steven dubois, md associate professor of pediatrics ucsf school of medicine
TRANSCRIPT
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Steven DuBois, MDAssociate Professor of Pediatrics
UCSF School of Medicine
Applying Current Findings to Improve the Care of Patients
with Ewing Sarcoma
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EWS/FLI&
Olaparib
Garnett et al, 2012
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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
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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
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Orphan receptorNo clinical grade small molecule inhibitorsNo clinical grade monoclonal antibodies
Therefore focus on targeting downstream effectors
Targeting GPR64 in Ewing Sarcoma
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Targeting MMP-1 in Ewing Sarcoma
Yabe et al, 2002Fuchs et al, 2003
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Coussens et al, 2002
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Targeting Placental Growth Factor in Ewing Sarcoma
Dalal et al, 2005Bagley et al, 2011
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Cautionary Tale of Bevacizumab in Ewing Sarcoma?
Boige et al, 2012
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Challenging pharmacologically since a transcription factor (like EWS fusion proteins themselves)
Targeting HOXD13 in Ewing Sarcoma
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Applying EZH2 and BMI-1 in EWS
Richter et al, 2009Cooper et al, 2011
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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%
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NIH/NCI K23 CA154530
Sarcoma Foundation of America
Campini Foundation
Hope Street Kids Foundation
Acknowledgements