Computational systems biology approach for permanent tumor elimination and normal tissue protection using negative biasing: Experimental validation in malignant melanoma as case study.

Abstract

Complete spontaneous tumor regression (without treatment) is well documented to occur in animals and humans as epidemiological analysis show, whereby the malignancy is permanently eliminated. We have developed a novel computational systems biology model for this unique phenomenon to furnish insight into the possibility of therapeutically replicating such regression processes on tumors clinically, without toxic side effects. We have formulated oncological informatics approach using cell-kinetics coupled differential equations while protecting normal tissue. We investigated three main tumor-lysis components: (ⅰ) DNA blockade factors, (ⅱ) Interleukin-2 (IL-2), and (ⅲ) Cytotoxic T-cells (CD8+ T). We studied the temporal variations of these factors, utilizing preclinical experimental investigations on malignant tumors, using mammalian melanoma microarray and histiocytoma immunochemical assessment. We found that permanent tumor regression can occur by: 1) Negative-Bias shift in population trajectory of tumor cells, eradicating them under first-order asymptotic kinetics, and 2) Temporal alteration in the three antitumor components (DNA replication-blockade, Antitumor T-lymphocyte, IL-2), which are respectively characterized by the following patterns: (a) Unimodal Inverted-U function, (b) Bimodal M-function, (c) Stationary-step function. These provide a time-wise orchestrated tri-phasic cytotoxic profile. We have also elucidated gene-expression levels corresponding to the above three components: (ⅰ) DNA-damage G2/M checkpoint regulation [genes: CDC2-CHEK], (ⅱ) Chemokine signaling: IL-2/15 [genes: IL2RG-IKT3], (ⅲ) T-lymphocyte signaling (genes: TRGV5-CD28). All three components quantitatively followed the same activation profiles predicted by our computational model (Smirnov-Kolmogorov statistical test satisfied, α = 5%). We have shown that the genes CASP7-GZMB are signatures of Negative-bias dynamics, enabling eradication of the residual tumor. Using the negative-biasing principle, we have furnished the dose-time profile of equivalent therapeutic agents (DNA-alkylator, IL-2, T-cell input) so that melanoma tumor may therapeutically undergo permanent extinction by replicating the spontaneous tumor regression dynamics.