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PARP Inhibitors for the treatment of MPNST Christine Kivlin, Roman Belousov, Gonzalo Lopez, Quan-Sheng Zhu, Kai-Lieh Huang, Davis Ingram, Keila E. Torres,

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Presentation on theme: "PARP Inhibitors for the treatment of MPNST Christine Kivlin, Roman Belousov, Gonzalo Lopez, Quan-Sheng Zhu, Kai-Lieh Huang, Davis Ingram, Keila E. Torres,"— Presentation transcript:

1 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 Sarcoma Research Laboratory University of Texas, MD Anderson Cancer Center

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 and in vivo

7 Experimental Models Lopez et al., 2011 Time (weeks) Tumor volume (mm 3 )

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

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

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

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

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

13 AZD2281 induces apoptosis control 2.5uM AZD 5.0uM AZD10.0uM AZD MPNST 724 96 hour treatment 8% total apoptosis 30% total apoptosis35% total apoptosis 42% total apoptosis

14 Effect on tumor growth MPNST Xenograft: Subcutaneous Injection (16 mice) Tumors grow to 5mm Treatment (8 mice) 50mg/kg/day AZD2281 Vehicle (8 mice) PBS+10%DMSO+10%HPCB Sacrifice mice when vehicle group reaches 1500mm 3, measure tumor volume and weight, preserve tissue Intraperitoneal injection

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

19 PARP Function and Inhibition

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

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

22 Rad51 37kDa NSC 26T 724 462 ST88 T265 Β-Actin NSC 26T 724462 T265 ST88 PARP 1 B-Actin DNA damage PCR array Results


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