Treatment with a new dual cell cycle and angiogenesis pathway inhibitor blocks VEGF-induced vascular permeability, inhibits tumour angiogenesis and induces apoptosis in human tumour models said Dr. Gerhard Siemeister of Schering AG, Corporate Research, Berlin speaking at the 18th meeting of the European Association of Cancer Research.
Loss of cell cycle control (runaway growth) and tumour-induced angiogenesis (development of new blood vessels to supply the growing tumour with oxygen) are two major hallmarks of cancer. Loss of cell cycle control as a consequence of aberrant cyclin-dependent kinase (CDK) control has been directly linked to the molecular pathology of cancer. CDK's are a family of enzymes required for the correct timing and order of events in the cell division cycle. Vascular endothelial growth factor (VEGF) / VEGF-receptor tyrosine kinase (VEGF-RTK) and platelet-derived growth factor (PDGF)-RTKs are two molecules known to be involved in tumour angiogenesis.
The new compound, called 'ZK-CDK', is a novel, chemically synthesized small molecule ATP-competitive kinase inhibitor that is unique in that combines the inhibition of tumour cell growth as well as inhibition of tumour angiogenesis in one single molecule.
ZK-CDK was shown to inhibit a range of CDK's as well as VEGF-RTK's and PDGF-RTK's resulting in an inhibition of the proliferation of human tumour cell lines in vivo. ZK-CDK blocked cell cycle progression in G1 and induced apoptosis, blocked VEGF-induced vascular permeability in vivo and reduced the blood supply of human tumour xenografts. "These animal data are very promising in terms of anti-tumour efficacy and tolerability", said Dr. Siemeister. "VEGF-RTK inhibitors have been shown to be well-tolerated by patients and we hope that ZK-CDK will be well tolerated. The CDK inhibiting mechanism of ZK-CDK, in contrast to cytotoxic chemotherapy, should arrest the proliferation of normal cells but not kill them, allowing them to recover during drug-free cycles".
ZK-CDK was tested on mice as an oral preparation. The compound was tested against several tumour models including both solid tumours and haematological tumours. The compound showed efficacy in all models. However, ZK-CDK was particularly efficacious in slow-growing, hormone-independent, p53-negative models e.g. advanced, anti-hormone refractory breast and prostate tumours.
"This new compound is highly efficacious at inhibiting tumour growth and works by acting on two separate mechanisms that are involved in the development and perpetuation of human cancer cells", said Dr. Siemeister. The compound has already entered phase I clinical trials to determine tolerability and pharmacokinetics in humans and to establish its efficacy in humans".