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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.

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.

SUBMITTER: Cardo-Vila M

PROVIDER: S-EPMC4973658 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Publications

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

Cardó-Vila Marina M Marchiò Serena S Sato Masanori M Staquicini Fernanda I FI Smith Tracey L TL Bronk Julianna K JK Yin Guosheng G Zurita Amado J AJ Sun Menghong M Behrens Carmen C Sidman Richard L RL Lee J Jack JJ Hong Waun K WK Wistuba Ignacio I II Arap Wadih W Pasqualini Renata R

The American journal of pathology 20160616 8

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 l ...[more]

PMID: 27317903

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Project description:Alzheimer disease (AD) is now considered as a multifactorial neurodegenerative disorder and rapidly increasing to an alarming situation and causing higher death rate. One target one ligand hypothesis does not provide complete solution of AD due to multifactorial nature of the disease and one target one drug fails to provide better treatment against AD. Moreover, currently available treatments are limited and most of the upcoming treatments under clinical trials are based on modulating single target. So, the current AD drug discovery research is shifting towards a new approach for a better solution that simultaneously modulates more than one targets in the neurodegenerative cascade. This can be achieved by network pharmacology, multi-modal therapies, multifaceted, and/or the more recently proposed term "multi-targeted designed drugs". Drug discovery project is a tedious, costly and long-term project. Moreover, multi-target AD drug discovery added extra challenges such as the good binding affinity of ligands for multiple targets, optimal ADME/T properties, no/less off-target side effect and crossing of the blood-brain barrier. These hurdles may be addressed by insilico methods for an efficient solution in less time and cost as computational methods successfully applied to single target drug discovery project. Here, we are summarizing some of the most prominent and computationally explored single targets against AD and further, we discussed a successful example of dual or multiple inhibitors for same targets. Moreover, we focused on ligand and structure-based computational approach to design MTDL against AD. However, it is not an easy task to balance dual activity in a single molecule but computational approach such as virtual screening docking, QSAR, simulation and free energy is useful in future MTDLs drug discovery alone or in combination with a fragment-based method. However, rational and logical implementations of computational drug designing methods are capable of assisting AD drug discovery and play an important role in optimizing multi-target drug discovery.

Dataset Information

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

Publications

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

Similar Datasets

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