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Applying Current Findings to Improve the Care of Patients with Ewing Sarcoma. Steven DuBois, MD Associate Professor of Pediatrics UCSF School of Medicine. EWS/FLI & Olaparib. Garnett et al, 2012. Lessons in Planning PARP Trials. From this morning ’ s talk: Not all inhibitors the same

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Applying Current Findings to Improve the Care of Patients with Ewing Sarcoma


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applying current findings to improve the care of patients with ewing sarcoma

Applying Current Findings to Improve the Care of Patients with Ewing Sarcoma

Steven DuBois, MD

Associate Professor of Pediatrics

UCSF School of Medicine

slide2

EWS/FLI

&

Olaparib

Garnett et al, 2012

lessons in planning parp trials
Lessons in Planning PARP Trials
  • From this morning’s talk:
  • Not all inhibitors the same
  • Other agents synergize
    • Relation to DNA damage

Garnett et al, 2012

Brenner et al, 2012

selected clinical trials of parp inhibitors in ewing sarcoma
Selected Clinical Trials of PARP Inhibitors in Ewing Sarcoma
  • Adult phase 2 trial of olaparib
    • 0 / 12 patients with a response (AACR 2013)
  • Adult phase 1 trial of olaparib + temozolomide
    • Ongoing
  • COG phase 1 / 2 trial of BMN-673 + temozolomide
    • In development
  • SARC phase 1 / 2 trial of niraparib + temozolomide
    • In development
targeting gpr64 in ewing sarcoma
Targeting GPR64in Ewing Sarcoma
  • Orphan receptor
  • No clinical grade small molecule inhibitors
  • No clinical grade monoclonal antibodies
  • Therefore focus on targeting downstream effectors
targeting mmp 1 in ewing sarcoma
Targeting MMP-1 in Ewing Sarcoma

Yabe et al, 2002

Fuchs et al, 2003

targeting placental growth factor in ewing sarcoma
Targeting Placental Growth Factor in Ewing Sarcoma

Dalal et al, 2005

Bagley et al, 2011

targeting hoxd13 in ewing sarcoma
Targeting HOXD13 in Ewing Sarcoma
  • Challenging pharmacologically since a transcription factor (like EWS fusion proteins themselves)
applying ezh2 and bmi 1 in ews
Applying EZH2 and BMI-1 in EWS

Richter et al, 2009

Cooper et al, 2011

acknowledgements
Acknowledgements

NIH/NCI K23 CA154530

Sarcoma Foundation of America

Campini Foundation

Hope Street Kids Foundation