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

// Ellen L. Weisberg 1, 4 , Martin Sattler 1, 4 , Abdel Kareem Azab 1, 4 , Dirk Eulberg 3 , Anna Kruschinski 3 , Paul W. Manley 2 , Richard Stone 1, 4 and James D. Griffin 1, 4 1 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA 2 Novartis Institutes of Biomedical Research, CH-4002 Basel, Switzerland 3 Noxxon Pharma, Max-Dohrn-Strasse 8-10, 10589 Berlin, Germany 4 Department of Medicine, Harvard Medical School, Boston, MA 02115, USA Correspondence to: Ellen L. Weisberg, email: ellen_weisberg@dfci.harvard.edu James D. Griffin, email: james_griffin@dfci.harvard.edu Keywords: chronic myeloid leukemia; SDF-1; NOX-A12; nilotinib; drug resistance Received: July 08, 2017      Accepted: October 25, 2017      Published: November 06, 2017 ABSTRACT 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.