Trop-2 overexpression as an independent marker for poor overall survival in ovarian carcinoma patients

Bignotti, Eliana; Todeschini, Paola; Calza, Stefano; Falchetti, Marcella; Ravanini, Maria; Tassi, Renata; Ravaggi, Antonella; Bandiera, Elisabetta; Romani, Chiara; Zanotti, Laura; Tognon, Germana; Odicino, Franco; Facchetti, Fabio; Pecorelli, Sërgio; Santin, Alessandro D.

doi:10.1016/j.ejca.2009.12.019

Cited by 107 publications

(111 citation statements)

References 29 publications

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“…The findings suggest that the development of therapeutic agents to target Trop2 may require strategies that target Trop2 on malignant tissues in order to minimize potential toxicities to essential normal tissues that also express high levels of Trop2. (J Histochem Cytochem 59:701-710, 2011) Keywords Trop2, tissue distribution, human, murine, cancer ovarian (Bignotti et al 2010), colorectal (Ohmachi et al 2006), pancreatic , gastric (Muhlmann et al 2009), and squamous cell carcinoma of the oral cavity ) compared with the corresponding normal tissue. High Trop2 expression appears to correlate with poor patient prognosis in these studies, leading to the suggestion that Trop2 could be a therapeutic target for various carcinomas.…”

Section: Discussionmentioning

confidence: 99%

Expression of Trop2 Cell Surface Glycoprotein in Normal and Tumor Tissues

Stepan

Trueblood

Hale

et al. 2011

J Histochem Cytochem.

190

125

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Trop2 is a cell-surface glycoprotein reported to be overexpressed in various types of adenocarcinomas with minimal expression in normal tissues. Recent findings that Trop2 expression correlates with tumor aggressiveness have increased interest in Trop2 as a potential target for cancer immunotherapy. The goal of this study was to extensively evaluate Trop2 expression at the transcript and protein levels in normal and tumor tissues. It was determined that Trop2 is overexpressed on some carcinomas relative to the corresponding normal tissue. However, in human and mouse, Trop2 is highly expressed at both the transcript and protein levels on several essential normal tissues. The findings suggest that the development of therapeutic agents to target Trop2 may require strategies that target Trop2 on malignant tissues in order to minimize potential toxicities to essential normal tissues that also express high levels of Trop2.

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Section: Discussionmentioning

confidence: 99%

Expression of Trop2 Cell Surface Glycoprotein in Normal and Tumor Tissues

Stepan

Trueblood

Hale

et al. 2011

J Histochem Cytochem.

190

125

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“…Trop2 is a known regulator of migration; it is highly upregulated in numerous types of tumors, where it promotes migration [49][50][51] and is linked to increased metastasis [52][53][54][55][56][57] . We have shown that Trop2 regulates the migration of fetal lung cells [37,58] , which suggests a previously unrecognized role of Trop2 during lung development.…”

Section: The Effect Of Iugr On Molecular Factors That Regulate Granulmentioning

confidence: 99%

Intrauterine Growth Restriction Alters the Postnatal Development of the Rat Cerebellum

et al. 2017

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Intrauterine growth restriction (IUGR) is a major cause of antenatal brain injury. We aimed to characterize cerebellar deficits following IUGR and to investigate the potential underlying cellular and molecular mechanisms. At embryonic day 18, pregnant rats underwent either sham surgery (controls; n = 23) or bilateral uterine vessel ligation to restrict blood flow to fetuses (IUGR; n = 20). Offspring were collected at postnatal day 2 (P2), P7, and P35. Body weights were reduced at P2, P7, and P35 in IUGR offspring (p < 0.05) compared with controls. At P7, the width of the external granule layer (EGL) was 30% greater in IUGR than control rats (p < 0.05); there was no difference in the width of the proliferative zone or in the density of Ki67-positive cells in the EGL. Bergmann glia were disorganized at P7 and P35 in IUGR pups, and by P35, there was a 10% decrease in Bergmann glial fiber density (p < 0.05) compared with controls. At P7, trophoblast antigen-2 (Trop2) mRNA and protein levels in the cerebellum were decreased by 88 and 40%, respectively, and astrotactin 1 mRNA levels were increased by 20% in the IUGR rats (p < 0.05) compared with controls; there was no difference in ASTN1 protein. The expressions of other factors known to regulate cerebellar development (astrotactin 2, brain-derived neurotrophic factor, erb-b2 receptor tyrosine kinase 4, neuregulin 1, sonic hedgehog and somatostatin) were not different between IUGR and control rats at P7 or P35. These data suggest that damage to the migratory scaffold (Bergmann glial fibers) and alterations in the genes that influence migration (Trop2 and Astn1) may underlie the deficits in postnatal cerebellar development following IUGR.

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“…Immunohistochemical analysis on human tumor samples has demonstrated expression of Trop-2 protein in multiple tumor types, including pancreatic (8), ovarian (9), endometrial (10), non-small cell lung (NSCLC; ref. 11), colon (12), gastric (13), and oral cancers (14).…”

Section: Introductionmentioning

confidence: 99%

“…Trop-2 (trophoblast cell-surface antigen 2), also referred to as M1S1, GA733-1 (gastric antigen 733-1), EGP-1 (epithelial glycoprotein-1), or TACSTD2 (tumor-associated calcium signal transducer 2), is a type I transmembrane cell-surface glycoprotein originally identified in human placental trophoblasts (4) and subsequently found to be highly expressed in most human carcinomas. Although the biological role of Trop-2 is still under investigation (5), various studies have shown that overexpression of Trop-2 correlates with increased cancer growth (6,7), tumor aggressiveness, metastasis, and poor prognosis in various human carcinomas (8)(9)(10)(11)(12)(13)(14). Studies have also shown that Trop-2 contributes to tumor pathogenesis, at least in part, by activating the ERK1/2 MAPK pathway, which has important implications in cancer cell proliferation, migration, invasion, and survival (15).…”

Section: Introductionmentioning

confidence: 99%

RN927C, a Site-Specific Trop-2 Antibody–Drug Conjugate (ADC) with Enhanced Stability, Is Highly Efficacious in Preclinical Solid Tumor Models

Strop

Tran

Dorywalska

et al. 2016

Molecular Cancer Therapeutics

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Trop-2, also known as TACSTD2, EGP-1, GA733-1, and M1S1, is frequently expressed on a variety of human carcinomas, and its expression is often associated with poor prognosis of the diseases. However, it is also present on the epithelium of several normal tissues. A comprehensively designed Trop-2-targeting antibodydrug conjugate (ADC), balancing both efficacy and toxicity, is therefore necessary to achieve clinical utility. To this end, we developed a cleavable Trop-2 ADC (RN927C) using a site-specific transglutaminase-mediated conjugation method and a proprietary microtubule inhibitor (MTI) linker-payload, PF-06380101. Robust in vitro cytotoxicity of RN927C was observed on a panel of Trop-2-expressing tumor cell lines, with IC 50 generally in the subnanomolar range. As expected for an MTI-containing ADC, RN927C readily induced mitotic arrest of treated cells in vitro and in vivo, followed by subsequent cell death. The in vivo efficacy of RN927C was tested in multiple cell line and patient-derived xenograft tumor models, including pancreatic, lung, ovarian, and triple-negative breast tumor types. Single-dose administration of RN927C at 0.75 to 3 mg/kg was generally sufficient to induce sustained regression of Trop-2-expressing tumors and showed superior efficacy over standard treatment with paclitaxel or gemcitabine. Administration of RN927C in nonhuman primate toxicity studies resulted in target-mediated effects in skin and oral mucosa, consistent with Trop-2 expression in these epithelial tissues with minimal, non-dose limiting off-target toxicities. On the basis of the combined efficacy and safety results, RN927C is postulated to have a favorable therapeutic index for treatment of solid tumors. Mol Cancer Ther; 15(11); 2698-708. Ó2016 AACR.

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Trop-2 overexpression as an independent marker for poor overall survival in ovarian carcinoma patients

Cited by 107 publications

References 29 publications

Expression of Trop2 Cell Surface Glycoprotein in Normal and Tumor Tissues

Expression of Trop2 Cell Surface Glycoprotein in Normal and Tumor Tissues

Intrauterine Growth Restriction Alters the Postnatal Development of the Rat Cerebellum

RN927C, a Site-Specific Trop-2 Antibody–Drug Conjugate (ADC) with Enhanced Stability, Is Highly Efficacious in Preclinical Solid Tumor Models

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