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- W2599888622 abstract "e19574 Background: In multiple myeloma, tumor cells and stroma exert a reciprocal effect on each other that leads to tumor expansion in the bone marrow and bone destruction. Hepatocyte growth factor (HGF) is a main player in osteolytic bone destruction and also stimulates myeloma cell proliferation, migration and adhesion in the bone marrow. Additionally, VEGF plays a key neovascularization role in multiple myeloma. Therefore, we investigated whether MP0250, a bispecific DARPin simultaneously inhibiting tumor stroma HGF and VEGF, could potentiate the anti-tumor effect of the standard of care proteasome inhibitor bortezomib. Methods: MP0250 was tested as monotherapy and in combination with 0.6 mg/kg of bortezomib in an orthotopic murine model, where human multiple myeloma cells are implanted in the murine bone marrow. Tumor growth and invasion into the muscle were monitored by X-ray, whereas bone destruction was analyzed by microCT. Results: MP0250 significantly inhibited bone lysis and tumor invasion both as monotherapy and in combination with bortezomib. MicroCT and X-ray imaging showed superior inhibition of bone lysis by the combination of MP0250/bortezomib versus bortezomib monotherapy (p≤0.05), as measured by the total and cortical bone volumes. CT scans registered a highly significant reduction of tumor infiltration into the tibial muscle relative to vehicle (p<0.0001) in both the MP0250 and MP0250/bortezomib groups, as assessed by volume measurements of the leg muscle (vehicle 1187mm3, MP0250 180mm3, MP0250/bortezomib 143mm3). Altogether, this indicates that blockade of HGF and VEGF by MP0250 impairs myeloma cell migration, invasion and bone destruction. Importantly, no toxicity was observed for MP0250 as monotherapy or in combination with bortezomib. Conclusions: MP0250, a DARP in specifically blocking HGF and VEGF in tumor cells and in the tumor microenvironment, is a potent inhibitor of multiple myeloma-mediated bone lysis and myeloma cell invasion. MP0250 improves the efficacy of the standard of care therapy bortezomib with no added toxicity. This suggests a potential therapeutic opportunity in combining cytotoxic therapies with MP0250." @default.
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- W2599888622 date "2014-05-20" @default.
- W2599888622 modified "2023-10-14" @default.
- W2599888622 title "Potency of bortezomib in combination with MP0250, a bispecific VEGF- and HGF-targeting darpin, in a preclinical multiple myeloma model." @default.
- W2599888622 doi "https://doi.org/10.1200/jco.2014.32.15_suppl.e19574" @default.
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