Presentation on theme: "Potent Inhibition of Human Liposarcoma Growth and Survival by a Novel Modulator of MDM2-p53 Interaction CTOS 17th Annual Meeting1 Yi-Xiang Zhang, PhD Dana-Farber."— Presentation transcript:
Potent Inhibition of Human Liposarcoma Growth and Survival by a Novel Modulator of MDM2-p53 Interaction CTOS 17th Annual Meeting1 Yi-Xiang Zhang, PhD Dana-Farber Cancer Institute
CTOS 17th Annual Meeting2 The Rationale of Targeting MDM2 in Liposarcoma Courtesy of Dr. Jason L. Hornick, Boston, MA Dr. Jonathan A. Fletcher, Boston, MA MDM2 p53 Induction of p21 Cell Cycle Arrest Induction of BAX, PUMA, NOXA Cell Death Other Biological Functions WDLPSDDLPS MDM2 Amplification MDM2/p53 Feed Back Loop ✗ ✗ ✗ Ubiquitination Degradation
CTOS 17th Annual Meeting3 The Rationale of Targeting MDM2 in Liposarcoma MDM2 p53 Induction of p21 Cell Cycle Arrest Induction of BAX, PUMA, NOXA Cell Death MDM2Antagonists Other Biological Functions MDM2/p53 Feed Back Loop
CTOS 17th Annual Meeting4 Here, we have established primary human liposarcoma tumor xenograft models, and evaluated efficacy of a novel MDM2 antagonist SAR in vitro and in vivo. 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 S æ ter, 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.
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 Meeting5 Characterization of Liposarcoma Cell Lines and Primary Tumor Xenografts
SAR is a Potent Inducer of p53 Activity CTOS 17th Annual Meeting 6 AB CD
SAR Decreases Cell Viability in Liposarcoma Cells with Wild-type p53 CTOS 17th Annual Meeting7 AB D C LP6 (p53 wt) LP6 (p53 mut) LP6 (+p53 siRNA)
CTOS 17th Annual Meeting8 SAR Blocks Cell Cycle Progression and Induces Apoptosis in Liposarcoma Cells Cell Cycle AnalysisApoptosis Analysis
CTOS 17th Annual Meeting9 SAR Restores p53 Activity in vivo
CTOS 17th Annual Meeting10 Complete Regression of Primary Liposarcoma Tumor Xenograft LPS3 Treated with SAR *, p<0.05; **, p<0.01; ***, p<0.001; ****, p<0.0001; compared with respective control group treated with vehicle.
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 Meeting11
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 Meeting12 Funding Support D.K. Ludwig Fund for Cancer Research supporting the Dana- Farber/Harvard Ludwig Center Peter and Paula Fasseas Fund for Liposarcoma Research