Krakow, Poland – 26 April 2018 – Institute of Hematology and Transfusion Medicine, the leading Polish hematology and blood transfusion institute, jointly with Selvita, a clinical stage drug discovery and development company focused on innovative medicines for oncology patients, have published results of a research projects concerning therapeutic potential of SEL24 in chronic lymphocytic leukemia (CLL).
The article titled “Microenvironment-induced PIM kinases promote CXCR4-triggered mTOR pathway required for chronic lymphocytic leukaemia cell migration” was published online in the Journal of Cellular and Molecular Medicine, on April 17, 2018.
SEL24 is a Selvita-developed first-in-class orally available dual PIM/FLT3 kinase inhibitor with a unique activity profile, currently investigated for the treatment of patients with relapsed/refractory (R/R) AML. The program entered Phase I/II in early 2017. In March 2017, Selvita signed a global license agreement with Menarini Group for further research, development, manufacture and commercialization of SEL24/MEN1703 worldwide.
It is known that CLL cells overexpress PIM kinases, which regulate apoptosis, cell cycle and migration. In this publication, researchers demonstrate that BCR crosslinking, CD40 stimulation, and co-culture with stromal cells increased PIMs expression in CLL cells, indicating microenvironment-dependent PIMs regulation.
In this paper, our group shows that Inhibition of PIM kinases in primary CLL cells with a clinical candidate pan-PIM inhibitor, SEL24-B489, decreases PIM-specific substrate phosphorylation and induces dose-dependent apoptosis in leukemic, but not in normal B cells – comments prof. Przemyslaw Juszczynski, Scientific Director of the Institute of Hematology and Transfusion Medicine. At the same time, cytotoxicity of SEL24-B489 was similar in TP53-mutant and TP53-wild type cells, and was not significantly diminished by the presence of stromal cell support.
In addition, we found that inhibition of PIM kinases decreases CXCR4-mediated CLL cell chemotaxis. It is extremely important finding, as homing of CLL cells to a proliferation-conducive and protective lymphoid compartments is predominantly regulated by CXCR4 chemokine receptor. We have also dissected the mechanism, whereby PIM inhibitor blocks CXCR4- driven chemotaxis: by decreasing CXCR4 surface expression, and by limiting CXCR4-triggered signaling. CXCR4 ligand, CXCL12, induced marked activation of mTOR pathway, which was blocked in the presence of SEL24-B489. Importantly, CXCL12-induced mTOR activity was required for CLL cell chemotaxis, since PIM kinase and mTOR inhibitors similarly impaired CLL cell migration in a transwell assay.
Our cooperation with the Institute of Hematology and Transfusion Medicine dates few years back, and this joint publication is yet another example of how business-academia relationship could work – says dr Krzysztof Brzózka, CSO at Selvita S.A. Prof. Juszczynski’s team has had an exceptional input into the SEL24 development process up to date. The research results published, show that given the microenvironment-modulated PIM expression, their pro-survival function and a role of PIMs in CXCR4-induced migration, inhibition of these kinases might override microenvironmental protection and be an attractive therapeutic strategy in treatment of CLL patients.
About The Institute of Hematology and Transfusion Medicine
Established in 1951, the Institute of Hematology and Transfusion Medicine, based in Warsaw, is the main research center in the country, focusing on oncohematology, blood coagulation disorders and immunohematology, as well as a reference clinical and diagnostic center. The Institute conducts diagnostic, therapeutic, scientific, organizational and didactic activities through various forms of scientific, specialized and continuing education. In terms of its areas, the Institute is an advisory body, and in some cases also the executive of the Ministry of Health.
Selvita S.A. is a clinical stage drug discovery company engaged in the research and development of novel cancer therapies, as well as provision of integrated drug discovery services. Selvita is headquartered in Krakow, Poland, with offices in the USA (Greater Boston, San Francisco Bay), and in the UK (Cambridge). Selvita has currently several projects at early or late discovery stage. Drug discovery clients of Selvita include numerous large and medium-sized pharmaceutical and biotechnology companies from USA and Europe. The company is listed on the Warsaw Stock Exchange (WSE:SLV)