A novel target in multiple solid cancers for an antibody-drug conjugate is trophoblast cell-surface antigen, or Trop-2, also known as tumor-associated calcium signal transducer (TACSTD2), epithelial glycoprotein-1 (EGP-1), gastrointestinal tumor-associated antigen (GA733-1), and surface marker 1 (M1S1). The expression, role, and function of Trop-2 have been of interest since about 1990, when our anti-Trop-2 monoclonal antibody was shown to bind to many different cancer types. It is encoded by a single-copy gene (TACSTD2) mapped on chromosome 1p32, which hybridizes to a single 1.8-kb mRNA encoding the GA733-1 gene. The 36 kDa nascent polypeptide, which is post-translationally modified by N-linked glycosylation, forms a type-1 transmembrane protein that is distinct from EpCAM (EGP-2). First described as a cell-surface glycoprotein of a human trophoblast cell, Trop-2 was believed at that time to be involved in regulating the growth and invasion of cancer cells. The Trop-2/TACSTD2 gene has been cloned and found to encode a transmembrane Ca++-signal transducer. Functionally, it is linked to cell migration and anchorage-independent growth, with higher expression in a variety of human epithelial cancers, including breast, lung, gastric, colorectal, pancreatic, prostatic, cervical, head-and-neck, and ovarian carcinomas, compared to normal tissues. The increased expression of Trop-2 is reported to be necessary and sufficient for stimulation of cancer growth, while a bi-cistronic cyclin D1-Trop-2 mRNA chimera is an oncogene. Importantly, elevated expression is associated with more aggressive disease and a poor prognosis in several cancer types, including breast cancer. Increased Trop-2 mRNA is a strong predictor of poor survival and lymph node metastasis in patients with invasive ductal breast cancers, and Kaplan-Meier survival curves show that breast cancer patients with high Trop-2 expression have a significantly shorter survival. Using genomic analyses of breast cancers, it was proposed that Trop-2 is a potentially attractive target for triple-negative breast cancer (TNBC).
Goldenberg DM, et al. Trop-2 is a novel target for solid cancer therapy with sacituzumab govitecan (IMMU-132), an antibody-drug conjugate (ADC). Oncotarget. 2015;6(26):22496-22512.