Systems Biology: A Therapeutic Target for Tumor Therapy

Abstract

Tumor-related activities that seem to be operationally induced by the division of function, such as inflammation, neoangiogenesis, Warburg effect, immune response, extracellular matrix remodeling, cell proliferation rate, apoptosis, coagulation effects, present itself from a systems perspective as an enhancement of complexity. We hypothesized, that tumor systems-directed therapies might have the capability to use aggregated action effects, as adjustable sizes to therapeutically modulate the tumor systems' stability, homeostasis, and robustness. We performed a retrospective analysis of recently published data on 224 patients with advanced and heavily pre-treated (10% to 63%) vascular sarcoma, melanoma, renal clear cell, cholangiocellular, carcinoma, hormone-refractory prostate cancer, and multivisceral Langerhans' cell histiocytosis enrolled in nine multi-center phase II trials (11 centers). Each patient received a multi-targeted systems-directed therapy that consisted of metronomic low-dose chemotherapy, a COX-2 inhibitor, combined with one or two transcription modulators, pioglitazone +/− dexamethasone or IFN-alpha. These treatment schedules may attenuate the metastatic potential, tumor-associated inflammation, may exert site-specific activities, and induce long-term disease stabilization followed by prolonged objective response (3% to 48%) despite poor 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. Understanding systems biology as adjustable size may break through the barrier of complex tumor-stroma-interactions in a therapeutically relevant way: 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 as adjustable sizes available for targeted biomodulatory therapies.

Multi-omics Analysis of Serum Samples Demonstrates Reprogramming of Organ Functions Via Systemic Calcium Mobilization and Platelet Activation in Metastatic Melanoma

“…PAF-R are mainly expressed by mesenchymal cells, which may explain the implication of adipose, muscle, liver, and heart tissue, as well as gut barrier and brain dysfunctions in cachexia, supporting our proposed model (31,32,(62)(63)(64). Also, the described crosstalk between wasting of fat tissue and skeletal muscle is compatible with the proposed mechanism (65)(66)(67).…”

“…Second, the interpretation of the present data suggests a comprehensive model for a tumor-associated damage signature related to melanoma-mediated cachexia. Third, understanding the origin and effects of powerful tumor promoters provides us with means to establish novel therapeutic options for both cancer in general as well as cancer-associated cachexia (52,66). Evidently, many anti-cancer strategies already exist.…”

Biomodulatory therapy induces complete molecular remission in chemorefractory acute myeloid leukemia

“…angiogenesis, inflammation and anticancer immune response. 12,13 Despite the heterogeneity of AML characteristics in our cohort, APA therapy induced ongoing morphological CR in 3 of 5 patients, including 2 molecular CRs. In one patient with secondary AML transformed from CMML-2, AML blasts decreased during APA treatment.…”

“…As recently shown, biomodulatory combination therapies are widely applicable in metastatic tumor disease and have the capacity to control metastatic lesions and to induce CRs in single patients. 13 By targeting the physical constituents (rationalizations) of the hallmarks of cancer with "top-down" approaches, we may bypass (molecular-)genetic heterogeneity in chemorefractory AML. To our knowledge, this is the first report describing the combined use of low-dose AZA, PGZ and ATRA to successfully overcome resistance to induction chemotherapy.…”

Evolution Theory: Its Practical Relevance for Understanding Tumor Development and Specifying Tumor Therapy

“…To overcome problems with combined single-track therapies, it is necessary to process quantitative proteomic data from appropriate hypothesis-driven models. Evolution-adjusted tumor pathophysiology provides the necessary diagnostic instruments for modeling drug effects [39,44,[46][47][48][49] by introducing the reconstruction of tumor-promoting rationalization processes. Rationalization processes represent the multidimensional networks available for constituting tumor-promoting normative notions, i.e., angiogenesis, immune response etc.…”