Olaratumab Exerts Antitumor Activity in Preclinical Models of Pediatric Bone and Soft Tissue Tumors through Inhibition of Platelet-Derived Growth Factor Receptor α

Abstract

Purpose: Platelet-derived growth factor receptor α (PDGFRα) is implicated in several adult and pediatric malignancies, where activated signaling in tumor cells and/or cells within the microenvironment drive tumorigenesis and disease progression. Olaratumab (LY3012207/IMC-3G3) is a human mAb that exclusively binds to PDGFRα and recently received accelerated FDA approval and conditional EMA approval for treatment of advanced adult sarcoma patients in combination with doxorubicin. In this study, we investigated olaratumab in preclinical models of pediatric bone and soft tissue tumors. Experimental Design: PDGFRα expression was evaluated by qPCR and Western blot analysis. Olaratumab was investigated in in vitro cell proliferation and invasion assays using pediatric osteosarcoma and rhabdoid tumor cell lines. In vivo activity of olaratumab was assessed in preclinical mouse models of pediatric osteosarcoma and malignant rhabdoid tumor. Results: In vitro olaratumab treatment of osteosarcoma and rhabdoid tumor cell lines reduced proliferation and inhibited invasion driven by individual platelet-derived growth factors (PDGFs) or serum. Furthermore, olaratumab delayed primary tumor growth in mouse models of pediatric osteosarcoma and malignant rhabdoid tumor, and this activity was enhanced by combination with either doxorubicin or cisplatin. Conclusions: Overall, these data indicate that olaratumab, alone and in combination with standard of care, blocks the growth of some preclinical PDGFRα-expressing pediatric bone and soft tissue tumor models. Clin Cancer Res; 24(4); 847–57. ©2017 AACR.

Receptor Tyrosine Kinases in Osteosarcoma Treatment: Which Is the Key Target?

“…On the contrary, other studies have shown that OS and PFS analysis was not different between osteosarcoma patients on the basis of PDGFs/PDGFRs expression level ( 113 , 114 ). The use of PDGFR inhibitor alone in clinical trials is not efficacy, whereas its combination with other drugs seems more promising ( 27 , 115 – 117 ). As shown in Table 1 and Figure 3 , axitinib and cediranib are effective inhibitors of PDGFRs, yet their efficacy in osteosarcoma is as poor as imatinib.…”

Olaratumab in soft tissue sarcoma – Current status and future perspectives

“…Olaratumab has been shown to inhibit ligand-induced phospho-activation of PDGFRa, with attendant reduction in proliferation and invasion across a number of PDGFRa-expressing sarcoma cell lines. Effective inhibition of PDGFRa by olaratumab is indicated by clinical pharmacodynamic data that demonstrate an expected increase in circulating platelet-derived growth factors (PDGFs), cognate ligands of PDGFRa [18,24]. However, the degree of PDGF increase showed no association with anti-tumour efficacy in phase I studies, as was the case with tumour PDGFRa expression in the JGDG study.…”

Novel Aspects of Genetics, Molecular Biology and Clinical Oncology of Sarcomas

“…Jedná se o lidskou monoklonální proti látku třídy IgG1, která specificky a s vyso kou afinitou rozeznává extracelulární li gandvazebnou doménu PDGFRα, čímž zabraňuje vazbě ligandu a aktivaci re ceptoru. V in vitro a in vivo podmínkách olaratumab signifikantně inhiboval růst řady sarkomových buněčných linií [24] a překvapivě dobrého výsledku bylo dosaženo v kombinované klinické stu dii fáze I/ II (studie JGDG), u které kombi nace olaratumabu a doxorubicinu prak ticky zdvojnásobila celkovou dobu přežití oproti monoterapii doxorubicinem u sou boru pa cientů s pokročilými sarkomy měkkých tkání [25]. Na konferenci CTOS 2018 byla představena návazná studie (přednáška dr. S. Bauer), u které byl kombi nován olaratumab s kombinační chemote rapií doxorubicinem a ifosfamidem.…”