Abstract LB-B01: The anti-platelet-derived growth factor receptor α antibody olaratumab (Lartruvo) increases overall survival in metastatic mouse models of human osteosarcoma

Abstract

Platelet-derived growth factor receptor alpha (PDGFRα) is implicated in several types of adult and pediatric malignancies, where its aberrant expression and/or activation in tumor cells and/or tumor-associated stromal cells promote primary tumor growth and metastasis. Therefore, PDGFRα signaling may regulate disease progression via autocrine and paracrine modes of activation and facilitating crosstalk between the tumor and stroma. Olaratumab is a fully humanized monoclonal antibody that selectively binds human PDGFRα and blocks signaling initiated by ligand binding. We evaluated the efficacy of olaratumab and 1E10, a high affinity anti-mouse PDGFRα antibody in preclinical metastatic models of human osteosarcoma. A metastatic derivative of the PDGFRα-positive human osteosarcoma cell line HuO9 (HuO9-H3) was implanted in the gastrocnemius of mice. Olaratumab/1E10 was administered twice weekly once tumors grew to ~ 150 mm3. When tumors reached an average of volume of 1600 mm3, tumor-bearing limbs were amputated and four separate treatment cohorts were evaluated. These cohorts were as follows: (1) continuous IgG control antibody treatment, (2) continuous olaratumab/1E10 treatment prior to and after amputation, (3) olaratumab/1E10 treatment pre-amputation followed by IgG administration post-amputation, and (4) IgG treatment pre-amputation followed by olaratumab treatment post-amputation. A statistically significant and prolonged overall survival (OS) benefit (p<0.001) was observed in the continuous olaratumab/1E10 treatment group only, and correlated with a reduced tumor burden in the lung as determined by histologic evaluation. An olaratumab/1E10-dependent statistically significant OS benefit (p<0.001) was also observed in the HuO9-H3 and PDGFRα/PDGFRβ-positive MG63.3 human osteosarcoma cell lines introduced via tail vein injection. Interestingly, histologic review shows reduced tumor burden in the lung and lung pleura/mediastinum of these models. Mouse-specific bright field in situ hybridization (BRISH) showed increased expression of PDGFRA, PDGFRB, associated ligands, and VEGFA in the murine lung stroma prior to histologically apparent metastases. These data indicate that olaratumab/1E10-mediated PDGFRα blockade significantly increases OS in preclinical mouse models of human osteosarcoma and suggest a novel role for the PDGFRα pathway in the pathogenesis of metastatic osteosarcoma lung lesions. Citation Format: Amy K. LeBlanc, Gerard J. Oakley, Caitlin D. Lowery, Arnulfo Mendoza, Ling Ren, Timothy Holzer, Kelly Credille, Cynthia Winings, Amanda Estelle, Mia Chen, Patrick Finnegan, Wayne Blosser, Andrew Schade, Symantha Melemed, Louis F. Stancato. The anti-platelet-derived growth factor receptor α antibody olaratumab (Lartruvo) increases overall survival in metastatic mouse models of human osteosarcoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-B01.