Systems biology basis of permanent tumor regression with normal tissue protection: Experimentally validated signaling pathway framework.

Abstract

e15066 Background: Clinicians generally deal with malignant tumors in progression phase only, but there is a reverse complimentary process, namely permanent spontaneous regression of tumors, a well-known phenomenon occurring across human populations at 22%-46% rate (Scandinavian and Wisconsin Screening Registries: 0.33 million and 2.95 million populace respectively; Lancet Oncol.12: 1118-24, 2011; J.Nat.Cancer.Inst.36: 37-47, 2006). Probing such a phenomenon can illuminate how one can induce a permanent regression process on human tumors therapeutically. Here we develop a systems biology approach for this process, that we validate by experimental findings. Methods: Mathematical System Biology Formulation: For permanent tumor regression, we develop a coupled differential equations-based cell kinetic analysis, keeping normal tissue protected. Thereby, we mathematically model the temporal variation of the level of three essential tumor-lysis components: DNA replication-blockade, Antitumor Lymphocyte, Cytokine interleukin-2. Experimental Investigation: We investigate the temporal process of spontaneous tumor regression of melanoma (in Liebechov pigs) and analyze the microarray signal using IPA platform Gene expression signature: Using IPA analysis, we find the signaling pathways associated with the permanent tumor regression. Results: Mathematical System Biology Formulation: We find the temporal behavior of tumor-lysis components are: (1) DNA replication-blockade activation: Unimodal inverted U function (2) Antitumor Lymphocyte activation: Bimodal M function; (3) Interleukin-2 activation as Stationary step function. Experimental findings: Our microarray analysis gives temporal pattern of gene-expression levels corresponding to above three components: G2/M DNA damage checkpoint regulation (genes CCNB1, CDC2), Chemokine signaling activation - Interleukin 2 ( GRB2, PIK3CG), T Lymphocyte Receptor Signaling (CCR5, PRF1). These three temporal components respectively show Unimodal, Bimodal, and Stationary activation. Validation: We show that the three mathematically-derived temporal activation functions are well corroborated by corresponding experimental temporal pathway activation data (Smirnov-Kolmogorov statistical test satisfied; α = 5%). Conclusions: A novel tri-phasic activation of three antitumor signaling pathways (DNA blockade, Interleukin 2, Cytotoxic T cell) can permanently regress melanoma tumor in the experimental setting if the pathways are activated at different time points and not simultaneously; These temporally orchestrated patterns are much different from conventional chemotherapy/ immunotherapy protocols where the temporal activations are simultaneous and empirically chosen. Optimal temporal profiling of administration of antitumor agents is thus crucial from a therapeutic standpoint.