American Association for Cancer Research
Browse

Supplementary Tables from The Novel Pan-PIM Kinase Inhibitor, PIM447, Displays Dual Antimyeloma and Bone-Protective Effects, and Potently Synergizes with Current Standards of Care

Download (62.32 kB)
journal contribution
posted on 2023-03-31, 20:10 authored by Teresa Paíno, Antonio Garcia-Gomez, Lorena González-Méndez, Laura San-Segundo, Susana Hernández-García, Ana-Alicia López-Iglesias, Esperanza M. Algarín, Montserrat Martín-Sánchez, David Corbacho, Carlos Ortiz-de-Solorzano, Luis A. Corchete, Norma C. Gutiérrez, María-Victoria Maetos, Mercedes Garayoa, Enrique M. Ocio

-Supplementary Table 1. Combination indices (CI) corresponding to the indicated double or triple combinations of PIM447, bortezomib and dexamethasone. -Supplementary Table 2. Combination indices (CI) corresponding to the indicated double or triple combinations of PIM447, lenalidomide and dexamethasone. -Supplementary Table 3. Combination indices (CI) corresponding to the indicated double or triple combinations of PIM447, pomalidomide and dexamethasone.

Funding

RTICC-Hematology Group

FIS

FEDER

Junta de Castilla y León, Consejerías de Sanidad

y Educación

History

ARTICLE ABSTRACT

Purpose: PIM kinases are a family of serine/threonine kinases recently proposed as therapeutic targets in oncology. In the present work, we have investigated the effects of the novel pan-PIM kinase inhibitor, PIM447, on myeloma cells and myeloma-associated bone disease using different preclinical models.Experimental Design: In vitro/ex vivo cytotoxicity of PIM447 was evaluated on myeloma cell lines and patient samples. Synergistic combinations with standard treatments were analyzed with Calcusyn Software. PIM447 effects on bone cells were assessed on osteogenic and osteoclastogenic cultures. The mechanisms of PIM447 were explored by immunoblotting, qPCR, and immunofluorescence. A murine model of disseminated multiple myeloma was employed for in vivo studies.Results: PIM447 is cytotoxic for myeloma cells due to cell-cycle disruption and induction of apoptosis mediated by a decrease in phospho-Bad (Ser112) and c-Myc levels and the inhibition of mTORC1 pathway. Importantly, PIM447 demonstrates a very strong synergy with different standard treatments such as bortezomib + dexamethasone (combination index, CI = 0.002), lenalidomide + dexamethasone (CI = 0.065), and pomalidomide + dexamethasone (CI = 0.077). PIM447 also inhibits in vitro osteoclast formation and resorption, downregulates key molecules involved in these processes, and partially disrupts the F-actin ring, while increasing osteoblast activity and mineralization. Finally, PIM447 significantly reduced the tumor burden and prevented tumor-associated bone loss in a disseminated murine model of human myeloma.Conclusions: Our results demonstrate dual antitumoral and bone-protective effects of PIM447. This fact, together with the very strong synergy exhibited with standard-of-care treatments, supports the future clinical development of this drug in multiple myeloma. Clin Cancer Res; 23(1); 225–38. ©2016 AACR.

Usage metrics

    Clinical Cancer Research

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC