Inhibition of SDF-1-induced migration of oncogene-driven myeloid leukemia by the L-RNA aptamer (Spiegelmer), NOX-A12, and potentiation of tyrosine kinase inhibition
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Ellen L. Weisberg1,4, Martin Sattler1,4, Abdel Kareem Azab1,4, Dirk Eulberg3, Anna Kruschinski3, Paul W. Manley2, Richard Stone1,4 and James D. Griffin1,4
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
2Novartis Institutes of Biomedical Research, CH-4002 Basel, Switzerland
3Noxxon Pharma, Max-Dohrn-Strasse 8-10, 10589 Berlin, Germany
4Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
Ellen L. Weisberg, email: firstname.lastname@example.org
James D. Griffin, email: email@example.com
Keywords: chronic myeloid leukemia; SDF-1; NOX-A12; nilotinib; drug resistance
Received: July 08, 2017 Accepted: October 25, 2017 Published: November 06, 2017
Resistance to targeted tyrosine kinase inhibitors (TKI) remains a challenge for the treatment of myeloid leukemias. Following treatment with TKIs, the bone marrow microenvironment has been found to harbor a small pool of surviving leukemic CD34+ progenitor cells. The long-term survival of these leukemic cells has been attributed, at least in part, to the protective effects of bone marrow stroma. We found that the NOX-A12 'Spiegelmer', an L-enantiomeric RNA oligonucleotide that inhibits SDF-1α, showed in vitro and in vivo activity against BCR-ABL- and FLT3-ITD-dependent leukemia cells. NOX-A12 was sufficient to suppress SDF-1-induced migration in vitro. The combination of NOX-A12 with TKIs reduced cell migration in the same in vitro model of SDF-1-induced chemotaxis to a greater extent than either drug alone, suggesting positive cooperativity as a result of the SDF-1 blocking function of NOX-A12 and cytotoxicity resulting from targeted oncogenic kinase inhibition. These results are consistent with our in vivo findings using a functional pre-clinical mouse model of chronic myeloid leukemia (CML), whereby we demonstrated the ability of NOX-A12, combined with the ABL kinase inhibitor, nilotinib, to reduce the leukemia burden in mice to a greater extent than either agent alone. Overall, the data support the idea of using SDF-1 inhibition in combination with targeted kinase inhibition to override drug resistance in oncogene-driven leukemia to significantly diminish or eradicate residual leukemic disease.
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