LRRC15 Targeting in Soft-Tissue Sarcomas: Biological and Clinical Implications
Open Access
- 23 March 2020
- Vol. 12 (3), 757
- https://doi.org/10.3390/cancers12030757
Abstract
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.This publication has 14 references indexed in Scilit:
- LRRC15 Is a Novel Mesenchymal Protein and Stromal Target for Antibody-Drug ConjugatesCancer Research, 2018
- Myxofibrosarcoma primary cultures: molecular and pharmacological profileTherapeutic Advances in Medical Oncology, 2017
- Tumor-Associated Macrophages Can Contribute to Antitumor Activity through FcγR-Mediated Processing of Antibody–Drug ConjugatesMolecular Cancer Therapeutics, 2017
- Patterns of care and outcomes of patients with METAstatic soft tissue SARComa in a real-life setting: the METASARC observational studyBMC Medicine, 2017
- Immunological hallmarks of stromal cells in the tumour microenvironmentNature Reviews Immunology, 2015
- Collagen type V promotes the malignant phenotype of pancreatic ductal adenocarcinomaCancer Letters, 2014
- The Pancreas Cancer MicroenvironmentClinical Cancer Research, 2012
- Trends in survival for patients with metastatic soft‐tissue sarcomaCancer, 2010
- Inhibition of Hedgehog Signaling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic CancerScience, 2009
- Expression of Transforming Growth Factor β Isoforms and Their Receptors in Malignant Fibrous Histiocytoma of Soft TissuesClinical Cancer Research, 2004