Interleukin-11 Receptor Is a Candidate Target for Ligand-Directed Therapy in Lung Cancer: Analysis of Clinical Samples and BMTP-11 Preclinical Activity.
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.
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.
Marina
M
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; Department of Oncology, University of Turin, Turin, Italy; Candiolo Cancer Institute-IRCCS, Candiolo, Italy.
Serena
S
Marchiò
First Surgery Department, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Masanori
M
Sato
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.
Fernanda I
FI
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
TL
Smith
Department of Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
Julianna K
JK
Bronk
Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
Guosheng
G
Yin
Department of Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
Amado J
AJ
Zurita
Tissue Bank and Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.
Menghong
M
Sun
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
Carmen
C
Behrens
Department of Neurology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, Massachusetts.
Richard L
RL
Sidman
Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
J Jack
JJ
Lee
Division of Cancer Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
Waun K
WK
Hong
Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
Ignacio I
II
Wistuba
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.
Wadih
W
Arap
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.
Renata
R
Pasqualini
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000032:analysis*; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010455:Peptides / Q000494:pharmacology*; D053702:Receptors, Interleukin-11 / Q000096:biosynthesis*; D012189:Retrospective Studies; D046888:Tissue Array Analysis; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D010455:Peptides; D053702:Receptors, Interleukin-11; C000601739:bone metastasis-targeting peptidomimetic-11