Targeting the interleukin‐11 receptor α in metastatic prostate cancer: A first‐in‐man study

作者：Renata Pasqualini, Randall E. Millikan, Dawn R. Christianson, Marina Cardó‐Vila, Wouter H. P. Driessen, Ricardo J. Giordano, Amin Hajitou, Anh Hoang, Sijin Wen, Kirstin F. Barnhart, Wallace B. Baze, Valerie D. Marcott, David H. Hawke, Kim‐Anh Do, Nora M. Navone, Eleni Efstathiou, Patricia Troncoso, Roy R. Lobb, Christopher J. Logothetis, Wadih Arap · 发表于：Cancer · 年份：2015 · DOI：10.1002/cncr.29344 · 被引用次数：53 · 研究领域：Chemokine receptors and signaling、Inflammasome and immune disorders、Prostate Cancer Treatment and Research

BACKGROUND: Receptors in tumor blood vessels are attractive targets for ligand-directed drug discovery and development. The authors have worked systematically to map human endothelial receptors ("vascular zip codes") within tumors through direct peptide library selection in cancer patients. Previously, they selected a ligand-binding motif to the interleukin-11 receptor alpha (IL-11Rα) in the human vasculature. METHODS: The authors generated a ligand-directed, peptidomimetic drug (bone metastasis-targeting peptidomimetic-11 [BMTP-11]) for IL-11Rα-based human tumor vascular targeting. Preclinical studies (efficacy/toxicity) included evaluating BMTP-11 in prostate cancer xenograft models, drug localization, targeted apoptotic effects, pharmacokinetic/pharmacodynamic analyses, and dose-range determination, including formal (good laboratory practice) toxicity across rodent and nonhuman primate species. The initial BMTP-11 clinical development also is reported based on a single-institution, open-label, first-in-class, first-in-man trial (National Clinical Trials number NCT00872157) in patients with metastatic, castrate-resistant prostate cancer. RESULTS: BMTP-11 was preclinically promising and, thus, was chosen for clinical development in patients. Limited numbers of patients who had castrate-resistant prostate cancer with osteoblastic bone metastases were enrolled into a phase 0 trial with biology-driven endpoints. The authors demonstrated biopsy-verified localization of BMTP-11 t...