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

Cecilia Rietz, Renata Pasqualini, Wadih Arap, Erkki Koivunen, George A Calin, Jorge E Cortes, Hagop M Kantarjian, Susan O'Brien, Amado J Zurita, Katja Karjalainen, Marina Cardó-Vila, Wouter H P Driessen, Akihiko Kuniyasu, Yan Sun, Laura Bover, Carlos Bueso-Ramos, Diana E Jaalouk

Journal: Clinical cancer research : an official journal of the American Association for Cancer Research 2016;21(13):3041-51

PMID: 25779950

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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.

Address: Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. Department of Biological and Environmental Science, The University of Helsinki, Helsinki, Finland.; Department of Biology, American University of Beirut, Beirut, Lebanon.; Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.; Department of Genomic Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.; Department of Cancer Systems Imaging, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.; Department of Molecular Cell Pharmacology, Sojo University, Kumamoto, Japan.; Roche, Basel, Switzerland.; University of New Mexico 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 Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.; Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.; Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.; Department of Biological and Environmental Science, The University of Helsinki, Helsinki, Finland. Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.; University of New Mexico Cancer Center, University of New Mexico School of Medicine, Albuquerque, New Mexico. Division of Hematology/Oncology, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico. [email protected] [email protected].; University of New Mexico 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. [email protected] [email protected].

DOI: 10.1158/1078-0432.CCR-13-3059

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MeSH Terms: Amino Acid Sequence, Antineoplastic Agents, Cell Line, Tumor, Cell Survival, Drug Screening Assays, Antitumor, Humans, Inhibitory Concentration 50, Leukemia, Ligands, Lymphoma, Molecular Sequence Data, Peptides, Receptors, Interleukin-11