BMTP-11 is active in preclinical models of human osteosarcoma and a candidate targeted drug for clinical translation

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 30; pp. 8065 - 8070
• Main Authors: Lewis, Valerae O., Devarajan, Eswaran, Cardó-Vila, Marina, Thomas, Dafydd G., Kleinerman, Eugenie S., Marchiò, Serena, Sidman, Richard L., Pasqualini, Renata, Arap, Wadih
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 25.07.2017
• Subjects: Adults; Animal models; Animals; Apoptosis; Autocrine Communication; Autocrine signalling; Biocompatibility; Biological Sciences; Biomedical materials; Bone cancer; Bone Neoplasms - drug therapy; Bone Neoplasms - metabolism; Cell Line, Tumor; Cell proliferation; Cell surface; Chemotherapy; Children; Colonization; Drug Screening Assays, Antitumor; Gemcitabine; Humans; Interleukin 11; Interleukin-11 Receptor alpha Subunit - antagonists & inhibitors; Interleukin-11 Receptor alpha Subunit - metabolism; Lung Neoplasms - metabolism; Lung Neoplasms - prevention & control; Lung Neoplasms - secondary; Lungs; Male; Metastases; Metastasis; Mice, Nude; Neoplasm Metastasis; Osteosarcoma; Osteosarcoma - drug therapy; Osteosarcoma - metabolism; Osteosarcoma cells; Patients; Peptides - pharmacology; Peptides - therapeutic use; Quality; Respiratory diseases; Surface markers; Translation; Translational Medical Research; Tumors; Young adults; mouse models; IL-11Rα; BMTP-11; osteosarcoma; target therapy
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1704173114

Osteosarcoma occurs predominantly in children and young adults. High-grade tumors require multidisciplinary treatment consisting of chemotherapy in the neoadjuvant and adjuvant settings, along with surgical intervention. Despite this approach, death from respiratory failure secondary to the development and progression of pulmonary metastases remains a significant problem. Here, we identify the IL-11 receptor α subunit (IL-11Rα) as a cell surface marker of tumor progression that correlates with poor prognosis in patients with osteosarcoma. We also show that both IL-11Rα and its ligand, IL-11, are specifically up-regulated in human metastatic osteosarcoma cell lines; engagement of this autocrine loop leads to tumor cell proliferation, invasion, and anchorage-independent growth in vitro. Consistently, IL-11Rα promotes lung colonization by human metastatic osteosarcoma cells in vivo in an orthotopic mouse model. Finally, we evaluate the IL-11Rα–targeted proapoptotic agent bone metastasis-targeting peptidomimetic (BMTP-11) in preclinical models of primary intratibial osteosarcomas, observing marked inhibition of both tumor growth and lung metastases. This effect was enhanced when BMTP-11 was combined with the chemotherapeutic drug gemcitabine. Our combined data support the development of approaches targeting IL-11Rα, and establish BMTP-11 as a leading drug candidate for clinical translation in patients with high-risk osteosarcoma.