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PARP Inhibitors for the treatment of MPNST

Sarcoma Research Laboratory University of Texas, MD Anderson Cancer Center. PARP Inhibitors for the treatment of MPNST.

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PARP Inhibitors for the treatment of MPNST

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  1. Sarcoma Research Laboratory University of Texas, MD Anderson Cancer Center PARP Inhibitors for the treatment of MPNST Christine Kivlin, Roman Belousov, Gonzalo Lopez, Quan-Sheng Zhu, Kai-Lieh Huang, Davis Ingram, Keila E. Torres, Alexander J. Lazar, Raphael E. Pollock, Dina Lev

  2. Malignant Peripheral Nerve Sheath Tumor (MPNST) • Accounts for 3–10% of soft tissue sarcomas • Up to 1,200 new cases in the U.S. per year • High metastatic potential • Neurofibromatosis type I (NF1)-related cases (50%) and sporadic (50%) • Associated with a precursor lesion (NF1-related, deep neurofibromata)

  3. MPNST treatment and outcome • Surgical excision is the mainstay of treatment • Radiation/chemotherapy =? • High rate of local and systemic recurrence Zou et al., 2009

  4. There is a critical need for novel effective therapies in MPNST

  5. PARP inhibitors for the treatment of cancer • PARPi have been used in clinical trials over the past few years for common cancers, role for sarcoma unknown • Tumors with DNA repair defects are most highly sensitive

  6. The goal of our studies was to determine the effects of PARP inhibitors on MPNST in vitro andin vivo

  7. Experimental Models Tumor volume (mm3) Time (weeks) Lopez et al., 2011

  8. PARPi treatment reduces PARP activity MPNST 724 MPNST 26T Relative PARP Activity Relative PARP Activity PARP inhibitor (10uM) AZD2281 Olaparib (AstraZeneca) ABT888 Veliparib (Abbott Laboratories) BSI201 Iniparib (Sanofi Aventis) PARP inhibitor (10uM)

  9. Decrease in cell proliferation with AZD2281 Control Cell lines 96 hour treatment % cell growth MDA-231 MDA-436 724 AZD2281 (uM)

  10. Decrease in cell proliferation with AZD2281 MPNST Cell Lines 96 hour treatment % cell growth 462 724 ST88 26T NSC AZD2281 (uM)

  11. AZD2281 treatment decreases colony forming ability MPNST 724 control 0.6125 1.25 2.5 10.0 5.0 AZD2281 (uM)

  12. AZD2281 causes G2/M cell cycle arrest MPNST 724 24 hour treatment 2.5uM AZD 10.0uM AZD control 5.0uM AZD G1 G2 G2 G2 G1 G1 G2 S S S S G1 G2/M: 22.794% G2/M: 53.217% G2/M: 79.795% G2/M: 66.366%

  13. AZD2281 induces apoptosis MPNST 724 96 hour treatment 2.5uM AZD control 5.0uM AZD 10.0uM AZD 42% total apoptosis 8% total apoptosis 30% total apoptosis 35% total apoptosis

  14. Effect on tumor growth MPNST Xenograft: Subcutaneous Injection (16 mice) Tumors grow to 5mm Intraperitoneal injection Vehicle (8 mice) PBS+10%DMSO+10%HPCB Treatment (8 mice) 50mg/kg/day AZD2281 Sacrifice mice when vehicle group reaches 1500mm3, measure tumor volume and weight, preserve tissue

  15. AZD2281 abrogates tumor growth MPNST 724 MPNST 26T MPNST 724 p= 0.0002 * p= 0.0002 * p= 0.0002 *

  16. Conclusions • MPNST cells are relatively sensitive to PARP inhibition in vitro • Decrease in cell proliferation • G2/ M cell cycle arrest • Enhanced apoptosis • Anti-tumor effect of PARPi in vivo • Cytostatic effect on tumor proliferation • Role of PARPi in combination with chemotherapy preclinical/clinical trials?

  17. Acknowledgements

  18. PARP Function and Inhibition

  19. PARP Activity Assay AZD2281 ABT888 BSI 201 -Add PARPi of interest -Add cell lysate -Add PARP cocktail, incubate Histone- coated strip wells + - NAD Read Absorbance at 450nm Biotinylated NAD: Strepavidin HRP: Add HCl Add TACS Sapphire

  20. Complex MPNST Karyotype 724 The chromosome # in this cell line ranged from 47-91 , the modal chromosome # being 58

  21. DNA damage PCR array Results ST88 T265 26T NSC 724 462 PARP 1 B-Actin ST88 T265 26T 724 NSC 462 Rad51 37kDa Β-Actin

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