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Coordinate activation of Shh and PI3K signaling in PTEN-deficient glioblastoma: new therapeutic opportunities

Nature Medicine volume 19, pages 1518–1523 (2013)Cite this article

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Abstract

In glioblastoma, phosphatidylinositol 3-kinase (PI3K) signaling is frequently activated by loss of the tumor suppressor phosphatase and tensin homolog (PTEN)1. However, it is not known whether inhibiting PI3K represents a selective and effective approach for treatment. We interrogated large databases and found that sonic hedgehog (SHH) signaling is activated in PTEN-deficient glioblastoma. We demonstrate that the SHH and PI3K pathways synergize to promote tumor growth and viability in human PTEN-deficient glioblastomas. A combination of PI3K and SHH signaling inhibitors not only suppressed the activation of both pathways but also abrogated S6 kinase (S6K) signaling. Accordingly, targeting both pathways simultaneously resulted in mitotic catastrophe and tumor apoptosis and markedly reduced the growth of PTEN-deficient glioblastomas in vitro and in vivo. The drugs tested here appear to be safe in humans; therefore, this combination may provide a new targeted treatment for glioblastoma.

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Figure 1: Coordinate activation of the SHH and PI3K pathways in PTEN-deficient glioblastoma.
Figure 2: A combination of PI3K and SMO inhibition reduces tumor growth in vivo.
Figure 3: Cellular basis for the efficacy of combination treatment.
Figure 4: Combination therapy targets the PI3K, SHH and S6K pathways.

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Acknowledgements

We thank V. Monrose and K. Jones for technical assistance and C. Stiles for helpful discussions. We thank N. Gray (Dana-Farber Cancer Institute) for PF-4708671 and C. David James (University of California San Francisco) for the hBT70 and hBT75 lines. This work was supported by an Austrian Programme for Advanced Research and Technology (APART) fellowship of the Austrian Academy of Sciences (M.G.F.), grants from the US National Institutes of Health (R.A.S.) and Novartis Pharmaceuticals.

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Authors and Affiliations

  1. Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

    Mariella Gruber Filbin, Sukriti K Dabral, Maria F Pazyra-Murphy, Andrew L Kung, Ekaterina Pak, Jarom Chung, Yu Sun, David S Shulman, Qi Wang, Jean Zhao & Rosalind A Segal

  2. Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA

    Mariella Gruber Filbin, Sukriti K Dabral, Maria F Pazyra-Murphy, Andrew L Kung, Ekaterina Pak, Jarom Chung, Yu Sun, David S Shulman, Qi Wang, Jean Zhao & Rosalind A Segal

  3. Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA

    Mariella Gruber Filbin, Sukriti K Dabral, Maria F Pazyra-Murphy, Ekaterina Pak, Jarom Chung, Yu Sun & Rosalind A Segal

  4. Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria

    Mariella Gruber Filbin

  5. Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Shakti Ramkissoon, Matthew A Theisen, Barbara Tabak, Rameen Beroukhim & Keith L Ligon

  6. Department of Pathology, Children's Hospital Boston and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Shakti Ramkissoon & Keith L Ligon

  7. Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Andrew L Kung & Yanping Sun

  8. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, Massachusetts, USA

    Yoko Franchetti

  9. Department of Neurological Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Navid Redjal

  10. Sanofi-Aventis, Cambridge, Massachusetts, USA

    Marion Dorsch

  11. Novartis Institutes for Biomedical Research,

    Silvia Buonamici & Joseph F Kelleher

  12. Cambridge, Massachusetts, USA,

    Silvia Buonamici & Joseph F Kelleher

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  1. Mariella Gruber Filbin
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Contributions

M.G.F., S.K.D., E.P. and R.A.S. wrote the manuscript with input from all authors. M.G.F., S.K.D., E.P., J.C., M.F.P.-M. and Yu Sun executed the in vitro studies and analyzed the in vitro and in vivo studies. A.L.K., Yanping Sun, Y.F., J.F.K., S.B. and M.D. performed the in vivo studies. M.A.T., K.L.L. and S.R. generated GBM lines and analyzed tumor pathology. D.S.S. and N.R. initiated the studies. B.T. and R.B. analyzed databases. J.Z. and Q.W. provided shRNA specific to PTEN.

Corresponding author

Correspondence to Rosalind A Segal.

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Competing interests

This work was supported in part by grants from Novartis Institute of BioMedical research. J.F.K. is an employee of, and R.A.S. had a consulting agreement with, Novartis Institute of BioMedical Research.

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Gruber Filbin, M., Dabral, S., Pazyra-Murphy, M. et al. Coordinate activation of Shh and PI3K signaling in PTEN-deficient glioblastoma: new therapeutic opportunities. Nat Med 19, 1518–1523 (2013). https://doi.org/10.1038/nm.3328

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