1

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.

5

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

7

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.

11

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

12

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