Comparative profiling of the novel epothilone, sagopilone, in xenografts derived from primary non-small cell lung cancer.

Abstract

PURPOSE:

Characterization of new anticancer drugs in a few xenograft models derived from established human cancer cell lines frequently results in the discrepancy between preclinical and clinical results. To take the heterogeneity of tumors into consideration more thoroughly, we describe here a preclinical approach that may allow a more rational clinical development of new anticancer drugs.

EXPERIMENTAL DESIGN:

We tested Sagopilone, an optimized fully synthetic epothilone, in 22 well-characterized patient-derived non-small cell lung cancer models and correlated results with mutational and genome-wide gene expression analysis.

RESULTS:

Response analysis according to clinical trial criteria revealed that Sagopilone induced overall responses in 64% of the xenograft models (14 of 22), with 3 models showing stable disease and 11 models showing partial response. A comparison with response rates for established drugs showed the strong efficacy of Sagopilone in non-small cell lung cancer. In gene expression analyses, Sagopilone induced tubulin isoforms in all tumor samples, but genes related to mitotic arrest only in responder models. Moreover, tumors with high expression of genes involved in cell adhesion/angiogenesis as well as of wild-type TP53 were more likely to be resistant to Sagopilone therapy. As suggested by these findings, Sagopilone was combined with Bevacizumab and Sorafenib, drugs targeting vascular endothelial growth factor signaling, in Sagopilone-resistant models and, indeed, antitumor activity could be restored.

CONCLUSION:

Analyses provided here show how preclinical studies can provide hypotheses for the identification of patients who more likely will benefit from new drugs as well as a rationale for combination therapies to be tested in clinical trials.

• Authors: Stefanie Hammer, Anette Sommer, Iduna Fichtner, Michael Becker, Jana Rolff, Johannes Merk, Ulrich Klar, Jens Hoffmann
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 16 Issue 5 Pg. 1452-65 (Mar 01 2010) ISSN: 1557-3265 [Electronic] United States
• PMID: 20179216 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Benzenesulfonates
• Benzothiazoles
• Epothilones
• Phenylurea Compounds
• Pyridines
• Niacinamide
• Bevacizumab
• Sorafenib
• sagopilone

Topics

• Animals
• Antibodies, Monoclonal (therapeutic use)
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents (therapeutic use)
• Benzenesulfonates (therapeutic use)
• Benzothiazoles (therapeutic use)
• Bevacizumab
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics)
• Drug Resistance, Neoplasm (drug effects, genetics)
• Epothilones (therapeutic use)
• Gene Expression Profiling
• Humans
• Lung Neoplasms (drug therapy, genetics)
• Mice
• Niacinamide (analogs & derivatives)
• Phenylurea Compounds
• Pyridines (therapeutic use)
• Reverse Transcriptase Polymerase Chain Reaction
• Sorafenib
• Xenograft Model Antitumor Assays (methods)