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PI3K/mTOR inhibition with PI-103 in Chordoma

PI3K/mTOR inhibition with PI-103 in Chordoma. Joseph Schwab, Cristina Antonescu, John Healey, Patrick Boland, G. Petur Nielsen, Andrew Rosenberg, Edwin Choy, David Harmon, Thomas DeLaney, Cao Yang, Francis Hornicek, Zhenfeng Duan MGH Chordoma Research Group

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PI3K/mTOR inhibition with PI-103 in Chordoma

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  1. PI3K/mTOR inhibition with PI-103 in Chordoma Joseph Schwab, Cristina Antonescu, John Healey, Patrick Boland, G. Petur Nielsen, Andrew Rosenberg, Edwin Choy, David Harmon, Thomas DeLaney, Cao Yang, Francis Hornicek, Zhenfeng Duan MGH Chordoma Research Group Memorial Sloan Kettering Cancer Center DF/Harvard Cancer Center

  2. Chordoma Background • Low Grade Malignancy of the Axial Spine • Surgery remains the standard of care • Local Recurrence 40 to 60% • Fuchs et al JBJS 2005, Bergh et al Cancer 2000 Samson et al JBJS 1993, Schwab et al under review • Metastasis >30% • Fuchs et al JBJS 2005, Bergh et al Cancer 2000, Samson et al JBJS 1993, Schwab et al under review

  3. Background • No effective systemic therapy exists for chordoma • PI-103 dual PI3k(class 1a)/mTOR inhibitor • Inhibits glioma growth Fan et al, Cancer Cell 2006 • Sensitized PTEN-mutant glioma cells to EGFR inhibition Fan et al Cancer Res 2007 • Sensitizes Glioblastoma to radiation (Chen et al, Mol Cancer Ther 2008) • Induces apoptosis and sensitized Leukemic cells (AML) to chemotherapy (Park et al, Leukemia 2008)

  4. PI-103

  5. Specific Aims • #1 Establish the presence of the PI3K/mTOR pathway in human chordoma tissue • #2 Demonstrate the efficacy of PI-103 in a human chordoma cell line with regard to proliferation and apoptosis • #3 To determine the effects of PI-103 when combined with conventional chemotherapeutic agents doxorubicin and cisplatin

  6. Methods • Western blot analysis of PDK, AKT, mTOR and S6 in human chordoma specimen • PI-103 0.1μM, 1 μM, 5 μM, 10 μM human chordoma cell line UCH-1 • Western blot analysis of phosho-AKT and phosho-mTOR post PI-103 • Proliferation and apoptosis assays in UCH-1 post PI-103 • Apoptosis assay in UCH-1 post PI-103 with doxorubicin or cisplatin

  7. 0.1 0.5 1 5 0 0.05 0.01 PI-103 (μM) pmTOR mTOR pAKT AKT BcL-XL pStat3 Brachyury β-Actin

  8. PI-103 and Decreased Chordoma Proliferation

  9. PI-103 Increases Chordoma Cell Apoptosis

  10. PI-103 increases apoptosis with Doxorubicin and Cisplatin

  11. Conclusion • #1 PI3K/mTOR pathway is active in human chordoma • #2 PI-103 inhibits the activation of AKT and mTOR in vitro • #3 PI-103 reduces proliferation and induces apoptosis of a human chordoma cell line • #4 PI-103 seems to sensitize human chordoma cells to doxorubicin and cisplatin in vitro

  12. PI3K/mTOR inhibition with PI-103 in Chordoma • Thank You

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