overcoming treatment challenges in sarcomas: promising novel targeted agents george d. demetri, md...
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Overcoming Treatment Challenges in Sarcomas:
Promising Novel Targeted Agents
George D. Demetri, MD
Center for Sarcoma and Bone Oncology
Dana-Farber Cancer Institute
Ludwig Center at Dana-Farber / Harvard
Boston, Massachusetts
Development ofDevelopment ofMolecularly Targeted AgentsMolecularly Targeted Agents
for Sarcomasfor Sarcomas
A Model for PersonalizedA Model for PersonalizedAnticancer Drug DevelopmentAnticancer Drug Development
OFF
Tumor Cell Growth Arrestand Cancer Regression
ONTumor CellSurvival andGrowth
Searching for Critical Switches in Sarcomas
Gain-of-Function Mutations of c-kit in Human Gastrointestinal Stromal Tumors
Seiichi Hirota, Koji Isozaki, Yasuhiro Moriyama, Koji Hashimoto, Toshirou Nishida, Shingo Ishiguro, Kiyoshi Kawano, Masato Hanada,
Akihiko Kurata, Masashi Takeda, Ghulam Muhammad Tunio, Yuji Matsuzawa, Yuzuru Kanakura, Yasuhisa Shinomura, Yukihiko Kitamura
Finding the Critical Switch in the Gastrointestinal Sarcoma known as GIST
Science 279:577-580, 1998.
Imatinib is a Highly EffectiveTargeted Agent in GIST
Baseline Pre-Imatinib
ON
1 month on Imatinib
OFF
Demetri GD, et al. Proc Am Soc Clin Oncol 2005; Abstract 4000.
Baseline Day 7 PET
NormalHeartandKidneys
PET after 7 days of Sunitinib
Sunitinib is an Effective Targeted Agentfor Imatinib-Resistant GIST
Targeting Pathogenic Pathwaysin Other Types of Sarcomas Besides GIST
P P P P
PDGFRA
PP P P
KIT
PI3K
AKT
mTOR
Raf
Mek
Ras
Erk
Nucleus Transcription factors
Cell adhesionCell survival
Cell proliferation
ApoptosisCell differentiation
Angiogenesis
PKCtheta
S6K
The Next Successful Application ofKinase Inhibition to Sarcoma Therapy
• Dermatofibrosarcoma Protuberans (DFSP)
– Balanced translocation - t(17;22) - leads to uncontrolled production of PDGF ligand
– This induces autocrine activation of the wild-type PDGF-receptor system
– Imatinib and Sunitinib also block PDGF-receptors
After 5 months of Imatinib
CompleteClinicalResponsesustainedandongoing> 5 years
Inhibiting PDGF-R with Imatinib inAdvanced Dermatofibrosarcoma Protuberans
(DFSP)
DFSP: Response to ImatinibDFSP: Response to Imatinib
McArthur et al. J Clin Oncol 2005; 23:866.
DecreasedCellularity
HyalineChange
Testing Kinase Inhibitors as Therapy for Other Sarcoma Subtypes
• Imatinib
– Occasional activity in desmoid tumors (SARC)
• Sorafenib
– Some activity in vascular sarcomas (MSKCC)
• Sunitinib
– Some activity in vascular sarcomas and desmoplastic small round cell tumor (MSKCC and DFCI)
• Dasatinib
– SARC trial ongoing
Testing Kinase Inhibitors as Therapy for Other Sarcoma Subtypes
• Pazopanib
– Oral Tyrosine Kinase Inhibitor with activity against VEGF-R, PDGFR, and KIT, tested by EORTC
– Activity demonstrated in several subtypes including leiomyosarcomas and synovial sarcoma
– Phase III clinical trial to begin soon with EORTC and other international collaborations
Targeting Pathogenic Pathwaysin Other Sarcomas
PP P P
KIT
P P P P
PDGFRA
PI3K
AKT
mTOR
Raf
Mek
Ras
Erk
Nucleus Transcription factors
Cell adhesion Cell
survival
Cell proliferation
ApoptosisCell differentiation
Angiogenesis
PKCtheta
S6K
mTOR
mTOR-driven Sarcomas
• LAM and PEComa family of tumors
– Lymphangioleiomyomatosis (LAM)
– Angiomyolipoma (AML)
– Perivascular Epitheliod Cell-oma (PEComa)
• LAM/AML can be associated with Tuberous Sclerosis Complex or sporadic
Patient with Metastatic PEComaResponding to mTOR Inhibitor
(Sirolimus)
Wagner, Morgan, Antonescu et al. 2008.
Deforolimus: a Novel mTOR Inhibitor
Non-prodrug rapamycin analog
Forms a tripartite complex with FKBP12 and mTOR
Inhibits mTOR activity at nM levels
Compatible with either i.v. or oral delivery
O
O
O O
ON
O
O
O
HO
OH
OO
O
P
O
Metcalf CA et al. Proc Am Assoc Cancer Res 2004; 45:2476.
FKBP mTOR (FRBDomain)
18 May 2004(Baseline)
08 Dec 200415 Sep 2004
Mita M, et al. Proc Eur J Cancer 2004; 40A, Abstract 409.
Phase I Deforolimus Trial: Objective Response in Chemotherapy-resistant Ewing’s Sarcoma
• 20-year old patient with metastatic Ewing’s sarcoma progressing despite nine prior anti-cancer regimens
• Daily dosing with Deforolimus, 15 mg (IV)
Response to the mTOR Inhibitor Deforolimusin Chemotherapy-resistant Osteosarcoma
PET Day 1 (Baseline) PET Day 53PET Day 5
Fused CT/PET Images
Sankhala KK, et al. Proc Am Soc Clin Oncol 2005; 23: 823.
Monitoring Deforolimus Inhibition ofmTOR Activity in Blood
V. Rivera, et al. Deforolimus Study Group.
Day
1- P
re
Day
1- 4
hr
Day
2- P
re
Target ofmTOR Activity
TotalTarget
0 4 24Hrs post-dose
Phase II Deforolimus Trial:Promising Progression-Free Survival (PFS)
Sarcoma Subtype 6-Month Rate Median (wks)
Bone Sarcoma 25% 16
Soft-tissue Sarcomas 24% 15
• Leiomyosarcoma 22% 16
• Liposarcoma 30% 16
• Other soft-tissue sarcomas 23% 15
Overall PFS 24% 15
• Benefits observed across all sarcoma subtypes
Historical Context for Promising Disease Control with Deforolimus in Sarcomas
Progression-free Survival (PFS) Compared with Historical Data from EORTC
Historical Data (EORTC)
DeforolimusInactive Agents
Active Agents
No. of Patients 158 234 146
Median PFS 15 wks 7 wks 8 wks
3-month PFS 58% 21% 39%
6-month PFS 24% 8% 14%
Phase II Activity of Deforolimus in Sarcomas
• Promising activity of Deforolimus in patients with a broad range of advanced soft-tissue and bone sarcomas– Achieved primary endpoint of ≥ 25% Clinical Benefit Response
in each histologic subgroup of advanced sarcomas• No significant differences among the 4 sub-groups
– 29% overall CBR rate despite low incidence of tumor shrinkage
– PFS more than double that of historical control (EORTC)• 24% 6-month PFS rate (vs. 8%)
• 15-week median PFS (vs. 7 weeks)
• Well-tolerated with manageable side-effects
• A solid foundation upon which a definitive phase III trial has been developed to test the activity of deforolimus
Phase III Trial (“SUCCEED”): Deforolimus vs. Placebo to Maintain Clinical Benefit from
Prior Chemotherapy in Sarcomas
Primary Endpoint• Progression-Free Survival
Secondary Endpoints• Overall Survival• Objective Response Rate• Improvement in Symptoms• Safety and Tolerability of Deforolimus
Confirmed Favorable Outcome (PR, CR, SD) After Prior Chemotherapy
(< 1 year on therapy)
1:1 Randomization
Placebo (Oral)Deforolimus (Oral)
IGF1 and IGF1-R Signaling is a Promising Target for Sarcomas
Nat Rev Cancer © 2004 Nature Publishing Group.
Anti-IGF1R Monoclonal Antibody R1507: Responses in Ewing Sarcomas- Phase I Clinical Study
Patient 7002: •27-year-old male •Ewing’s sarcoma with lung
metastasis•Partial Response (PR) after
25 weeks of R1507
Patient 8012: •28-year-old female •Ewing’s sarcoma with lung
metastasis •PR after 6 weeks of R1507
Restaging Week 25Dec 29, 2006
BaselineJune 19, 2006
Restaging Week 6Jan 25, 2007
BaselineDec 8, 2006
Targeting Hsp 90 in Sarcomas
Preferential targeting to cancer
Cancer cell Hsp90 is different from Cancer cell Hsp90 is different from Hsp90 in normal cellsHsp90 in normal cells
Specific chaperone function: stabilization of oncogenes in key cell signaling pathways
Wagner et al. ASCO 2008.
Activity of Hsp90 Inhibitor IPI-504 in Metastatic Liposarcoma
Baseline Cycle 9
• Prior gemcitabine/vinorelbine (13% growth after 2 cycles)
Not all Molecular Targeted Agents are Rationally Designed – but the clinical evaluation can be rational
and targeted
• Binds to DNA minor groove, bending the helix
• Interacts with transcription factors and other DNA binding proteins
• Major activity in myxoid/round cell liposarcoma with TLS/CHOP fusion oncoprotein (DNA binding protein)
Sea Tunicate, Ecteinascidia Turbinata
Ecteinascidin-743 (Trabectedin),
a tetrahydroisoquinoline alkaloid
(MW = 762)
p=0.0076HR: 0.647
Trabectedin Improves Time to Progression in AdvancedHistopathologically Confirmed Leiomyosarcomas and
Liposarcomas (Independent Review)
Grosso, Jones, Demetri, et al, Lancet Oncology 2007.
Efficacy of Trabectedin (ecteinascidin-743) in Advanced Pretreated Myxoid Liposarcomas:
a Retrospective Study
TrabectedinInduces Changes inTumor Density
Before TumorChanges in Size
0 +1 c
+5 c
+8 c
+11 c
Extrinsic and Intrinsic Apoptosis Pathways as Targets
Adapted from Ashkenazi A. Nat Rev Can 2002;2:420–430.
Intrinsicpathway
Caspase 3, 6, 7
Apoptosis
Pro-apoptotic ligand
FADD
FLIP
DR5
DR4
Extrinsicpathway
Procaspase 8, 10
p53p53
Caspase 9
Caspase 8, 10
p53
BAX, BAK
Mitochondria
SMAC/DIABLO
ChemotherapyRadiotherapy
DNA damage
PUMA, NOXA
APAF1
Cytochrome c
DNA damage
BID
IAP
BCL2, BCLXL,
MCL1
Molecularly Targeted Agents for SarcomasSummary
• Sarcomas represent a variety of clinicopathologic subtypes for discovery and development of rationally-designed drugs to target specific molecular pathways
• Inhibition of a single pathway (KIT signaling) has proven effective for GIST
• Inhibition of multiple pathways will likely provide the best results over time
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