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Potent anti-myeloma activity of the TOPK inhibitor OTS514 in pre-clinical models
Andrew T Stefka1, David Johnson1, Shaun Rosebeck1
1Department of Medicine, University of Chicago, Chicago, IL, USA.
Abstract:
Multiple myeloma (MM) continues to be considered incurable, necessitating new drug discovery. The mitotic kinase T-LAK cell-originated protein kinase/PDZ-binding kinase (TOPK/PBK) is associated with proliferation of tumor cells, maintenance of cancer stem cells, and poor patient prognosis in many cancers. In this report, we demonstrate potent anti-myeloma effects of the TOPK inhibitor OTS514 for the first time. OTS514 induces cell cycle arrest and apoptosis at nanomolar concentrations in a series of human myeloma cell lines (HMCL) and prevents outgrowth of a putative CD138+ stem cell population from MM patient-derived peripheral blood mononuclear cells. In bone marrow cells from MM patients, OTS514 treatment exhibited preferential killing of the malignant CD138+ plasma cells compared with the CD138- compartment. In an aggressive mouse xenograft model, OTS964 given orally at 100 mg/kg 5 days per week was well tolerated and reduced tumor size by 48%-81% compared to control depending on the initial graft size. FOXO3 and its transcriptional targets CDKN1A (p21) and CDKN1B (p27) were elevated and apoptosis was induced with OTS514 treatment of HMCLs. TOPK inhibition also induced loss of FOXM1 and disrupted AKT, p38 MAPK, and NF-κB signaling. The effects of OTS514 were independent of p53 mutation or deletion status. Combination treatment of HMCLs with OTS514 and lenalidomide produced synergistic effects, providing a rationale for the evaluation of TOPK inhibition in existing myeloma treatment regimens.
Insights
The TOPK inhibitor OTS514 shows potent anti-myeloma effects, inducing cell cycle arrest and apoptosis in multiple myeloma cells. This drug offers a promising new avenue for treating this incurable cancer.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Multiple myeloma (MM) remains an incurable malignancy, driving the need for novel therapeutic agents.
- T-LAK cell-originated protein kinase/PDZ-binding kinase (TOPK/PBK) is implicated in cancer cell proliferation and poor prognosis.
- Targeting TOPK presents a potential strategy for overcoming MM treatment resistance.
Purpose of the Study:
- To investigate the anti-myeloma efficacy of the TOPK inhibitor OTS514.
- To evaluate the effects of OTS514 on myeloma cell cycle, apoptosis, and stem cell populations.
- To assess the in vivo anti-tumor activity and safety of OTS514 in a preclinical model.
Main Methods:
- Treatment of human myeloma cell lines (HMCLs) and patient-derived cells with OTS514.
- Flow cytometry analysis to assess cell populations (CD138+ cells) and apoptosis.
- In vivo studies using a mouse xenograft model with oral administration of OTS964 (related compound).
- Western blot analysis to examine key signaling pathways (FOXO3, FOXM1, AKT, p38 MAPK, NF-κB).
Main Results:
- OTS514 demonstrated potent anti-myeloma activity at nanomolar concentrations, inducing cell cycle arrest and apoptosis.
- The drug selectively targeted CD138+ myeloma cells and inhibited the outgrowth of putative stem cells.
- Oral administration of OTS964 in a xenograft model was well-tolerated and significantly reduced tumor size.
- OTS514 modulated key signaling pathways, including upregulation of FOXO3 and its targets, and downregulation of FOXM1.
Conclusions:
- OTS514 exhibits significant preclinical anti-myeloma activity, targeting both bulk tumor cells and stem cell populations.
- The drug's efficacy is independent of p53 status, broadening its potential applicability.
- Synergistic effects observed with lenalidomide suggest a role for TOPK inhibitors in combination therapies for multiple myeloma.
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