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Review
. 2018 Jun 22;9(48):28989-29006.
doi: 10.18632/oncotarget.25615.

The emergence of trophoblast cell-surface antigen 2 (TROP-2) as a novel cancer target

David M Goldenberg  1   2 , Rhona Stein  1 , Robert M Sharkey  1   3
Affiliations
Review

The emergence of trophoblast cell-surface antigen 2 (TROP-2) as a novel cancer target

David M Goldenberg et al. Oncotarget. .

Abstract

TROP-2 is a glycoprotein first described as a surface marker of trophoblast cells, but subsequently shown to be increased in many solid cancers, with lower expression in certain normal tissues. It regulates cancer growth, invasion and spread by several signaling pathways, and has a role in stem cell biology and other diseases. This review summarizes TROP-2's properties, especially in cancer, and particularly its role as a target for antibody-drug conjugates (ADC) or immunotherapy. When the irinotecan metabolite, SN-38, is conjugated to a humanized anti-TROP-2 antibody (sacituzumab govitecan), it shows potent broad anticancer activity in human cancer xenografts and in patients with advanced triple-negative breast, non-small cell and small-cell lung, as well as urothelial cancers.

Keywords: TACSTD2; TROP-2; antibody-drug conjugates; immunotherapy; sacituzumab govitecan.

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Conflict of interest statement

CONFLICTS OF INTEREST Drs. Goldenberg and Sharkey own Immunomedics stock or stock options, and Dr. Goldenberg holds patented inventions. Dr. Goldenberg is the founder of the Center for Molecular Medicine and Immunology (CMMI), and also the retired founder of Immunomedics, Inc., and IBC Pharmaceuticals, Inc.

Figures

Figure 1
Figure 1. TROP-2 structure [as per Vidmar et al. [36]]
TROP-2 contains a 274-amino-acid extracellular epidermal growth factor-like repeat portion that contains 3 domains, a cysteine-rich domain, a thyroglobulin type-1 domain, and a cysteine-poor domain. The molecule traverses the membrane and terminates with a cytoplasmic tail that has a serine at position 303 that can be phosphorylated. The molecule has 4 N-glycosylation sites in the extracellular domain.
Figure 2
Figure 2. TROP-2 processing, cell signaling and its effects [adapted from Shvartsur and Bonavida, [9]]
In prostate cancer, studies have found several enzymes involved in the cleavage of the TM-IC portion of the molecule, with the extracellular domain remaining associated with the plasma membrane or found in the cytoplasm. β-catenin colocalized with TM-IC in the nucleus, which can lead to TROP-2-driven proliferation, but also it can upregulate cyclin D1 and c-myc, which can lead to cell growth. Apart from its processing, TROP-2 has the potential to influence several intracellular signaling pathways that can then lead to several different events. The phosphorylation of serine-303 appears be involved in the release intracellular Ca2+, which can activate Raf and NF-κB pathways, and stimulate MAPK signaling and cell cycle progression. TROP-2 can increase cyclin D1 and cyclin E, which together with ERK1/2 can mediate cell cycle progression. Studies with murine TROP-2 have revealed the stimulation of MAPK and downstream upregulation of phosphorylated ERK1/2 can induce the AP-1 transcription factor that can regulate a number of tumor-associated target genes involved in angiogenesis (e.g., via VEGF), proliferation (e.g., via cyclins and CDKs), apoptosis (e.g., via BCL-2, FasL), and invasion and metastasis (e.g., via matrix metalloproteinases, podoplanin, Ezrin, and CD33), as well as epithelial to mesenchymal transition (EMT) that can interact with β-catenin to affect cell growth. Studies with murine TROP-2 also found that increased ERK activity can induce the phosphorylation of FOXO3a, followed by its ubiquitination by mouse double minute 2 (MDM2), with its subsequent degradation. The degradation of FOXO3a can promote cancer cell survival.
Figure 3
Figure 3. Representation of structure of the CL2A linker used to bind SN-38 to the anti-TROP-2 IgG to form sacituzumab govitecan
The CL2A linker forms a water-soluble SN-38 conjugate with excellent yields. Water solubility is achieved by inserting a short polyethylene glycol segment. The linker binds to the 20th position of SN-38, forming a pH-sensitive carbonate bond. Binding to the 20th position stabilizes the lactone ring. A maleimide at the end of the linker will enable a stable thioether bond with sulfhydryl moieties formed after mild reduction of the antibody. This process will bind up to 8 moieties to the antibody without affecting antigen binding.
Figure 4
Figure 4. Immunohistochemical localization of TROP-2 in human cancers
Polyclonal antibody to human TROP-2 was used to reveal TROP-2 localization in tumor sections, mostly from commercial microarrays (bar = 0.1 mm). (A) prostate cancer, (B) triple-negative breast cancer, (C) estrogen-receptor and HER2 positive breast cancer, (D) urinary bladder cancer, (E) non-small-cell lung cancer, (F) small-cell lung cancer. All specimens selected based on their moderate (2+) to strong (3+) expression of TROP-2. Staining is found both on the membrane and in the cytoplasm.
Figure 5
Figure 5. Anti-tumor responses reported in patients with several epithelial cancers who were treated with sacituzumab govitecan, an antibody-drug conjugate targeting TROP-2
Waterfall diagrams depicting the maximum shrinkage observed by investigators in the target lesions selected at baseline after receiving sacituzumab govitecan therapy (response assessment provided only for patients who had at least one follow-up examination). Bar colors provide descriptors for the best overall response achieved in each patient based on RECIST 1.1 criteria. Results are for (A) TNBC as adapted from Bardia et al. [106], (B) NSCLC as adapted from Heist et al. [104] (C), SCLC as adapted from Gray et al. [103], and (D) UC as adapted from Tagawa et al. [105]. Identification of subpopulations of interest for NSCLC (squamous cell) and SCLC (sensitive vs. resistant to first-line platinum therapy) are provided.
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