Rapid optimization of drug combinations
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. The optimal synergistic drug combination was found to contain erlotinib, BEZ-235 and RAPTA- C. Successful translation of this drug combination was achieved in two preclinical in vivo tumor 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. (Weiss et al. Angiogenesis 18:233, 2015).
Angiogenesis and radiotherapy
Our aim is to gain insight in the mechanisms involved in the interaction between angiostatic therapy and to determine the optimal scheduling scheme for combination therapy in the clinical setting.
Apart from direct effects on the tumor vasculature, angiogenesis inhibitors also improve the response to radiotherapy (Dings, Int J Cancer, 2005; Dings, Cancer Res, 2003). This beneficial effect is caused by a short period of vessel normalization which improves blood flow and oxygenation (Dings et al., Clin Cancer Res, 2007;). Little is known regarding the cellular mechanisms that underlie the response to combination therapy. Furthermore, it is important to determine the normalization window of angiostatic agents in order to optimize combination therapy.
Combination of radiotherapy and anti-angiogenesis gives synergistic anti-tumor effect. Results give way to the hypothesis of vascular normalization. From Dings et al., Clin. Cancer Res. 2007.
Angiogenesis and immunotherapy
We investigate the relationship between angiogenesis and the immune system. The ultimate goal is to investigate whether angiogenesis inhibition can be used to improve immunotherapy.
Endothelial cell adhesion molecules like intercellular adhesion molecule-1 (ICAM-1) are suppressed by angiogenic growth factors such as bFGF and VEGF (Griffioen et al. Cancer Res. 56:1111, 1996). This leads to tumor escape from immunity (Dirkx et al. FASEB J. 2006). Angiostatic factors can therefore improve immunotherapy (Dings et al. Clin. Cancer Res. 2011).
Links below show video images of leukocyte vessel wall interactions in:
Relationship between angiogenesis inhibition and leukocyte infiltration. From Drikx et al. FASEB J., 2006.
Angiogenesis and photodynamic therapy
Photodynamic therapy induces an angiogenic response in the treated tissue. Combination with angiogenesis inhibition is therefore a promising strategy against cancer.
Angiography images of the CAM before (left) and 48h after PDT (right). Efficacy of the combination of PDT with Avastin is shown in lower right panel. From Nowak-Sliwinska et al. Angiogenesis 2010.