Preclinical Efficacy of Endoglin-Targeting Antibody–Drug Conjugates for the Treatment of Ewing Sarcoma

Abstract

Purpose: Endoglin (ENG; CD105) is a coreceptor of the TGFb family that is highly expressed in proliferating endothelial cells. Often coopted by cancer cells, ENG can lead to neoangiogenesis and vasculogenic mimicry in aggressive malignancies. It exists both as a transmembrane cell surface protein, where it primarily interacts with TGFb, and as a soluble matricellular protein (sENG) when cleaved by matrix metalloproteinase 14 (MMP14). High ENG expression has been associated with poor prognosis in Ewing sarcoma, an aggressive bone cancer that primarily occurs in adolescents and young adults. However, the therapeutic value of ENG targeting has not been fully explored in this disease. Experimental Design: We characterized the expression pattern of transmembrane ENG, sENG, and MMP14 in pre-clinical and clinical samples. Subsequently, the antineoplastic potential of two novel ENG-targeting monoclonal antibodydrug conjugates (ADC), OMTX503 and OMTX703, which differed only by their drug payload (nigrin-b A chain and cytolysin, respectively), was assessed in cell lines and preclinical animal models of Ewing sarcoma. Results: Both ADCs suppressed cell proliferation in proportion to the endogenous levels of ENG observed in vitro. Moreover, the ADCs significantly delayed tumor growth in Ewing sarcoma cell line-derived xenografts and patientderived xenografts in a dose-dependent manner. Conclusions: Taken together, these studies demonstrate potent preclinical activity of first-in-class anti-ENG ADCs as a nascent strategy to eradicate Ewing sarcoma.

<p>Advances and Prospects of Vasculogenic Mimicry in Glioma: A Potential New Therapeutic Target?</p>

“…Since its initial discovery, VM has been found in other solid tumors, including hepatocellular carcinoma, [9][10][11][12] Ewing's sarcoma, 12,13 acute leukemia, 14 ovarian carcinoma, 15,16 cervical cancer, 17 prostate adenocarcinoma, 18 nasopharyngeal carcinoma, 19 non-small cell lung cancer, 20 lung adenocarcinoma, 21 osteosarcoma, 22 gastric cancer, 23,24 breast cancer, 25,26 and renal clear cell carcinoma. 27 The in vitro detection of VM involves Periodic Acid-Schiff (PAS)-CD34 double immunohistochemical staining to observe the structure of the lumen in the section.…”

Wnt/β-catenin–activated Ewing sarcoma cells promote the angiogenic switch

“…Preclinical studies of VEGF inhibitors, such as bevacizumab, showed efficacy in preclinical models and clinical studies with combination approaches continue to be investigated (33). More recently, antibody-drug conjugates targeting the proangiogenic membrane receptor protein endoglin (ENG) have shown preclinical efficacy in Ewing models (37). ENG is highly expressed by endothelial cells, and by some Ewing tumor cells, and has been implicated in mediating tumor cell plasticity and invasion (38).…”

Current Approaches for Personalized Therapy of Soft Tissue Sarcomas

“…us, monoclonal endoglin-targeting antibodies, TRC105, OMTX503 and OMTX703, have demonstrated the decrease in tumor growth in Ewing sarcoma cell line-derived xenografts and patient-derived xenografts as well as in angiosarcoma in clinical trials of Phase I/II [43,44].…”