The emerging quest for the optimal angiostatic combination therapy

Weiss, Andrea; Berndsen, Robert H.; Abdul, U. Kulsoom; Winkel, Marije T. te; Nowak-Śliwińska, Patrycja

doi:10.1042/bst20140193

Cited by 18 publications

(15 citation statements)

References 64 publications

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“…Normalization can both enhance extravasation of small molecule chemotherapeutics to the intratumoral space, as well as enhance oxygen dependent treatment strategies. Our study also stresses the need for precise timing and scheduling of the combination treatment51. Further development of the encouraging results reported here in more advanced preclinical models will require extensive efforts to identify optimized dosages and timing schedules to maximally exploit the potential therapeutic benefits of such treatment strategies.…”

Section: Discussionmentioning

confidence: 74%

Angiostatic treatment prior to chemo- or photodynamic therapy improves anti-tumor efficacy

Weiss

Bonvin

Berndsen

et al. 2015

Sci Rep

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Tumor vasculature is known to be poorly organized leading to increased leakage of molecules to the extravascular space. This process can potentially increase interstitial fluid pressure impairing intra-tumoral blood flow and oxygen supply, and can affect drug uptake. Anti-angiogenic therapies are believed to reduce vascular permeability, potentially reducing interstitial fluid pressure and improving the extravasation of small molecule-based chemotherapeutics. Here we show that pretreatment of human ovarian carcinoma tumors with sub-optimal doses of the VEGFR targeting tyrosine kinase inhibitor axitinib, but not the EGFR targeting kinase inhibitor erlotinib, induces a transient period of increased tumor oxygenation. Doxorubicin administered within this window was found to enter the extravascular tumor space more rapidly compared to doxorubicin when applied alone or outside this time window. Treatment with the chemotherapeutics, doxorubicin and RAPTA-C, as well as applying photodynamic therapy during this period of elevated oxygenation led to enhanced tumor growth inhibition. Improvement of therapy was not observed when applied outside the window of increased oxygenation. Taken together, these findings further confirm the hypothesis of angiostasis-induced vascular normalization and also help to understand the interactions between anti-angiogenesis and other anti-cancer strategies.

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Section: Discussionmentioning

confidence: 74%

Angiostatic treatment prior to chemo- or photodynamic therapy improves anti-tumor efficacy

Weiss

Bonvin

Berndsen

et al. 2015

Sci Rep

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“…Their contribution to the prolongation of patient survival, however, is often limited mainly due to disease and patient heterogeneity [4, 5], toxicity [6], induction of metastasis [7] and drug resistance [8, 9]. Redundancy of growth factor signaling pathways makes angiogenesis a robust physiological function [10, 11], where targeting multiple pathways with drug combinations may be necessary for efficient therapy [12]. Although difficult to predict, in such drug combinations one may encounter synergistic, additive or antagonistic interactions between drugs.…”

Section: Introductionmentioning

confidence: 99%

Rapid optimization of drug combinations for the optimal angiostatic treatment of cancer

et al. 2015

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Drug combinations can improve angiostatic cancer treatment efficacy and enable the reduction of side effects and drug resistance. Combining drugs is non-trivial due to the high number of possibilities. We applied a feedback system control (FSC) technique with a population-based stochastic search algorithm to navigate through the large parametric space of nine angiostatic drugs at four concentrations to identify optimal low-dose drug combinations. This implied an iterative approach of in vitro testing of endothelial cell viability and algorithm-based analysis. The optimal synergistic drug combination, containing erlotinib, BEZ-235 and RAPTA-C, was reached in a small number of iterations. Final drug combinations showed enhanced endothelial cell specificity and synergistically inhibited proliferation (p < 0.001), but not migration of endothelial cells, and forced enhanced numbers of endothelial cells to undergo apoptosis (p < 0.01). Successful translation of this drug combination was achieved in two preclinical in vivo tumor models. Tumor growth was inhibited synergistically and significantly (p < 0.05 and p < 0.01, respectively) using reduced drug doses as compared to optimal single-drug concentrations. At the applied conditions, single-drug monotherapies had no or negligible activity in these models. We suggest that FSC can be used for rapid identification of effective, reduced dose, multi-drug combinations for the treatment of cancer and other diseases.Electronic supplementary materialThe online version of this article (doi:10.1007/s10456-015-9462-9) contains supplementary material, which is available to authorized users.

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“…Such strategies could combine different vascular targets, vascular targets and tumor cell targets, or, e.g., a combination of these with a vaccination strategy against the immune checkpoint molecules, such as CTLA-4 and PD/PDL-1. A review on the quest for anti-angiogenic combination therapy has been published recently [40]. A major attraction of anti-angiogenic cancer vaccination is that it may result in the near future in dual-or even triple therapy strategies, combined in a single vaccine.…”

Section: Future Perspectivesmentioning

confidence: 99%