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