1. Steven DuBois, MD Associate Professor of Pediatrics UCSF School of Medicine

2. EWS/FLI & Olaparib Garnett et al, 2012

3. Brenner et al, 2012 From this morning’s talk: Not all inhibitors the same Other agents synergize Relation to DNA damage

4. 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

5. Orphan receptor No clinical grade small molecule inhibitors No clinical grade monoclonal antibodies Therefore focus on targeting downstream effectors

6. Yabe et al, 2002 Fuchs et al, 2003

7. Coussens et al, 2002

8. Dalal et al, 2005 Bagley et al, 2011

9. Boige et al, 2012

10. Challenging pharmacologically since a transcription factor (like EWS fusion proteins themselves)

11. Richter et al, 2009 Cooper et al, 2011

12. Oberlin et al, 2006 StudyPatients with Any Marrow Involvement Patients with Isolated Marrow Involvement Ladenstein et al, 2010 123 / 271 = 45%19 / 271 = 7% Bernstein et al, 2006 Not Reported8 / 110 = 7% Oberlin et al, 2006 23 / 97 = 24%3 / 97 = 3%

14. NIH/NCI K23 CA154530 Sarcoma Foundation of America Campini Foundation Hope Street Kids Foundation