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Potent Inhibition of Human Liposarcoma Growth and Survival by a Novel Modulator of MDM2-p53 Interaction Yi-Xiang Zhang, PhD Dana-Farber Cancer Institute.

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Presentation on theme: "Potent Inhibition of Human Liposarcoma Growth and Survival by a Novel Modulator of MDM2-p53 Interaction Yi-Xiang Zhang, PhD Dana-Farber Cancer Institute."— Presentation transcript:

1 Potent Inhibition of Human Liposarcoma Growth and Survival by a Novel Modulator of MDM2-p53 Interaction Yi-Xiang Zhang, PhD Dana-Farber Cancer Institute CTOS 17th Annual Meeting

2 ✗ The Rationale of Targeting MDM2 in Liposarcoma
WDLPS DDLPS MDM2/p53 Feed Back Loop MDM2 p53 Ubiquitination Degradation Induction of p21 Cell Cycle Arrest Induction of BAX, PUMA, NOXA Cell Death Other Biological Functions MDM2 Amplification Courtesy of Dr. Jason L. Hornick, Boston, MA Dr. Jonathan A. Fletcher, Boston, MA CTOS 17th Annual Meeting

3 The Rationale of Targeting MDM2 in Liposarcoma
MDM2/p53 Feed Back Loop MDM2 MDM2 Antagonists p53 Induction of p21 Cell Cycle Arrest Induction of BAX, PUMA, NOXA Cell Death Other Biological Functions CTOS 17th Annual Meeting

4 The Development of MDM2 Antagonists for Liposarcoma
Science 303, (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, (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, (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. Here, we have established primary human liposarcoma tumor xenograft models, and evaluated efficacy of a novel MDM2 antagonist SAR in vitro and in vivo. CTOS 17th Annual Meeting

5 Characterization of Liposarcoma Cell Lines and Primary Tumor Xenografts
Cell lines: 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

6 SAR299155 is a Potent Inducer of p53 Activity
B C D CTOS 17th Annual Meeting

7 SAR299155 Decreases Cell Viability in Liposarcoma Cells with Wild-type p53
LP6 (p53 wt) LP6 (p53 mut) C LP6 (+p53 siRNA) D CTOS 17th Annual Meeting

8 SAR299155 Blocks Cell Cycle Progression and
Induces Apoptosis in Liposarcoma Cells Cell Cycle Analysis Apoptosis Analysis CTOS 17th Annual Meeting

9 SAR299155 Restores p53 Activity in vivo
CTOS 17th Annual Meeting

10 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. CTOS 17th Annual Meeting

11 Conclusion SAR 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

12 Acknowledgement Funding Support
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 Funding Support D.K. Ludwig Fund for Cancer Research supporting the Dana-Farber/Harvard Ludwig Center Peter and Paula Fasseas Fund for Liposarcoma Research CTOS 17th Annual Meeting


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