Tumor-induced neovascularization and the loss of cell cycle control represent a common phenotype for many cancers, including infiltrating ductal adenocarcinomas of the pancreas and neuroendocrine tumors of the gastroenteropancreatic system. This has led to a search for compounds that target the proliferative and angiogenic pathways, in an attempt to discover novel anti-oncogenic therapies. ZK 304709 is a first-in-class, oral Multi-target Tumor Growth Inhibitor™ (MTGI™) that induces apoptosis and tumor cell death via inhibition of cell cycle progression, mRNA synthesis, and tumor-induced angiogenesis. More specifically, at nanomolar concentrations ZK 304709 inhibits CDKs 1, 2, 4, 7 and 9, VEGF-receptor tyrosine kinases (RTKs) 1-3 and PDGF-RTKβ. This multi-targeted profile suggests ZK 304709 is a strong candidate for the treatment of pancreatic tumors. Using a flow cytometric assay, treatment with ZK 304709 was found to produce a blockade of cell cycle progression that was consistent with CDK inhibition. Inhibition of VEGF-induced vascular permeability, as measured by Evans blue dye extravasation (Miles assay) in nude mice, indicated that ZK 304709 blocks the VEGF-RTK system in vivo. Treatment of mice (8-10 per group), bearing subcutaneous or orthotopically implanted MIA PaCa-2 human pancreatic tumors, with ZK 304709 resulted in an inhibition of tumor growth, demonstrating a reduction in primary tumor weight of >80%. This is a 4-8 fold improvement compared with intraperitoneal gemcitabine treatment, which reduced subcutaneously implanted tumors by 42% and orthotopically implanted tumors by only 20%. ZK 304709 treatment of orthotopically implanted tumors also reduced macroscopically visible metastases below detection levels, whereas gemcitabine alone produced 60% of mice without visible metastases. When the two drugs were combined the weight of primary orthotopically implanted Capan-1 tumors was reduced by 92%, and no metastases were visible. In the orthotopically implanted BON human neuroendocrine pancreatic tumor model, ZK 304709 achieved an 80% reduction of primary tumor growth and markedly reduced the incidence of macroscopically visible liver metastases (30% vs 70% for ZK 304709 and control, respectively).Nanomolar concentrations of ZK 304709 demonstrated potency and efficacy in inhibiting the growth and metastasis formation of human pancreatic tumor xenografts, making it a promising potential therapeutic compound for the treatment of pancreatic cancer. ZK 304709 is currently in Phase I clinical trials in patients with advanced solid tumors.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]