steven dubois, md associate professor of pediatrics ucsf school of medicine

Steven DuBois, MDAssociate Professor of Pediatrics

UCSF School of Medicine

Applying Current Findings to Improve the Care of Patients

with Ewing Sarcoma

EWS/FLI&

Olaparib

Garnett et al, 2012

Lessons in Planning PARP Trials

Garnett et al, 2012Brenner et al, 2012

From this morning’s talk:• Not all inhibitors the same• Other agents synergize

• Relation to DNA damage

Adult phase 2 trial of olaparib0 / 12 patients with a response (AACR 2013)

Adult phase 1 trial of olaparib + temozolomideOngoing

COG phase 1 / 2 trial of BMN-673 + temozolomideIn development

SARC phase 1 / 2 trial of niraparib + temozolomideIn development

Selected Clinical Trials of PARP Inhibitors in Ewing Sarcoma

Orphan receptorNo clinical grade small molecule inhibitorsNo clinical grade monoclonal antibodies

Therefore focus on targeting downstream effectors

Targeting GPR64 in Ewing Sarcoma

Targeting MMP-1 in Ewing Sarcoma

Yabe et al, 2002Fuchs et al, 2003

Coussens et al, 2002

Targeting Placental Growth Factor in Ewing Sarcoma

Dalal et al, 2005Bagley et al, 2011

Cautionary Tale of Bevacizumab in Ewing Sarcoma?

Boige et al, 2012

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

Targeting HOXD13 in Ewing Sarcoma

Applying EZH2 and BMI-1 in EWS

Richter et al, 2009Cooper et al, 2011

Bone Marrow Metastatic Disease

Oberlin et al, 2006

Study Patients with Any Marrow Involvement

Patients with Isolated Marrow

Involvement

Ladenstein et al, 2010 123 / 271 = 45% 19 / 271 = 7%

Bernstein et al, 2006 Not Reported 8 / 110 = 7%

Oberlin et al, 2006 23 / 97 = 24% 3 / 97 = 3%

NIH/NCI K23 CA154530

Sarcoma Foundation of America

Campini Foundation

Hope Street Kids Foundation

Acknowledgements