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Potent Inhibition of Human Liposarcoma Growth and Survival by a Novel Modulator of MDM2-p53 Interaction . Yi- X iang Zhang, PhD Dana-Farber Cancer Institute. The Rationale of Targeting MDM2 in Liposarcoma. MDM2/p53 Feed Back Loop. WDLPS. DDLPS. MDM2. p53. Ubiquitination Degradation. ✗.

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Yi- X iang Zhang, PhD Dana-Farber Cancer Institute

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Yi x iang zhang phd dana farber cancer institute

Potent Inhibition of Human LiposarcomaGrowth and Survival by a Novel Modulatorof MDM2-p53 Interaction

Yi-Xiang Zhang, PhD

Dana-Farber Cancer Institute


Yi x iang zhang phd dana farber cancer institute

The Rationale of Targeting MDM2 in Liposarcoma

MDM2/p53 Feed Back Loop

WDLPS

DDLPS

MDM2

p53

Ubiquitination

Degradation

Induction of

BAX, PUMA, NOXA

Cell Death

Induction of p21

Cell Cycle Arrest

Other Biological Functions

MDM2 Amplification

Courtesy of Dr. Jason L. Hornick, Boston, MA

Dr. Jonathan A. Fletcher, Boston, MA


Yi x iang zhang phd dana farber cancer institute

The Rationale of Targeting MDM2 in Liposarcoma

MDM2/p53 Feed Back Loop

MDM2

Antagonists

MDM2

p53

Induction of

BAX, PUMA, NOXA

Cell Death

Induction of p21

Cell Cycle Arrest

Other Biological Functions


Yi x iang zhang phd dana farber cancer institute

The Development of MDM2 Antagonists for Liposarcoma

Science303, 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, ZoranFilipovic, 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, JianguoZhi, et al.

Here, we have established primary human liposarcoma tumor xenograft models, and evaluated efficacy of a novel MDM2 antagonist SAR299155 in vitro and in vivo.


Yi x iang zhang phd dana farber cancer institute

Characterization of Liposarcoma Cell Lines and Primary Tumor Xenografts

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


Sar299155 is a potent inducer of p53 activity

SAR299155 is a Potent Inducer of p53 Activity

A

B

C

D


Sar299155 decreases cell viability in liposarcoma cells with wild type p53

SAR299155 Decreases Cell Viability in Liposarcoma Cells with Wild-type p53

A

B

LP6 (p53 mut)

LP6 (p53 wt)

C

D

LP6 (+p53 siRNA)


Yi x iang zhang phd dana farber cancer institute

  • SAR299155 Blocks Cell Cycle Progression and

  • Induces Apoptosis in Liposarcoma Cells

Cell Cycle Analysis

Apoptosis Analysis


Sar299155 restores p53 activity in vivo

SAR299155 Restores p53 Activity in vivo


Yi x iang zhang phd dana farber cancer institute

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.


Conclusion

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 liposarcomaxenograft models will be useful tools for evaluating drug efficacy and identifying new biomarkers.


Acknowledgement

Acknowledgement

Dana-Farber Cancer Institute

Andrew J. Wagner, MD, PhD

EwaSicinska, 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


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