Despite recent advances in breast cancer treatment, over 500,000 women die yearly worldwide. Triple-Negative Breast Cancer (TNBC) represents only 15% of breast tumor cases but is highly metastatic and accounts for more than 25% of breast cancer deaths. Treatment of patients with TNBC remains particularly challenging since they cannot benefit from any currently available targeted therapies due to the absence of the estrogen receptor (ER), the growth factor receptor HER2 or other well-defined molecular targets on their tumors. Therapeutic options for TNBC are restricted to chemotherapy and radiation, which are insufficient to block tumor growth, relapse or metastatic dissemination, and have severe side effects. Thus, there is an urgent need for new targets for the treatment of TNBC. Recently, we identified the ADAM8 (A Disintegrin And Metalloprotease) protein as an essential player driving breast cancer growth and metastasis, and validated it as a promising novel target for TNBC treatment. Specifically, ADAM8 was detected in 34% of patient primary TNBC tumors, 48% of all breast cancer metastases and was an independent predictor of poor prognosis for breast cancer patients, in terms of both disease recurrence and overall survival. Consistently, our in vitro and animal studies demonstrated roles of ADAM8 in tumor growth/angiogenesis and adhesion to and invasion through the endothelium via its Metalloproteinase (MP) and Disintegrin (DIS) domains, respectively. As ADAM8 is a transmembrane surface protein and non-essential under normal physiological conditions, it constitutes an attractive target for treatment. Importantly, in mouse orthotopic models using human MDA-MB-231 TNBC cells, ADAM8 was accessible to an antibody-based therapy that successfully inhibited dissemination of pre-existing tumors to distant organs, in particular metastasis to the brain and lungs. Here, the hypotheses that ADAM8 is a novel target for the treatment of TNBC-derived tumors and that an antibody-based treatment targeting the MP and DIS domains of ADAM8 constitutes an effective therapy for ADAM8-positive TNBC patients will be tested. Notably, TNBC is known to be a heterogeneous disease with multiple molecular subtypes. Immunohistochemical analysis of TNBC Patient-Derived Xenograft (PDX) samples demonstrated high ADAM8 staining in Mesenchymal (M), Basal-like (BL)1, BL1/M and BL2/M tumors. We propose to test the effects of anti-ADAM8 antibody on growth and dissemination of pre-existing tumors derived from three ADAM8+ TNBC cell lines (Aim 1) and three PDX TNBC tumors (Aim 2) of these subclasses. These studies will determine whether ADAM8 antibody-based treatment constitutes an effective therapy for ADAM8+ TNBC in a variety of preclinical models. If confirmed, these experiments could revolutionize treatment regimens for patients with ADAM8-expressing TNBC by providing safe, effective interventions that reduce growth and metastases of these very aggressive tumors. Since ADAM8 is on the surface of pancreatic, hepatocellular and renal cancer, antibody targeting may have broader implications for cancer treatment.
Triple-Negative Breast Cancer (TNBC) represents only 15% of breast tumor cases but is highly metastatic, and accounts for more than 25% of the 500,000 breast cancer deaths yearly worldwide. There is an urgent need for new treatment regimens for TNBC as current options are restricted to chemotherapy and radiation, which are insufficient to block tumor progression, relapse or metastatic dissemination, and have severe side effects. Here we propose preclinical studies to validate a novel antibody-based therapy targeting two extracellular domains of a transmembrane protein called ADAM8, which if confirmed could revolutionize treatment modalities for patients with ADAM8-expressing TNBC by providing safe, effective interventions that reduce growth and metastases of these very aggressive tumors.
