Unfavourable biological prognostic factors in Multiple Myeloma

Abstract

Title I: Aurora kinase and FGFR3 inhibition results in significant apoptosis in molecular subgroups of multiple myeloma In our pre-clinical study we examined the role of Aurora kinase and FGFR3 inhibition in MM using a small molecule inhibitor A1014907 which induced aneuploidy in MM cell lines at low nanomolar doses. However, A1014907 induced more pronounced and dose dependent apoptosis in cell lines with t(4;14) translocation. Translocation t(4;14) is observed in about 15% of patients with MM leading to constitutive activation of FGFR3 in two-thirds of these patients. Further investigation of the mechanism of action of A1014907 revealed potent FGFR3 pathway inhibition only in the sensitive cell lines. Thus, our results show that aurora kinase inhibition causes cell cycle arrest and aneuploidy with minimal apoptosis whereas inhibiting both aurora kinase and FGFR3 activity induced potent apoptosis in MM cells. This study evaluates the role of simultaneous inhibition of Aurora Kinases and FGFR3 pathway which are both important deregulated pathways in MM patients; inducing potent apoptosis. Title II: Natural history of multiple myeloma with de novo del(17p) Our clinical study involved comparing the outcomes of 310 newly diagnosed MM patients with del(17p) detected by FISH to patients with high-risk...

Title I: Aurora kinase and FGFR3 inhibition results in significant apoptosis in molecular subgroups of multiple myeloma In our pre-clinical study we examined the role of Aurora kinase and FGFR3 inhibition in MM using a small molecule inhibitor A1014907 which induced aneuploidy in MM cell lines at low nanomolar doses. However, A1014907 induced more pronounced and dose dependent apoptosis in cell lines with t(4;14) translocation. Translocation t(4;14) is observed in about 15% of patients with MM leading to constitutive activation of FGFR3 in two-thirds of these patients. Further investigation of the mechanism of action of A1014907 revealed potent FGFR3 pathway inhibition only in the sensitive cell lines. Thus, our results show that aurora kinase inhibition causes cell cycle arrest and aneuploidy with minimal apoptosis whereas inhibiting both aurora kinase and FGFR3 activity induced potent apoptosis in MM cells. This study evaluates the role of simultaneous inhibition of Aurora Kinases and FGFR3 pathway which are both important deregulated pathways in MM patients; inducing potent apoptosis. Title II: Natural history of multiple myeloma with de novo del(17p) Our clinical study involved comparing the outcomes of 310 newly diagnosed MM patients with del(17p) detected by FISH to patients with high-risk...