Detection of soluble EpCAM (sEpCAM) in malignant ascites predicts poor overall survival in patients treated with catumaxomab

Seeber, Andreas; Braicu, Elena Ioana; Untergasser, Gerold; Nassir, Mani; Fong, Dominic; Botta, Laura; Gastl, Guenther; Fiegl, Heidi; Zeimet, Alain G.; Sehouli, Jalid; Spizzo, Gilbert

doi:10.18632/oncotarget.4496

Cited by 15 publications

(17 citation statements)

References 27 publications

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“…Serum levels of EpEX in tumor patients revealed low [ 46 , 110 , 112 – 114 ] but represent systemic levels, which suggests substantially higher intratumoral levels at the interface of tumor cells, where EpEX is actively shed [ 115 ]. Hence, production of EpEX by carcinoma cells could locally impact the regulation of EGFR-dependent proliferation and EMT.…”

Section: Discussionmentioning

confidence: 99%

EpCAM ectodomain EpEX is a ligand of EGFR that counteracts EGF-mediated epithelial-mesenchymal transition through modulation of phospho-ERK1/2 in head and neck cancers

et al. 2018

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Head and neck squamous cell carcinomas (HNSCCs) are characterized by outstanding molecular heterogeneity that results in severe therapy resistance and poor clinical outcome. Inter- and intratumoral heterogeneity in epithelial-mesenchymal transition (EMT) was recently revealed as a major parameter of poor clinical outcome. Here, we addressed the expression and function of the therapeutic target epidermal growth factor receptor (EGFR) and of the major determinant of epithelial differentiation epithelial cell adhesion molecule (EpCAM) in clinical samples and in vitro models of HNSCCs. We describe improved survival of EGFRlow/EpCAMhigh HNSCC patients (n = 180) and provide a molecular basis for the observed disparities in clinical outcome. EGF/EGFR have concentration-dependent dual capacities as inducers of proliferation and EMT through differential activation of the central molecular switch phosphorylated extracellular signal–regulated kinase 1/2 (pERK1/2) and EMT transcription factors (EMT-TFs) Snail, zinc finger E-box-binding homeobox 1 (Zeb1), and Slug. Furthermore, soluble ectodomain of EpCAM (EpEX) was identified as a ligand of EGFR that activates pERK1/2 and phosphorylated AKT (pAKT) and induces EGFR-dependent proliferation but represses EGF-mediated EMT, Snail, Zeb1, and Slug activation and cell migration. EMT repression by EpEX is realized through competitive modulation of pERK1/2 activation strength and inhibition of EMT-TFs, which is reflected in levels of pERK1/2 and its target Slug in clinical samples. Accordingly, high expression of pERK1/2 and/or Slug predicted poor outcome of HNSCCs. Hence, EpEX is a ligand of EGFR that induces proliferation but counteracts EMT mediated by the EGF/EGFR/pERK1/2 axis. Therefore, the emerging EGFR/EpCAM molecular cross talk represents a promising target to improve patient-tailored adjuvant treatment of HNSCCs.

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Section: Discussionmentioning

confidence: 99%

EpCAM ectodomain EpEX is a ligand of EGFR that counteracts EGF-mediated epithelial-mesenchymal transition through modulation of phospho-ERK1/2 in head and neck cancers

et al. 2018

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“…It was found that patients with soluble EpCAM present in ascites had a significantly shorter overall survival; the prognostic significance was particularly strong in patients with ovarian cancer. However, puncture-free survival and time to next puncture were not significantly different between soluble EpCAM-positive and -negative patients [ 128 ].…”

Section: Palliative Treatment For Malignant Ascitesmentioning

confidence: 99%

Advances in ovarian cancer therapy

Cortez

Tudrej

Kujawa

et al. 2017

Cancer Chemother Pharmacol

460

431

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Epithelial ovarian cancer is typically diagnosed at an advanced stage. Current state-of-the-art surgery and chemotherapy result in the high incidence of complete remissions; however, the recurrence rate is also high. For most patients, the disease eventually becomes a continuum of symptom-free periods and recurrence episodes. Different targeted treatment approaches and biological drugs, currently under development, bring the promise of turning ovarian cancer into a manageable chronic disease. In this review, we discuss the current standard in the therapy for ovarian cancer, major recent studies on the new variants of conventional therapies, and new therapeutic approaches, recently approved and/or in clinical trials. The latter include anti-angiogenic therapies, polyADP-ribose polymerase (PARP) inhibitors, inhibitors of growth factor signaling, or folate receptor inhibitors, as well as several immunotherapeutic approaches. We also discuss cost-effectiveness of some novel therapies and the issue of better selection of patients for personalized treatment.

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“…Hence, Amgen is currently advancing new versions of BiTE molecules by fusing the Fc domain. However, the fact that catumaxomab, a bispecific mAb for CD3, and EpCAM have been withdrawn due to toxicity issues, presumably because of FcγR or C1q binding of Fc [125][126][127][128] , indicates that for T-cell engagers, FcγR-related effector functions are detrimental with respect to clinical aspects. Therefore, simple Fc fusion for half-life extension purposes may lead to side effects, such as toxicity and/or shortened efficacy, at least in case of BiTE.…”

Section: Engineering Valency or Bispecificity Of Antibodiesmentioning

confidence: 99%

Boosting therapeutic potency of antibodies by taming Fc domain functions

2019

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Monoclonal antibodies (mAbs) are one of the most widely used drug platforms for infectious diseases or cancer therapeutics because they selectively target pathogens, infectious cells, cancerous cells, and even immune cells. In this way, they mediate the elimination of target molecules and cells with fewer side effects than other therapeutic modalities. In particular, cancer therapeutic mAbs can recognize cell-surface proteins on target cells and then kill the targeted cells by multiple mechanisms that are dependent upon a fragment crystallizable (Fc) domain interacting with effector Fc gamma receptors, including antibody-dependent cell-mediated cytotoxicity and antibody-dependent cellmediated phagocytosis. Extensive engineering efforts have been made toward tuning Fc functions by either reinforcing (e.g. for targeted therapy) or disabling (e.g. for immune checkpoint blockade therapy) effector functions and prolonging the serum half-lives of antibodies, as necessary. In this report, we review Fc engineering efforts to improve therapeutic potency, and propose future antibody engineering directions that can fulfill unmet medical needs.

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Detection of soluble EpCAM (sEpCAM) in malignant ascites predicts poor overall survival in patients treated with catumaxomab

Cited by 15 publications

References 27 publications

EpCAM ectodomain EpEX is a ligand of EGFR that counteracts EGF-mediated epithelial-mesenchymal transition through modulation of phospho-ERK1/2 in head and neck cancers

EpCAM ectodomain EpEX is a ligand of EGFR that counteracts EGF-mediated epithelial-mesenchymal transition through modulation of phospho-ERK1/2 in head and neck cancers

Advances in ovarian cancer therapy

Boosting therapeutic potency of antibodies by taming Fc domain functions

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