A Mathematical Model of Tumor-Immune Evasion and siRNA Therapy

Investigating the VEGF-BCL2-IL8 Pathway and its Role in Sustained Angiogenesis

Student: Harsh V. Jain

Collaborators: Dr. Jacques E. Nor, Department of Cariology, Restorative Sciences and Endontics

Project Summary: Recent experiments show that vascular endothelial growth factor (VEGF) is the crucial mediator of downstream events that ultimately lead to enhanced endothelial cell survival and increased vascular density within many tumors. The newly discovered pathway involves up-regulation of the anti-apoptotic protein Bcl-2, which in turn leads to increased production of interleukin-8 (CXCL8). The VEGF - Bcl-2 - CXCL8 pathway suggests new targets for the development of anti-angiogenic strategies including short interfering RNA (siRNA) that silence the CXCL8 gene and small molecule inhibitors of Bcl-2. Harsh is working to develop and validate mathematical models designed to predict the effect of the therapeutic blockage of VEGF, CXCL8, and Bcl-2 at early middle and late stages of tumor progression.

In agreement with experimental observations, the preliminary DDE model predicts that curtailing the production of CXCL8 early in development can result in a substantial delay in tumor growth and vascular development; however, it has little effect when applied at late stages of tumor progression. Blocking Bcl-2 up-regulation, either at early stages or after the tumor has fully developed, ensures that both microvascular and tumor cell density stabilize at very low values. Key Model Predictions

1. The model predicts the efficacy of two novel anti-angiogenesis treatment strategies, anti-CXCL8 and anti-BCL2, in a defined experimental assay.

2. The model predicts specific differences in the effects of each therapy on tumor growth and vascular development. Treatment with anti-CXCL8 antibodies delays tumor growth and vascular development six days at most; however the tumor and vasculature eventually reach their normal maximum densities. Treatment with a small molecule inhibitor of Bcl-2, on the other hand, is capable of producing not only significant delays in tumor growth and vascular development, but also results in substantial decreases in maximum tumor cell and blood vessel densities.

3. The model predicts a significant threshold effect for anti-BCL2 therapy. For therapies that are less than 60% effective, there is little effect on tumor cell and vascular density. However, therapies with higher efficacies result in a dramatic decrease in these quantities.

This preliminary mathematical model is one of the first to connect the molecular events associated with VEGFR2 dimerization and intracellular signaling with the temporal changes in endothelial cell proliferation, migration and survival. The preliminary results suggest that Bcl2 is the most promising target for anti-angiogenic therapies along the VEGF pathway of interest. Due to the abundance of experimental data describing the interaction of Bcl2 with its pro-apoptotic family members and the increasing interest in the mechanism of action and therapeutic potential of the small molecule inhibitor BL193, we believe it is important to modify our mathematical approach to include the current understanding of the intracellular apoptotic signaling that is mediated by the Bcl family of proteins. Such a model will be able to address the mechanism of action of BL193 and to relate its binding efficiency to its therapeutic efficacy; thereby predicting tumor response with increased accuracy. This is the current focus of our work.

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