Potent Inhibition of Human Liposarcoma Growth and Survival by a Novel Modulator of MDM2-p53...
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Transcript of Potent Inhibition of Human Liposarcoma Growth and Survival by a Novel Modulator of MDM2-p53...
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Potent Inhibition of Human Liposarcoma
Growth and Survival by a Novel Modulator
of MDM2-p53 Interaction
CTOS 17th Annual Meeting
Yi-Xiang Zhang, PhD
Dana-Farber Cancer Institute
2CTOS 17th Annual Meeting
The Rationale of Targeting MDM2 in Liposarcoma
Courtesy of Dr. Jason L. Hornick, Boston, MA Dr. Jonathan A. Fletcher, Boston, MA
MDM2
p53p53
Induction of p21
Cell Cycle Arrest
Induction of BAX, PUMA,
NOXACell Death
Other Biological Functions
WDLPS DDLPS
MDM2 Amplification
MDM2/p53 Feed Back Loop
✗ ✗ ✗
UbiquitinationDegradation
3CTOS 17th Annual Meeting
The Rationale of Targeting MDM2 in Liposarcoma
MDM2
p53p53
Induction of p21
Cell Cycle Arrest
Induction of BAX, PUMA,
NOXACell Death
MDM2Antagonists
Other Biological Functions
MDM2/p53 Feed Back Loop
4CTOS 17th Annual Meeting
Here, we have established primary human liposarcoma tumor xenograft models,
and evaluated efficacy of a novel MDM2 antagonist SAR299155 in vitro and in vivo.
The Development of MDM2 Antagonists for Liposarcoma
Science 303, 844-848 (2004)
In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2
Lyubomir T. Vassilev, Binh T. Vu, Bradford Graves, Daisy Carvajal, Frank Podlaski, Zoran Filipovic, et al.
Int. J. Cancer 121, 199-205 (2007)
Potential for Treatment of Lipoarcomas with the MDM2 Antagonist Nutlin-3A
Christoph R. Müller, Erik B. Paulsen, Paul Noordhuis, Florence Pedeutour, Gunnar Sæter, Ola Myklebost
Lancet Oncol. 13, 1133-1140 (2012)
Effect of the MDM2 Antagonist RG7112 on the P53 Pathway in Patients with MDM2-amplified, Well-differentiated or Dedifferentiated Liposarcoma: an exploratory proof-of-mechanism study.
Isabelle Ray-Coquard, Jean-Yves Blay, Antoine Italiano, Axel Le Cesne, Nicolas Penel, Jianguo Zhi, et al.
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Cell lines: 449 and 778: Courtesy of Dr. Florence Pedeutour, Nice, France LP3 and LP6: Courtesy of Dr. Eric L. Snyder, Boston, MA LPS141, LPS510 and LPS853: Courtesy of Dr. Jonathan A. Fletcher, Boston, MA CTOS 17th Annual Meeting
Characterization of Liposarcoma Cell Lines and Primary Tumor Xenografts
SAR299155 is a Potent Inducer of p53 Activity
CTOS 17th Annual Meeting 6
A B
C D
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SAR299155 Decreases Cell Viability in Liposarcoma Cells with Wild-type p53
CTOS 17th Annual Meeting
A B
DC
LP6 (p53 wt) LP6 (p53 mut)
LP6 (+p53 siRNA)
8CTOS 17th Annual Meeting
SAR299155 Blocks Cell Cycle Progression and Induces Apoptosis in Liposarcoma Cells
Cell Cycle Analysis Apoptosis Analysis
9CTOS 17th Annual Meeting
SAR299155 Restores p53 Activity in vivo
10CTOS 17th Annual Meeting
Complete Regression of Primary Liposarcoma Tumor Xenograft LPS3 Treated with SAR299155
*, p<0.05; **, p<0.01; ***, p<0.001; ****, p<0.0001; compared with respective control group treated with vehicle.
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Conclusion
• SAR299155 is a potent novel MDM2 antagonist, and is 5-fold more
potent than Nutlin-3 in biochemical and biological assays.
• Complete and durable tumor regression were achieved in a primary
human liposarcoma tumor xenograft model.
• Patient tumor-derived primary liposarcoma xenograft models will be
useful tools for evaluating drug efficacy and identifying new
biomarkers.
CTOS 17th Annual Meeting
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Acknowledgement
Dana-Farber Cancer Institute
Andrew J. Wagner, MD, PhD
Ewa Sicinska, MD
Jeffrey T. Czaplinski
Stephen P. Remillard, PhD
George D. Demetri, MD
Amanda L. Christie
Andrew L. Kung, MD, PhD
Sanofi
Laurent Debussche, PhD
University of Michigan
Shaomeng Wang, PhD
Jonathan A. Fletcher, MD
Florence Pedeutour, PhD
Eric L. Snyder, MD, PhD
CTOS 17th Annual Meeting
Funding Support
D.K. Ludwig Fund for Cancer Research supporting the Dana-Farber/Harvard Ludwig Center
Peter and Paula Fasseas Fund for Liposarcoma Research