In:
Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 8, No. 12_Supplement ( 2009-12-10), p. A39-A39
Abstract:
Background: The role of the IGF-1 receptor (IGF-1R) pathway in mediating proliferative, invasive and pro-survival responses in cancer has led to a plethora of agents targeting this pathway, including antibodies and small molecule tyrosine kinase inhibitors. In order to maximize the clinical utility of such agents, it is imperative that patient selection strategies be applied. The goal of this study was to develop and characterize predictive biomarkers for the small molecule IGF-1R/IR tyrosine kinase inhibitor, OSI-906, in colorectal cancer (CRC). Methods and Results: Twenty-seven human CRC cell lines were exposed in vitro to OSI-906 and classified according to the IC50 value as sensitive ( & lt; 1.5 mol/L) or resistant ( & gt; 1.5 mol/L). Immunoblotting and immuno-histochemistry for effector proteins was performed on all CRC cell lines as well as fluorescent in-situ hybridization (FISH) to assess IGF-1R gene amplification and KRAS/BRAF/PI3K mutation sequencing. Baseline expression levels of effector proteins were not predictive of OSI-906 sensitivity. Although IGF-IR FISH did not reveal amplification, the OSI-906 sensitive CRC cell lines displayed an “unbalanced gain” of IGF-IR based upon ploidy. Likewise, there was a trend toward KRAS wildtype status and sensitivity to OSI-906. Next, the baseline gene expression of selected in vitro and in vivo sensitive or resistant cell lines was analyzed using Affymetrix U133 Plus 2.0 gene arrays. These transcriptional profiling data led to the development of a k-Top Scoring Pair (k-TSP) classifier which identified three gene pairs as the final classifier: (PROM1 & gt;MT1E), (LY75 & gt; OXCT1) and (HSD17B2 & gt;CALD1). Pathway analysis at baseline indicated IGF-IR signaling and insulin pathways were among the top 20 up regulated BioCarta pathways whereas in the resistant cells, the ErbB, MAPK, VEGF, and multiple cell adhesion/motility signaling pathways were prominently represented. From these data an integrated genomic classifier of FISH, KRAS status, and the k-TSP was developed and tested against 5 human CRC explants in vivo. The classifier was able to predict with 100% accuracy the responsiveness of these explants to OSI-906. Conclusions: These results indicate that an integrated approach to the development of individualized therapy is feasible and should be applied early in the development of this and other novel classes of anticancer agents. Additionally, such data may be used to develop rationale combination partners, such as VEGF or MEK inhibitors, to enhance responsiveness to OSI-906. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A39.
Type of Medium:
Online Resource
ISSN:
1535-7163
,
1538-8514
DOI:
10.1158/1535-7163.TARG-09-A39
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2009
detail.hit.zdb_id:
2062135-8
SSG:
12
