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Rationale for the advancement of PI3K pathway inhibitors for personalized chordoma therapy

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Abstract

Purpose

Chordomas are rare and serious tumors with few effective treatments outside of aggressive surgery and radiation. Targeted therapies may present a more effective option for a subset of patients with lesions possessing certain genetic biomarkers.

Methods

A small molecule inhibitor library was tested in patient-derived UM-Chor1 cells to identify targeted therapies with potential efficacy. Targeted exome sequencing of UM-Chor1 and UM-Chor2 cells was performed to investigate genetic aberrations in relevant pathways. Chordoma cell lines were treated with inhibitors of the phosphotidylinositol 3-kinase (PI3K), epidermal growth factor receptor (EGFR), and cyclin dependent kinase (CDK) pathways, and responses were determined using resazurin cell viability assays, Annexin V apoptosis assays, and western blotting. Pan-PI3K inhibitor BKM120 was also tested in five chordoma xenograft models.

Results

Unbiased small molecule profiling nominated PI3K-AKT-mTOR pathway inhibitors as a promising therapy in chordoma, and genetic analyses of UM-Chor1 and UM-Chor2 cell lines revealed aberrations in PTEN, EGFR, and CDKN2A. Treatment of UM-Chor1 and UM-Chor2 with targeted PI3K, EGFR, and CDK inhibitors inhibited growth and proliferation and induced apoptosis more robustly than imatinib, a currently used chordoma therapy. Furthermore, BKM120 significantly inhibited tumor growth in a subset of the xenograft models tested.

Conclusion

Targeted therapies, especially those inhibiting PI3K, display promising effects in multiple chordoma cell line and xenograft models. Nevertheless, the limited effects of PI3K, EGFR, and CDK targeting agents in other models reveal the presence of resistance mechanisms, which motivates future research to both identify biomarkers of response and develop combination therapies.

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Acknowledgements

We acknowledge South Texas Accelerated Research Therapeutics (START) for evaluating inhibitors in xenograft chordoma models in conjunction with the Chordoma Foundation.

Funding

This study was funded using internal funds from the University of Michigan. NLM was supported by NSF Grant DGE-1256260, and MEHN was supported by an American Association for Otolaryngology – Head and Neck Surgery Fellowship (513933). Research reported in this publication using the services of the University of Michigan Flow Cytometry Core was supported by the National Cancer Institute of the National Institutes of Health under award number P30CA046592.

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Author notes

  1. N. L. Michmerhuizen, J. H. Owen and M. E. Heft Neal have contributed equally to this work.

Authors and Affiliations

  1. Department of Otolaryngology – Head and Neck Surgery, University of Michigan Medical School, 1150 E. Medical Center Dr., 9301B MSRB3, Ann Arbor, MI, 48109-0602, USA

    N. L. Michmerhuizen, J. H. Owen, M. E. Heft Neal, J. E. Mann, E. Leonard, J. Wang, J. C. Brenner & M. E. P. Prince

  2. Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA

    N. L. Michmerhuizen, J. Wang & J. C. Brenner

  3. Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA

    J. E. Mann & J. B. McHugh

  4. Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA

    J. Zhai & H. Jiang

  5. Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA

    H. Jiang, J. B. McHugh, J. C. Brenner & M. E. P. Prince

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  1. N. L. Michmerhuizen
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Contributions

NLM, MEPP, and JCB contributed to the study conception and design. NLM and JCB performed study development and established methodology. NLM, EL, JEM, and JW collected the data, and NLM, EL, JEM, JW, JZ, HJ, MEP, and JCB analyzed and interpreted the results. NLM, JHO, MEH, JBM, MEPP, and JCB provided administrative, technical, or material support. NLM, MEH, and JCB prepared the manuscript, which was reviewed and approved by all authors.

Corresponding author

Correspondence to J. C. Brenner.

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The authors declare that they have no conflict of interest.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the Institutional Animal Care and Use Committee protocol at START (#09-001).

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Michmerhuizen, N.L., Owen, J.H., Heft Neal, M.E. et al. Rationale for the advancement of PI3K pathway inhibitors for personalized chordoma therapy. J Neurooncol 147, 25–35 (2020). https://doi.org/10.1007/s11060-020-03418-7

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