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

Marina Cardó-Vila; Serena Marchiò; Masanori Sato; Fernanda I Staquicini; Tracey L Smith; Julianna K Bronk; Guosheng Yin; Amado J Zurita; Menghong Sun; Carmen Behrens; Richard L Sidman; J Jack Lee; Waun K Hong; Ignacio I Wistuba; Wadih Arap; Renata Pasqualini

doi:10.1016/j.ajpath.2016.04.013

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

Journal article

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

Marina Cardó-Vila, Serena Marchiò, Masanori Sato, Fernanda I Staquicini, Tracey L Smith, Julianna K Bronk, Guosheng Yin, Amado J Zurita, Menghong Sun, Carmen Behrens, …

The American journal of pathology, Vol.186(8), pp.2162-2170

08/2016

DOI: https://doi.org/10.1016/j.ajpath.2016.04.013

PMCID: PMC4973658

PMID: 27317903

Abstract

Immunohistochemistry

Cell Survival - drug effects

Apoptosis - drug effects

Biomarkers, Tumor - analysis

Tissue Array Analysis

Humans

Lung Neoplasms - metabolism

Lung Neoplasms - pathology

Male

Peptides - pharmacology

Xenograft Model Antitumor Assays

Animals

Flow Cytometry

Mice, Nude

Cell Line, Tumor

Female

Antineoplastic Agents - pharmacology

Cell Proliferation - drug effects

Mice

Mice, Inbred BALB C

Retrospective Studies

Carcinoma - metabolism

Carcinoma - pathology

Receptors, Interleukin-11 - biosynthesis

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.

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Title: Interleukin-11 Receptor Is a Candidate Target for Ligand-Directed Therapy in Lung Cancer: Analysis of Clinical Samples and BMTP-11 Preclinical Activity
Creators: Marina Cardó-Vila - 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
Serena Marchiò - 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
Masanori Sato - First Surgery Department, Hamamatsu University School of Medicine, Hamamatsu, Japan
Fernanda I Staquicini - 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
Tracey L Smith - 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
Julianna K Bronk - Department of Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Guosheng Yin - Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Amado J Zurita - Department of Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Menghong Sun - Tissue Bank and Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
Carmen Behrens - Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Richard L Sidman - Department of Neurology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, Massachusetts
J Jack Lee - Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Waun K Hong - Division of Cancer Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Ignacio I Wistuba - Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Wadih Arap - 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
Renata Pasqualini - 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
Publication Details: The American journal of pathology, Vol.186(8), pp.2162-2170
Date published: 08/2016
Grant note: P50 CA070907 / NCI NIH HHS P30 CA016672 / NCI NIH HHS
Academic Unit: Radiation Oncology; Cancer Institute of New Jersey at University Hospital
Language: English
Resource Type: Journal article
Identifiers: 991031654791304646