Abstract B231: Targeting Her2+ ductal breast cancer with PDL192, a novel humanized anti-TweakR monoclonal antibody
| Autor: | Lisa Durkan, Han Kim, Debra Chao, Yongke Zhang, Shiming Ye, Daniel E. H. Afar, Patricia Culp, Johnny Yin, Eric D. Hsi, Sonia Tomlinco, Peter Lambert, Doghee Choi, Mien Su, Mien Sho, Gary C. Starling |
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| Rok vydání: | 2009 |
| Předmět: | |
| Zdroj: | Molecular Cancer Therapeutics. 8:B231-B231 |
| ISSN: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.targ-09-b231 |
| Popis: | TWEAK receptor (TweakR), also known as Fn14, is a cell surface protein and member of the tumor necrosis factor receptor superfamily. TNFRSF family members are appealing therapeutic targets due to their expression and function in tumor cells. The goal of the current study was to examine the potential of TweakR as a therapeutic target in various subtypes of breast cancer by 1) determining expression of TweakR using immunohistochemistry (IHC) and 2) treating cells derived from breast cancer in vitro and in vivo with PDL192, a novel, humanized anti-TweakR mAb. Overexpression of TweakR protein in breast cancer was confirmed by IHC on formalin fixed paraffin embedded (FFPE) tissues. TweakR was elevated in infiltrating tumors when compared with normal adjacent tissues. 30 to 40% of various subtypes of invasive ductal breast cancer samples stained highly for TweakR; however, fewer than 5% of lobular breast cancer samples had high levels of TweakR. In addition, a strong positive correlation of TweakR and Her2 expression was observed, irrespective of ER status. More than 60% of Her2+ invasive ductal cancer exhibited elevated levels of TweakR. Strong TweakR expression was also observed in bone metastasis samples from primary breast cancer but rarely in benign tumors, such as DCIS. PDL192 inhibited the in vitro growth of various subtypes of TweakR-expressing breast cancer cell lines and this activity was augmented by crosslinking the mAb. In addition, PDL192 significantly inhibited the in vivo growth of a variant of the breast cancer xenograft model MDA-MB231 that exhibits metastatic potential. PDL192 administration exhibited a dose-dependent inhibition of primary tumor growth and lung metastasis and enhanced the anti-tumor activity of several chemotherapy agents currently used to treat breast cancer. These data provide the rationale to evaluate PDL192 as a potential therapy for the treatment of breast cancer. Currently, PDL192 is being tested in a phase I safety study for the treatment of patients with solid tumors. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B231. |
| Databáze: | OpenAIRE |
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