Combinatorial Administration of Molecules That Simultaneously Inhibit Angiogenesis and Invasion Leads to Increased Therapeutic Efficacy in Mouse Models of Malignant Glioma

Abstract

Purpose:We investigated the ability of the combinatorial administration of different inhibitors with activities on glioma angiogenesis, migration, and proliferation to produce a prolonged inhibition of glioma growth. Experimental Design: We combined inhibitors affecting solely tumor angiogenesis (PF-4/CTF, cyclo-VEGI) or inhibitors affecting both angiogenesis and invasion together (PEX, PF-4/DLR).Results: When administered in combination, these drugs produced a prolonged and increased inhibition of glioma growth independently from the type of inhibitor used. The combinatory administration was more effective than the administration of a single inhibitor alone, and a strong therapeutic response was reached with a significantly lower amount of protein. The strongest inhibition was observed when human PEX and PF-4/DLR, which affect both glioma angiogenesis and invasion by separate mechanisms, were combined.Conclusions: This supports the concept that prolonged glioma growth inhibition can be achieved by simultaneous delivery of molecules that target both tumor and endothelial cells and acting by separate mechanisms.

Nonlinear Modeling and Simulation of Tumor Growth

“…A number of experimental studies have recently shown that anti-angiogenic therapies may have this result [180,177,61,173,185,122,24]. Conversely, we found that increasing nutrient levels leads to greater morphological stability and increased tumor compactness, thereby rendering some tumors more resectable.…”

“…The multiscale model predicts that glioma tissue structure and tumor invasiveness are significantly influenced by diffusion gradients in the microenvironment, as observed experimentally [177,120,122,24,74] and in human patients [23]. These gradients may have a strong effect on glioma morphology [55,135], and are hypothesized in the model to reciprocally influence a growing tumor's continuously evolving vasculature in complex ways.…”

“…Such therapies affect cell-cell and cell-ECM adhesive properties of the tumor. A recent experimental study on mouse models of malignant glioma shows that fragmentation can be prevented, and tumor satellites may be eliminated by a combined antiangiogenic and anti-invasive therapy [24]. In the nutrient-poor growth regime, increasing cell-cell and cell-ECM adhesion of the microenvironment can help limit the rate of fragmentation and the extent of invasion.…”

“…This includes the application of mathematical and empirical methods to quantify the competition between cell substrate gradient-related pro-invasion phenomena and molecular forces that govern proliferation and taxis, and forces opposing invasion through cell adhesion. The latter, under normoxic conditions, often enforce compact non-infiltrative tumor morphology while local oxygen gradients promote invasion [190,156,185,120,160,122,24,177,173,174,61,55,74,135]. Interactions between cellular proliferation and adhesion and other phenotypic properties may be reflected in both the surface characteristics, e.g., stability, of the tumor-host interface and the growth characteristics of tumors [59,55,74,87,135].…”

“…Three-dimensional tissue morphology, cell phenotype, and molecular phenomena are intricately coupled; they influence cancer invasion potential by controlling tumor-cell proliferation and migration [78,187,198]. Hypoxia [88,210,186,70,91], acidosis [91,199,96], and associated diffusion gradients, caused by heterogeneous delivery of oxygen and nutrients and removal of metabolites [104,103] due to highly disorganized microvasculature [92,106] and often exacerbated by therapy (e.g., anti-angiogenic [160,177]), can induce heterogeneous spatial distribution and invasiveness of tumor cells through a variety of molecular [175,209,208,44,165,173,145,118,28,29,190,156,185,120,122,24,160,177,174,61] and tissue-scale [59,127,72] mechanisms corresponding to different tissue-scale invasive patterns [78,164,194,167,<...>…”