Targeting IL11 Receptor in Leukemia and Lymphoma: A Functional Ligand-Directed Study and Hematopathology Analysis of Patient-Derived Specimens.

Abstract

PURPOSE:

The IL11 receptor (IL11R) is an established molecular target in primary tumors of bone, such as osteosarcoma, and in secondary bone metastases from solid tumors, such as prostate cancer. However, its potential role in management of hematopoietic malignancies has not yet been determined. Here, we evaluated the IL11R as a candidate therapeutic target in human leukemia and lymphoma.

EXPERIMENTAL DESIGN AND RESULTS:

First, we show that the IL11R protein is expressed in a variety of human leukemia- and lymphoma-derived cell lines and in a large panel of bone marrow samples from leukemia and lymphoma patients, whereas expression is absent from nonmalignant control bone marrow. Moreover, a targeted peptidomimetic prototype (termed BMTP-11), specifically bound to leukemia and lymphoma cell membranes, induced ligand-receptor internalization mediated by the IL11R, and resulted in a specific dose-dependent cell death induction in these cells. Finally, a pilot drug lead-optimization program yielded a new myristoylated BMTP-11 analogue with an apparent improved antileukemia cell profile.

CONCLUSIONS:

These results indicate (i) that the IL11R is a suitable cell surface target for ligand-directed applications in human leukemia and lymphoma and (ii) that BMTP-11 and its derivatives have translational potential against this group of malignant diseases.

• Authors: Katja Karjalainen, Diana E Jaalouk, Carlos Bueso-Ramos, Laura Bover, Yan Sun, Akihiko Kuniyasu, Wouter H P Driessen, Marina Cardó-Vila, Cecilia Rietz, Amado J Zurita, Susan O'Brien, Hagop M Kantarjian, Jorge E Cortes, George A Calin, Erkki Koivunen, Wadih Arap, Renata Pasqualini
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 21 Issue 13 Pg. 3041-51 (Jul 01 2015) ISSN: 1557-3265 [Electronic] United States
• PMID: 25779950 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Ligands
• Peptides
• Receptors, Interleukin-11
• bone metastasis-targeting peptidomimetic-11

Topics

• Amino Acid Sequence
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Drug Screening Assays, Antitumor
• Humans
• Inhibitory Concentration 50
• Leukemia (drug therapy)
• Ligands
• Lymphoma (drug therapy)
• Molecular Sequence Data
• Peptides (pharmacology)
• Receptors, Interleukin-11 (antagonists & inhibitors)