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The CNS-penetrating taxane drug TPI 287 potentiates antiglioma activity of the AURKA inhibitor alisertib in vivo

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Abstract

Introduction

Glioblastoma (GBM) has a very poor prognosis despite current treatment. We previously found cytotoxic synergy between the AURKA inhibitor alisertib and the CNS-penetrating taxane TPI 287 against GBM tumor cells in vitro.

Methods

We used an orthotopic human GBM xenograft mouse model to test if TPI 287 potentiates alisertib in vivo. Western blotting, immunohistochemistry, siRNA knockdown, annexin V binding, and 3-dimensional Matrigel invasion assays were used to investigate potential mechanisms of alisertib and TPI 287 treatment interactions.

Results

Alisertib + TPI 287 combination therapy significantly prolonged animal survival compared to vehicle (p = 0.011), but only marginally compared to alisertib alone. Alisertib, TPI 287, and combined alisertib + TPI 287 reduced animal tumor volume compared to vehicle-treated controls. This was statistically significant for the combination therapy at 4 weeks (p < 0.0001). Alisertib + TPI 287 treatment decreased anti-apoptotic Bcl-2 protein levels in vivo and in vitro. Expression of the pro-apoptotic protein Bak was significantly increased by combination treatment (p < 0.0001). Pro-apoptotic Bim and Bak knockdown by siRNA decreased apoptosis by alisertib + TPI 287 in GB9, GB30, and U87 cells (p = 0.0005 to 0.0381). Although alisertib and TPI 287 significantly reduced GBM cell invasion (p < 0.0001), their combination was no more effective than TPI 287 alone.

Conclusions

Results suggest that apoptosis is the dominant mechanism of potentiation of GBM growth inhibition by alisertib + TPI 287, in part through effects on Bcl-2 family proteins, providing a rationale for further laboratory testing of an AURKA inhibitor plus TPI 287 as a potential therapy against GBM.

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Acknowledgements

We thank the Brown Cancer Animal Imaging Core Facility for performing magnetic resonance imaging. This work was supported by the National Institute of Health (NIH) grant R01-NS081125 (NLL).

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Authors and Affiliations

  1. Biochemistry and Molecular Genetics, University of Louisville, 505 S Hancock St, KY, 40202, Louisville, USA

    Müge Sak & Norman L. Lehman

  2. Pathology and Laboratory Medicine, University of Louisville, Louisville, KY, 40202, USA

    Cory T. Zumbar, Mustafa N. G. Al-Kawaaz, Aastha Kakar, Andrew J. Hey, Megan J. Wilson, Leslie M. Schier & Norman L. Lehman

  3. Neurological Surgery, University of Louisville, Louisville, KY, 40202, USA

    Brian J. Williams

  4. The Brown Cancer Center, University of Louisville, Louisville, KY, 40202, USA

    Brian J. Williams & Norman L. Lehman

  5. Bioengineering, University of Louisville, Louisville, KY, 40202, USA

    Landon Teer & Joseph Chen

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  1. Müge Sak
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Contributions

NLL BJW, JC, CTZ and MS contributed to the study design. Study conception and supervision was performed by NLL. Material preparation, data collection and analysis were performed by MS, BJW, CTZ, LT, MNGAl-K, AK, AJH, MJW, LMS, JC, and NLL. The first draft of the manuscript was written by MS and CTZ. All the authors commented on previous versions of the manuscript. All the authors read and approved the final manuscript.

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Correspondence to Norman L. Lehman.

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Supplementary Information

Below is the link to the electronic supplementary material.

280_2023_4503_MOESM1_ESM.eps

Supplementary file1 Fig. S1 GB9 and GB30 cell line growth comparison. Their proliferation rates (slopes) are significantly different (*p=0.0337), simple linear regression analysis (EPS 1518 KB)

280_2023_4503_MOESM2_ESM.pdf

Supplementary file2 Fig. S2 Western blotting of Bcl-2 family proteins in synchronized U87 cells. U87 cells were synchronized with double thymidine block, treated with 30 nM alisertib, 700 pM TPI 287, or both. Cell lysates were collected at 0, 24-, 48-, 72-, and 120 hr a. Western blotting of Bcl-2 family members. b. Bcl-2 c. Mcl-1 d. Bak and e. Bim protein level quantification (PDF 885 KB). Circles, squares, triangles and upside-down triangles represent each biological replicate for vehicle, alisertib, TPI 287, and alisertib + TPI 287 treatments, respectively. Representative blots, n = 3, two-way ANOVA, p values 

280_2023_4503_MOESM3_ESM.eps

Supplementary file3 Fig. S3 Western blotting for a. Bim and b. Bak knockdown confirmation in GB9, U87 and GB30 cells (EPS 1872 KB)

Supplementary file4 Supplementary Video 1. Representative 72 hr time-lapse video of GB9 cells embedded in 3D Matrigel treated with vehicle (AVI 28731 KB)

Supplementary file5 Supplementary Video 2. Representative 72 hr time-lapse video of GB9 cells embedded in 3D Matrigel treated with 30 nM alisertib (AVI 22104 KB)

Supplementary file6 Supplementary Video 3. Representative 72 hr time-lapse video of GB9 cells embedded in 3D Matrigel treated with 1 nM TPI 287 (AVI 19041 KB)

Supplementary file7 Supplementary Video 4. Representative 72 hr time-lapse video of GB9 cells embedded in 3D Matrigel treated with 30 nM alisertib + 1 nM TPI 287 (AVI 24110 KB)

Supplementary file8 Supplementary Video 5. Representative 72 hr time-lapse video of GB30 cells embedded in 3D Matrigel treated with vehicle (AVI 29535 KB)

Supplementary file9 Supplementary Video 6. Representative 72 hr time-lapse video of GB30 cells embedded in 3D Matrigel treated with 30 nM alisertib (AVI 20976 KB)

Supplementary file10 Supplementary Video 7. Representative 72 hr time-lapse video of GB30 cells embedded in 3D Matrigel treated with 1 nM TPI 287 (AVI 23741 KB)

Supplementary file11 Supplementary Video 8. Representative 72 hr time-lapse video of GB30 cells embedded in 3D Matrigel treated with 30 nM alisertib + 1 nM TPI 287 (AVI 20271 KB)

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Sak, M., Williams, B.J., Zumbar, C.T. et al. The CNS-penetrating taxane drug TPI 287 potentiates antiglioma activity of the AURKA inhibitor alisertib in vivo. Cancer Chemother Pharmacol 91, 191–201 (2023). https://doi.org/10.1007/s00280-023-04503-0

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