Rapid optimization of drug
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).
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.
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.
of radiotherapy and anti-angiogenesis gives synergistic anti-tumor
Results give way to the hypothesis of vascular normalization.
Dings et al., Clin. Cancer Res. 2007.
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.
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).
show video images
of leukocyte vessel wall interactions in:
normal control tissue
tumor tissue of mice treated with
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
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.
Nowak-Sliwinska et al. Angiogenesis 2010.