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Am J Pathol. 2016 Aug;186(8):2162-2170. doi: 10.1016/j.ajpath.2016.04.013. Epub 2016 Jun 16.

Interleukin-11 Receptor Is a Candidate Target for Ligand-Directed Therapy in Lung Cancer: Analysis of Clinical Samples and BMTP-11 Preclinical Activity.

Author information

1
University of New Mexico Comprehensive Cancer Center, University of New Mexico School of Medicine, Albuquerque, New Mexico; Division of Molecular Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico; Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico.
2
University of New Mexico Comprehensive Cancer Center, University of New Mexico School of Medicine, Albuquerque, New Mexico; Division of Molecular Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico; Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico; Department of Oncology, University of Turin, Turin, Italy; Candiolo Cancer Institute-IRCCS, Candiolo, Italy.
3
First Surgery Department, Hamamatsu University School of Medicine, Hamamatsu, Japan.
4
Department of Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
5
Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
6
Tissue Bank and Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.
7
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
8
Department of Neurology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, Massachusetts.
9
Division of Cancer Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
10
Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
11
University of New Mexico Comprehensive Cancer Center, University of New Mexico School of Medicine, Albuquerque, New Mexico; Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico; Division of Hematology/Oncology, University of New Mexico School of Medicine, Albuquerque, New Mexico. Electronic address: warap@salud.unm.edu.
12
University of New Mexico Comprehensive Cancer Center, University of New Mexico School of Medicine, Albuquerque, New Mexico; Division of Molecular Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico; Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico. Electronic address: rpasqual@salud.unm.edu.

Abstract

We previously isolated an IL-11-mimic motif (CGRRAGGSC) that binds to IL-11 receptor (IL-11R) in vitro and accumulates in IL-11R-expressing tumors in vivo. This synthetic peptide ligand was used as a tumor-targeting moiety in the rational design of BMTP-11, which is a drug candidate in clinical trials. Here, we investigated the specificity and accessibility of IL-11R as a target and the efficacy of BMTP-11 as a ligand-targeted drug in lung cancer. We observed high IL-11R expression levels in a large cohort of patients (n = 368). In matching surgical specimens (i.e., paired tumors and nonmalignant tissues), the cytoplasmic levels of IL-11R in tumor areas were significantly higher than in nonmalignant tissues (n = 36; P = 0.003). Notably, marked overexpression of IL-11R was observed in both tumor epithelial and vascular endothelial cell membranes (n = 301; P < 0.0001). BMTP-11 induced in vitro cell death in a representative panel of human lung cancer cell lines. BMTP-11 treatment attenuated the growth of subcutaneous xenografts and reduced the number of pulmonary tumors after tail vein injection of human lung cancer cells in mice. Our findings validate BMTP-11 as a pharmacologic candidate drug in preclinical models of lung cancer and patient-derived tumors. Moreover, the high expression level in patients with non-small cell lung cancer is a promising feature for potential translational applications.

PMID:
27317903
PMCID:
PMC4973658
DOI:
10.1016/j.ajpath.2016.04.013
[Indexed for MEDLINE]
Free PMC Article

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