Bisphosphonate drugs inhibit osteoclastic bone resorption and are widely used to treat skeletal complications in patients with tumor-induced osteolysis. We now show that zoledronic acid, a new generation bisphosphonate with a heterocyclic imidazole substituent, is also a potent inhibitor of angiogenesis. In vitro, zoledronic acid inhibits proliferation of human endothelial cells stimulated with fetal calf serum, basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (IC(50) values 4.1, 4.2, and 6.9 microM, respectively), and modulates endothelial cell adhesion and migration. In cultured aortic rings and in the chicken egg chorioallantoic membrane assay, zoledronic acid reduces vessel sprouting. When administered systemically to mice, zoledronic acid potently inhibits the angiogenesis induced by subcutaneous implants impregnated with bFGF [ED(50), 3 microg/kg (7.5 nmol/kg) s.c.]. These findings indicate that zoledronic acid has marked antiangiogenic properties that could augment its efficacy in the treatment of malignant bone disease and extend its potential clinical use to other diseases with an angiogenic component.
IGF-IR-mediated signaling promotes survival, anchorage-independent growth, and oncogenic transformation, as well as tumor growth and metastasis formation in vivo. NVP-AEW541 is a pyrrolo[2,3-d]pyrimidine derivative small molecular weight kinase inhibitor of the IGF-IR, capable of distinguishing between the IGF-IR (IC50 = 0.086 microM) and the closely related InsR (IC50 = 2.3 microM) in cells. As expected for a specific IGF-IR kinase inhibitor, NVP-AEW541 abrogates IGF-I-mediated survival and colony formation in soft agar at concentrations that are consistent with inhibition of IGF-IR autophosphorylation. In vivo, this orally bioavailable compound inhibits IGF-IR signaling in tumor xenografts and significantly reduces the growth of IGF-IR-driven fibrosarcomas. Thus, NVP-AEW541 represents a class of selective, small molecule IGF-IR kinase inhibitors with proven in vivo antitumor activity and potential therapeutic application.
Although DNA damaging agents have revolutionized chemotherapy against solid tumors, a narrow therapeutic window combined with severe side effects has limited their broader use. Here we show that RAD001 (everolimus), a rapamycin derivative, dramatically enhances cisplatin-induced apoptosis in wild-type p53, but not mutant p53 tumor cells. The use of isogenic tumor cell lines expressing either wild-type mTOR cDNA or a mutant that does not bind RAD001 demonstrates that the effects of RAD001 are through inhibition of mTOR function. We further show that RAD001 sensitizes cells to cisplatin by inhibiting p53-induced p21 expression. Unexpectedly, this effect is attributed to a small but significant inhibition of p21 translation combined with its short half-life. These findings provide the molecular rationale for combining DNA damaging agents with RAD001, showing that a general effect on a major anabolic process may dramatically enhance the efficacy of an established drug protocol in the treatment of cancer patients with solid tumors.
As a result of our efforts to discover novel p53:MDM2 protein-protein interaction inhibitors useful for treating cancer, the potent and selective MDM2 inhibitor NVP-CGM097 (1) with an excellent in vivo profile was selected as a clinical candidate and is currently in phase 1 clinical development. This article provides an overview of the discovery of this new clinical p53:MDM2 inhibitor. The following aspects are addressed: mechanism of action, scientific rationale, binding mode, medicinal chemistry, pharmacokinetic and pharmacodynamic properties, and in vivo pharmacology/toxicology in preclinical species.
Biomarkers for patient selection are essential for the successful and rapid development of emerging targeted anti-cancer therapeutics. In this study, we report the discovery of a novel patient selection strategy for the p53–HDM2 inhibitor NVP-CGM097, currently under evaluation in clinical trials. By intersecting high-throughput cell line sensitivity data with genomic data, we have identified a gene expression signature consisting of 13 up-regulated genes that predicts for sensitivity to NVP-CGM097 in both cell lines and in patient-derived tumor xenograft models. Interestingly, these 13 genes are known p53 downstream target genes, suggesting that the identified gene signature reflects the presence of at least a partially activated p53 pathway in NVP-CGM097-sensitive tumors. Together, our findings provide evidence for the use of this newly identified predictive gene signature to refine the selection of patients with wild-type p53 tumors and increase the likelihood of response to treatment with p53–HDM2 inhibitors, such as NVP-CGM097.DOI:
http://dx.doi.org/10.7554/eLife.06498.001
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