抑制CDK9/13可减缓多发性骨髓瘤及骨髓瘤诱导的骨病进展——一项临床前研究

Cyclin-dependent kinases (CDKs) are promising targets in many cancers. OBP-004 is an oral highly potent and selective small-molecule dual inhibitor of CDK9/13 with a half-life of 17-20 hours, high tissue biodistribution in brain, lung, spleen and kidneys, and with no observed safety issues. Multiple myeloma (MM) is a plasma cell malignancy that is primarily growing in bone marrow and has a strong association with bone. At advanced stages, MM patients develop bone disease leading to increased bone loss and bone pain. In this study, we used OBP-004 to study if CDK9/13 is a suitable drug target in MM and MM associated bone disease. For studying efficacy on hematological cancers, female NMRI nude mice were inoculated intravenously with luciferase-labelled MV4-11 human acute myeloid leukemia cells and randomized to treatment groups at day 15 based on body weight and bioluminescence imaging (BLI) signal. OBP-004 was given orally at a dose of 1.0 mg/kg three times a week (3-day on, 4-day off). Tumor burden was monitored by BLI and the study was terminated at day 32. In the MM model, NPG mice were inoculated intratibially with luciferase-labelled RPMI-8226 human MM cells and randomized to treatment groups at day 3 based on body weight and BLI signal, and treatments were started at day 3. OBP-004 was given orally at a dose of 0.6 mg/kg daily. The standard-of-care therapies bortezomib (0.8 mg/kg, ip, BIW) and zoledronic acid (0.1 mg/kg, sc, QW) were used as reference compounds. Tumor burden was monitored by BLI and cancer-induced bone loss by scoring X-ray images. The study was terminated at day 56. The initial 1.0 mg/kg dosing (3-day on, 4-day off) of OBP-004 in the MV4-11 study resulted in slight decrease of body weight without any clinical signs. After optimizing the dose and the dosing schedules, the daily dose of 0.6 mg/kg showed no body weight loss or clinical signs during the 54 days treatment period. In the MV4-11 model, OBP-004 showed strong decrease (>97%) of brain, lung and lymph node metastases, and almost complete (>99.99%) abolishment of bone metastases. In the RPMI-8226 model, bortezomib inhibited tumor growth but zoledronic acid showed no effects, and zoledronic acid inhibited cancer-induced bone loss but bortezomib showed no effects. OBP-004 showed significantly stronger tumor growth inhibition than bortezomib and decreased cancer-induced bone loss similarly to zoledronic acid. We conclude that CDK9/CDK13 is a potential target in hematological malignancies including MM. By targeting CDK9/13, it is possible to affect both tumor growth and cancer-induced bone loss.