Disconnect between in vitro and in vivo efficacy of the MPS1 inhibitor NTRC 0066-0 against glioblastoma

TL;DR

A drug that works well in lab tests to kill brain tumor cells fails to show effectiveness in animal models, highlighting the gap between lab results and real-world treatment outcomes.

Contribution

The study reveals a disconnect between in vitro and in vivo efficacy of the MPS1 inhibitor NTRC 0066-0 in treating glioblastoma.

Findings

NTRC 0066-0 efficiently induces GBM cell death in vitro with low nanomolar IC50s.

Despite high brain penetration and dose-dense regimens, NTRC 0066-0 showed no antitumor efficacy in an orthotopic GBM mouse model.

Combining NTRC 0066-0 with standard chemotherapy and radiotherapy did not improve outcomes in vivo.

Abstract

Glioblastoma (GBM) is the most common adult primary brain tumor for which new therapeutic strategies are desperately needed. Monopolar spindle 1 (MPS1) is a mitotic kinase that plays a pivotal role in the spindle assembly checkpoint (SAC). GBM appears to be dependent on SAC fidelity, as MPS1 is overexpressed in many GBM patients. Thus, inhibiting MPS1 seems a viable therapeutic strategy to enhance mitotic cell death by attenuating SAC fidelity. NTRC 0066-0 is an MPS1 inhibitor that combines low nanomolar potency with a relatively long on-target residence time.

We here investigate the potential of NTRC 0066-0 as monotherapy and in combination with chemo-radiation for treatment of GBM using various in vitro and orthotopic in vivo models.

We show that NTRC 0066-0 efficiently induces GBM cell death in vitro, following continuous exposure with IC50s in the low nanomolar range. In vivo, we demonstrate that NTRC 0066-0 has a high brain penetration, although it is a substrate of the efflux transporter P-glycoprotein at the blood-brain barrier. However, despite using recipient Abcb1a/b; Abcg2−/− mice with superior brain penetration and administering NTRC 0066-0 using a dose-dense regimen, we did not observe antitumor efficacy against an orthotopic GBM mouse model, neither as monotherapy nor in combination with standard-of-care temozolomide chemotherapy and radiotherapy.

These data indicate that developing MPS1 inhibitors for treatment of GBM will be challenging and would require further understanding of in vivo determinants of translating SAC inhibition to antitumor efficacy.

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