Antitumor Activity Of Inhibiting Syk Kinase With Tak-659, An Investigational Agent, In Dlbcl Models.

8580 Background: Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is a common member of various signal transduction cascades in cells of the hematopoietic lineage including those involved in B-cell receptor (BCR) activation, B cell migration, and B cell polarization. Abnormal SYK activation has been implicated in several hematopoietic malignancies including chronic lymphocytic leukemia (CLL), peripheral T-cell lymphoma (PTCL) and diffuse large B-cell lymphoma (DLBCL). Methods: TAK-659 is an investigational inhibitor of SYK that is currently being evaluated in a Phase I clinical trial (NCT02000934). Results: TAK-659 inhibits SYK with an IC50 of 3.2nM and has the ability to inhibit cellular proliferation in relevant models with an EC50 between 25 to 400nM. Daily oral administration of 60 mg/kg TAK-659 showed anti-tumor activity in DLBCL cell-line xenograft models representing ABC (OCI-LY-10 (TGI 50%), HBL-1 (TGI 40%) and a primary human tumor xenograft model, PHTX-95L (TGI 70%), GCB (OCI-LY-19 (TGI 37%) and non-ABC/GCB (WSU (TGI 50%)) subtypes. Interestingly, in the OCI-LY-19 GCB-type DLBCL model, 60 mg/kg TAK-659 (TGI 37%) showed increased activity over a BTK inhibitor (TGI 15%) suggesting the hypothesis that inhibition of BCR signaling upstream of BTK could be beneficial in treating a broader range of sub-types of B-cell malignancies. The time course of pSYK (pSYK525) and pBLNK (pBLNK65) expression were assessed following single doses of TAK-659. Time dependent inhibition of these phospho-proteins and also increase in expression of cleaved caspase 3, an apoptosis marker was observed in the DLBCL models studied here. Phenotypic assessment of 15 primary DLBCL samples for pSYK and other relevant pathway markers revealed that SYK activation occurs in a considerable number of molecularly heterogeneous DLBCL samples and is consistently associated with activation of the BCR pathway. Conclusions: These results together suggest that SYK activation occurs in various subsets of DLBCL samples and TAK-659 showed activity in pre-clinical models of the various subtypes of DLBCL supporting its clinical investigation in DLBCL patients.