Summary: giant cell tumor of bone

Summary: giant cell tumor of bone

• Safety and efficacy of denosumab for giant cell tumor of bone

– What have we learnt, and where to from here?

Summary: chondrosarcomas

• GDC-0449 in patients with advanced chondrosarcomas: a French/US and French National Cancer Institutes Phase II collaborative study (Italiano)

• Outcomes of inoperable central chondrosarcoma (Picci)

• SRC signaling is involved in chemoresistance and migration of chondrosarcoma cells (van Oosterwijk)

POSTER: MTORC1 inhibitor targets SRC oncogenic signaling via MIRs in human chondrosarcoma

• PRP1 (an MTORC1 inhibitor) targets SRC via upregulation of MIR181A/99A/450A/199b5b

• SRC downregulates these MIRs• MIR99A regulates MTOR/FGFR3• Complex feedback loops involving RAS/MAPK and PI3K

pathways• PRP1 has cytostatic effects

Galoian, Temple

Galoian, Temple

Summary: chordoma

• High-dose single fraction radiotherapy for the management of chordomas of the spine and sacrum (Yamada et al)

• Germline polymorphisms in brachyury chordoma risk (Flanagan et al)

• The landscape of mutations in chordoma: PIK3CA and epigenetic modifiers (Campbell)

POSTER: HDAC inhibitor (Panobinostat) effects on mesenchymal tumors and chordomas

• Panobinostat inhibits growth of chondrosarcoma line JJ012

• No effect on chordoma lines• Effects independent on effects on ubiquitin ligase

pathway• Suggest combinations with other agents where

resistance exists

Galoian, Temple

Galoian, Temple

Galoian, Temple

HIF-1 Signaling in Chordoma is Identical to Nucleus Pulposus and

Confers Survival Advantage in Hypoxic Environment

John A Abraham, MD 1

Francis J Hornicek MD PhD 2

Irving Shapiro PhD 1

Makarand Risbud PhD 1

1Rothman Institute atThomas Jefferson University

Philadelphia, PA2Massachussetts General Hospital

Boston, MA

• Hypothesis: – Chordoma is embryologically similar to nucleus pulposus cells– HIF-1 is an important factor in protecting NP cells from apoptosis in the hypoxic

conditions in which they reside. – The purpose of this study was to determine if a similar mechanism could be

functioning in Chordoma cells.• Summary of Findings

– Chordoma and NP cells show identical patterns of HIF-1a expression under normoxic and hypoxic conditions, unlike cells derived from most other tissues

– Transcription of HIF-1 in both Chordoma and NP increases significantly in hypoxic conditions

– Hypoxia protects NP cells from apoptotic stimuli. Serum starvation under hypoxic conditions produces significantly less apoptosis that under normoxic conditions

• Discussion– HIF-1 is likely a key factor in Chordoma cell survival under hypoxic conditions.– Interruption of HIF-1 signaling may be a therapeutic mechanism

HIF-1 Signaling in Chordoma is Identical to Nucleus Pulposus and Confers

Survival Advantage in Hypoxic Environment