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Clinical data indicate that radiotherapy commonly leads to a reorganization of rationalizations constituting tumor-promoting normative notions and consecutive to resistance towards combined modularized tumor therapies

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Table 2.7 Overview of outcome following combined targeting of the modular tumor architecture in pre-treated patients (80 %)
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Toxicities of combined modularized therapies were manageable by early dose reductions according protocol in case of grade 2 toxicities, and therefore, facilitate long-time administration of study therapy. Only 3 % of patients permanently discontinued therapy due to site effects ([7, 23], Chap. 5). Long-term tumor control can be achieved in elderly (up to 86 years) and medically non-fit patients (Chap. 5) on the basis of moderate treatment-related toxicity, particularly less grade 3 and 4 toxicities.

Tumor-specific and stage-specific therapeutic accessibility of inflammation-related processes to induce response in all tumor types indicate a constitutive spin-off of novel rationalized systems functions during the metastatic process [24]. Furthermore, this accessibility shows differential integration of inflammation processes into the context-dependent ‘living world’ of tumor compartments that is marked by tumor-specific and subtype-specific rationalization processes: Inflammation-related activities are communicatively promoted and differentially adapted during tumor evolution. Empirically, differences may be detected in the modalities of developing evolutionary systems and in the acquired functional impact of inflammation-related systems [24].

The observed response patterns, either very rapid or delayed tumor responses, indicate that communicative inconsistencies may be therapeutically met (Achilles’ heels). Disturbances in intersystemic exchange processes are suggested, if biomarkers (e.g., C-reactive protein) or signatures depicting the redirection of normative notions (here tumor-associated inflammation) show a low sensitivity to predict clinical benefit [24].

Temporally limited metronomically administered, combined modularized therapies may facilitate biological memory for stably sustaining long-term tumor growth control (12.5–15 months) without disease specific therapy in patients, who discontinued study medication due to non-tumor-related surgical interventions (Chap. 19).

Differential approaches implementing combined transcriptional modulation plus metronomic chemotherapy demonstrated the capacity to redirect and modulate tumor-immanent normative functions in a multifaceted way (inflammation control, anti-osteoplastic effect, immunregulation, biological memory, induction of continuous complete remission; long-term maintenance at minimal residual disease), in renal clear cell carcinoma, multiple myeloma and castration-resistant prostate cancer (Tables 2.7, 2.8, Chap. 19). Targeting the tumors’ normativity by combined transcriptional modulation allows to diversifying therapeutic instruments for purposive rationale therapies with the aim to specify palliative care (Chap. 15).

Table 2.8 Combined transcriptional modulation led to an impressive redirection of the tumors’ normativity in quite different tumor histologies. Induction of biological memory (more than 10 fold longer times to PSA doubling after discontinuation of study medication compared to base-line PSA doubling time) and induction of continuous complete remissions are pivotal findings
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Metastatic lesions, pretreated with palliative radiotherapy, had frequently shown local progression in the radiation field (86 % of n = 56 previously locally irradiated patients), despite disease stabilization or response towards combined modularized therapies at other metastatic tumor sites.

Discussion

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, i.e. the different cell compartments, pathways, oncogenes, tumor suppressor genes, etc. Combined modularized therapies (1) help to detect multifaceted, situatively adapted rationalization processes available for ubiquitously occurring tumor-immanent normative notions [2, 7, 8, 15] and (2) corresponding novel tools of biomarkers [5, 7, 9, 22], (3) may uncover novel regulatory systems in tumor biology (e.g., hubs) (Chaps. 16 and 17), (4) pathologies within communication processes (e.g., inconsistencies, disturbances in intersystemic exchange processes) [7, 24], (5) are a basis for studying communicative rules mediating the ‘metabolism’ of tumor evolution ([24], Chap. 12), and (6) may pave the way for inducing biological memory in metastatic tumors [25, 26] (Table 2.9, Chap. 19).

Table 2.9 Evolution-adjusted tumor pathophysiology enables to study novel biomarkers depicting the evolvability of tumors within their ‘living world’ as well as the therapy-induced redirection and modulation of the tumors’ normativity
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Induction of long-term tumor response or continuous complete remission in metastatic tumors indicates that tumor-promoting rationalizations at metastatic sites are uniquely constituted within an individual tumor disease and are efficaciously targeted with combined modularized tumor therapies. This way, biomodulatory therapies overcome the major obstacle of ‘bottom-up’ strategies, namely cytogenetic heterogeneity in tumor cells at primary and metastatic tumor sites (Figs. 2.4, 2.5).

Vice ver sa, preceding radiation therapy frequently induces intrinsic resistance towards biomodulatory therapy in irradiated tumor lesions. This observation suggests that radiation therapies accomplish heterogeneity of the tumor’s growth-promoting rationalization processes as cause for resistance towards combined modularized tumor therapies.

Understanding systems biology as adjustable size ( ‘ top-down ’ technology) may break through the barrier of complex tumor-stroma-interactions in a therapeutically relevant way (Table 2.7): Comparatively high efficacy at moderate toxicity. Structured systems-directed therapies in metastatic cancer may get a source for detecting the topology of tumor-associated complex aggregated action effects accessible for combined modularized therapies (Figs. 2.4, 2.5).

Biomodulatory therapies are tools for uncovering novel modular structures and rationalizations in tumor systems, for probing cellular activation states and for identifying key hubs in both normal and diseased tissues. The concept of protein modularity is central to the field of combined modularized therapies and synthetic biology [7, 27]. With biomodulatory therapies we may design new approaches to disrupt tumor-promoting signaling via remodeling of signaling pathways based on principles derived from modular tumor pathophysiology [22, 28–30].

Observations on the activity profile of combined modularized therapies, i.e. rapid versus delayed response, induction of biological memory, the possibility to achieve response induction via purposive-rational modulation and redirection of tumor-associated normative notions, and the successful application of drug repurposing may not be explained with traditional evolution historical considerations, but facilitate the development of an evolution theory, i.e. the formal-pragmatic communication theory [31, 32].

Specifying ‘ top-down ’ approaches necessitates novel pathophysiological considerations, the application of an evolution-adjusted tumor pathophysiology, which focuses on the systematic comprehension of tumor systems objects’ communicative expression, their validity and denotation in a distinct evolutionary context (Fig. 2.6).

Fig. 2.6
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Applied systems biology for the control of metastatic cancer: Shaping and focusing systems’ communication by disrupting the holistic thicket with a ‘top-down’ strategy. Tumors are not any more considered as ‘objects’, which have to be destroyed with ‘single track’ or combined ‘single track’ targeted therapy approaches, but as subjects within a communicative context, which allow to implement multifold novel combined modularized therapies (multi-track approaches). Bottom-up and top-down strategy have in common to redirect and modulate the tumors’ normativity as prerequisite for tumor growth control

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Evolution-adjusted tumor pathophysiology provides contently and methodologically novel approaches to succeed in personalizing tumor therapy. By targeting the tumors’ normativity, genetically based tumor heterogeneity is efficaciously addressed [33]. Uniquely constituted rationalization processes within a distinct tumor disease are a common denominator for successful modular therapeutic access and long-term tumor control.

Evolution-adjusted tumor pathophysiology should be introduced as clinically orientated discipline, equivalent with traditional disciplines, thereby increasing their value and accomplishing ethical demands. A tumor type-specific, systems stage-specific, metastatic site-specific or disease trait-orientated therapy seems to be within grasp.