Inflammatory Breast Cancer (IBC) is a rare, highly aggressive form of cancer that is frequently locally advanced or metastasized at the time of diagnosis. The Triple-Negative subtype of IBC (TN-IBC), in particular, is characterized by very poor overall survival. TN-IBC lacks targeted therapies and is primarily treated with radiation or chemotherapy, which are inefficient. Recently, we identified the cell surface transmembrane ADAM8 (A Disintegrin and Metalloproteinase) protein as a driver of Triple-Negative Breast Cancer (TNBC) growth and metastasis via its Metalloproteinase (MP) and Disintegrin (DI) domains, respectively. In in vivo proof-of-concept experiments with a prototype reagent, we demonstrated that simultaneous, antibody-based, targeting of the ADAM8 MP and DI domains is an effective therapeutic approach for TNBC (Romagnoli et al., EMBO Mol. Med. 6:278, 2014).
The aggressive behavior of IBC cells has been attributed to a stem-like cancer cell compartment with high ALDH activity (ALDH+). Our studies of the green tea compound epigallocatechin-3 gallate (EGCG) revealed that it reduced growth of tumors derived from ALDH+ SUM-149 TN-IBC cells. We now report that EGCG concurrently decreases tumor levels of ADAM8 mRNA. This led us to assess the role of ADAM8 in TN-IBC. Tumor biopsies from 15 patients taken at the time of diagnosis and/or after neo-adjuvant treatment with chemotherapy, as well as paired lymph node and skin samples (when available) were analyzed by immunohistochemistry for ADAM8 expression. We report that 45.5% of primary TN-IBC patient tumors and 50.0% of metastases within the axillary lymph nodes express high levels of ADAM8 and its expression is largely unaffected by chemotherapy. In addition, ADAM8 expression was higher in the aggressive ALDH+ stem-like SUM-149 cell compartment. Consistently, knockdown of ADAM8 dramatically reduced the ability of SUM-149 cells to grow in an anchorage independent fashion and to migrate through Matrigel. A newly prepared anti-human ADAM8 mouse monoclonal antibody (ADP13) inhibited the MP and DI domains of ADAM8 on SUM-149 cells. ADP13 reduced orthotopic growth of tumors derived from SUM-149 cells by 40% in mice treated by i.p. injection 2 days a week with a dose of 4.5 mg/kg (n=7). Dose-response curves and survival experiments are in progress.
Conclusions: ADAM8 expression is present in almost half of TN-IBC patient tumors and their metastases, and promotes aggressive phenotype of TN-IBC cells in in vitro 3D-assays. A pre-clinical mouse model of TN-IBC validated ADAM8 as an accessible and promising new target for therapeutic intervention against this highly aggressive disease.
Citation Format: Mathilde Romagnoli, Stefania Pianetti, Sonia G. Das, Delphine Loussouarn, Carole Gourmelon, Mario Campone, Sophie Barillé-Nion, Giang T. Nguyen, Srimathi Srinivasan, Gail E. Sonenshein, Nora D. Mineva. ADAM8 drives aggressive phenotype of triple-negative inflammatory breast cancer & constitutes a novel therapeutic target [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1137. doi:10.1158/1538-7445.AM2017-1137