The growth factor heregulin (HRG), expressed in about 30% of breast cancer tumors, activates the erbB-2 receptor via induction of heterodimeric complexes of erbB-2 with erbB-3 or erbB-4. HRG induces tumorigenicity and metastasis of breast cancer cells. Our investigation into whether HRG is a factor likely to promote tumor formation independently of erbB-2 overexpression concludes that blockage of HRG expression suppresses the aggressive phenotype of MDA-MB-231 breast cancer cells by inhibiting cell proliferation, preventing anchorageindependent growth, and suppressing the invasive potential of the cells in vitro. More importantly, we observed a marked reduction in tumor formation, tumor size, and a lack of metastasis in vivo. These studies were achieved by blocking HRG expression in MDA-MB-231 cells using an HRG antisense cDNA. In the search for the mechanism by which blockage of HRG reverts this aggressive phenotype, we discovered that the cells in which HRG is blocked exhibit a marked decrease in erbB activation and a significant reduction in MMP-9 activity, demonstrating a direct causal role in HRG induction of tumorigenicity. Our study is the first report and serves as a proof of the concept that HRG is a key promoter of breast cancer tumorigenicity and metastasis independently of erbB-2 overexpression and should be deemed a potential target in developing therapies for breast cancer.
2071 Background: EGFRvIII is a mutant version of EGF receptor resulting from the genomic deletion of exons 2 through 7 and is expressed only in certain tumors. AMG 595 is an experimental therapeutic specifically targeting EGFRvIII and consists of an EGFRvIII-specific antibody conjugated to the maytansinoid antimicrotubule agent DM-1. Due to its specificity, mechanism of action, and pre-clinical activity, AMG 595 is expected to have clinical effect only in tumors expressing EGFRvIII. Since the reported prevalence of EGFRvIII in glioblastoma multiforme (GBM) is ~30%, prospective selection of patients with EGFRvIII positive tumors was desired for clinical development. An immunohistochemical (IHC) assay developed with Dako using a novel EGFRvIII antibody is currently being employed for patient selection for the AMG 595 phase I study in recurrent GBM (NCT01475006). Methods: An appropriate IHC reagent for human tissue was created using the variable region of a novel EGFRvIII-specific antibody developed using Xenomouse technology. Staining conditions were optimized using Dako pharmDx reagents, the Dako Link 48 Autostainer, and FFPE tissue sections. Confirmatory transcript analyses of adjacent sections were conducted using the NanoString platform. Results: Robust and reproducible staining for EGFRvIII was observed using archived GBM resections. Percentage of stained cells correlated with levels of EGFRvIII transcripts, and tumors without staining did not express EGFRvIII transcripts. Although some tumors exhibited homogenous staining, most were heterogeneous with varying distribution and percentages of stained tumor cells similar to literature reports of IHC analysis utilizing other EGFRvIII-specific antibodies. Tumor samples from patients entering into the AMG 595 Phase 1 study analyzed with this IHC test have displayed the predicted staining prevalence. Conclusions: The developed EGFRvIII IHC assay, approved under an Investigational Device Exemption, is currently being successfully employed to prospectively select patients in an ongoing phase I trial. Use of this well characterized IHC test will enable correlation of clinical outcome and staining characteristics to inform subsequent studies.
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