LRRC15 Targeting in Soft-Tissue Sarcomas: Biological and Clinical Implications
| Autor: | Ying Huang, Audrey Laroche-Clary, Prafulla C. Gokhale, Eytan Ben-Ami, Marie-Paule Algeo, Félicie Courgeon, George D. Demetri, Valérie Velasco, Raul Perret, Benjamin K. Eschle, James W. Purcell, Antoine Italiano, François Le Loarer |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Stromal cell sarcoma medicine.medical_treatment lcsh:RC254-282 Article 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Downregulation and upregulation In vivo LRRC15 Medicine business.industry medicine.disease lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens 030104 developmental biology Cytokine Oncology Monomethyl auristatin E chemistry 030220 oncology & carcinogenesis Cancer cell Cancer research ABBV-085 Immunohistochemistry Sarcoma business |
| Zdroj: | Cancers Volume 12 Issue 3 Cancers, Vol 12, Iss 3, p 757 (2020) |
| ISSN: | 2072-6694 |
| DOI: | 10.3390/cancers12030757 |
| Popis: | Background: LRRC15 is a member of the LRR (leucine-rich repeat) superfamily present on tumor-associated fibroblasts (CAFs) and stromal cells. The expression of LRRC15 is upregulated by the pro-inflammatory cytokine TGFβ. ABBV-085 is a monomethyl auristatin E (MMAE)-containing antibody-drug conjugate (ADC) designed to target LRRC15, and which has shown significant anti-tumor activity in several tumor models. This is the first focused examination of LRRC15 expression and ABBV-085 activity in soft-tissue sarcomas (STS). Methods: We analyzed the LRRC15 expression profile by immunohistochemistry in 711 STS cases, covering a broad spectrum of STS histologies and sub-classifications. In vivo experiments were carried out by using LRRC15-positive and LRRC15-negative patient-derived xenograft (PDX) models of STS. Results: In contrast to patterns observed in epithelial tumors, LRRC15 was expressed not only by stromal cells but also by cancer cells in multiple subsets of STS with significant variations noted between histological subtypes. Overexpression of LRRC15 is positively correlated with grade and independently associated with adverse outcome. ABBV-085 has robust preclinical efficacy against LRRC15 positive STS patient-derived xenograft (PDX) models. Conclusion: We provide the first preclinical evidence that LRRC15 targeting with an antibody-drug conjugate is a promising strategy in LRRC15-positive STS. ABBV-085 is being evaluated in an ongoing clinical trial in STS and other malignancies. |
| Databáze: | OpenAIRE |
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