Targeting the P53 Pathway in Ewing Sarcoma

Overview

Journal Sarcoma

Publisher Wiley

Date 2011 Jan 4

PMID 21197471

Citations 13

Authors

Paul M Neilsen

Kathleen I Pishas

David F Callen

David M Thomas

Affiliations

Soon will be listed here.

Abstract

The p53 tumour suppressor plays a pivotal role in the prevention of oncogenic transformation. Cancers frequently evade the potent antitumour surveillance mechanisms of p53 through mutation of the TP53 gene, with approximately 50% of all human malignancies expressing dysfunctional, mutated p53 proteins. Interestingly, genetic lesions in the TP53 gene are only observed in 10% of Ewing Sarcomas, with the majority of these sarcomas expressing a functional wild-type p53. In addition, the p53 downstream signaling pathways and DNA-damage cell cycle checkpoints remain functionally intact in these sarcomas. This paper summarizes recent insights into the functional capabilities and regulation of p53 in Ewing Sarcoma, with a particular focus on the cross-talk between p53 and the EWS-FLI1 gene rearrangement frequently associated with this disease. The development of several activators of p53 is discussed, with recent evidence demonstrating the potential of small molecule p53 activators as a promising systemic therapeutic approach for the treatment of Ewing Sarcomas with wild-type p53.

Citing Articles

Factor-specific generative pattern from large-scale drug-induced gene expression profile.

Ahn S, Kim J Sci Rep. 2023; 13(1):6339.

PMID: 37072452 PMC: 10113368. DOI: 10.1038/s41598-023-33061-x.

Breakthrough Technologies Reshape the Ewing Sarcoma Molecular Landscape.

Salguero-Aranda C, Amaral A, Olmedo-Pelayo J, Diaz-Martin J, de Alava E Cells. 2020; 9(4).

PMID: 32225029 PMC: 7226764. DOI: 10.3390/cells9040804.

The Optimal Outcome of Suppressing Ewing Sarcoma Growth With Biocompatible Bioengineered miR-34a-5p Prodrug.

Li D, Yuan Y, Tu M, Hu X, Li Y, Yi W Front Oncol. 2020; 10:222.

PMID: 32161722 PMC: 7052494. DOI: 10.3389/fonc.2020.00222.

GD2-directed CAR-T cells in combination with HGF-targeted neutralizing antibody (AMG102) prevent primary tumor growth and metastasis in Ewing sarcoma.

Charan M, Dravid P, Cam M, Audino A, Gross A, Arnold M Int J Cancer. 2019; 146(11):3184-3195.

PMID: 31621900 PMC: 7440656. DOI: 10.1002/ijc.32743.

Secondary Malignant Transformation of Giant Cell Tumor of Bone: Is It a Fate?.

Movahedinia S, Shooshtarizadeh T, Mostafavi H Iran J Pathol. 2019; 14(2):165-174.

PMID: 31528174 PMC: 6679673. DOI: 10.30699/IJP.14.2.165.

References

Gokgoz N, Wunder J, Mousses S, Eskandarian S, Bell R, Andrulis I . Comparison of p53 mutations in patients with localized osteosarcoma and metastatic osteosarcoma. Cancer. 2001; 92(8):2181-9. DOI: 10.1002/1097-0142(20011015)92:8<2181::aid-cncr1561>3.0.co;2-3. View

Lain S, Hollick J, Campbell J, Staples O, Higgins M, Aoubala M . Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator. Cancer Cell. 2008; 13(5):454-63. PMC: 2742717. DOI: 10.1016/j.ccr.2008.03.004. View

Lessnick S, Dacwag C, Golub T . The Ewing's sarcoma oncoprotein EWS/FLI induces a p53-dependent growth arrest in primary human fibroblasts. Cancer Cell. 2002; 1(4):393-401. DOI: 10.1016/s1535-6108(02)00056-9. View

Neilsen P, Cheney K, Li C, Chen J, Cawrse J, Schulz R . Identification of ANKRD11 as a p53 coactivator. J Cell Sci. 2008; 121(Pt 21):3541-52. DOI: 10.1242/jcs.026351. View

Shvarts A, Bazuine M, Dekker P, Ramos Y, Steegenga W, Merckx G . Isolation and identification of the human homolog of a new p53-binding protein, Mdmx. Genomics. 1997; 43(1):34-42. DOI: 10.1006/geno.1997.4775. View

Prieur A, Tirode F, Cohen P, Delattre O . EWS/FLI-1 silencing and gene profiling of Ewing cells reveal downstream oncogenic pathways and a crucial role for repression of insulin-like growth factor binding protein 3. Mol Cell Biol. 2004; 24(16):7275-83. PMC: 479730. DOI: 10.1128/MCB.24.16.7275-7283.2004. View

Martini A, La Starza R, Janssen H, Bilhou-Nabera C, Corveleyn A, Somers R . Recurrent rearrangement of the Ewing's sarcoma gene, EWSR1, or its homologue, TAF15, with the transcription factor CIZ/NMP4 in acute leukemia. Cancer Res. 2002; 62(19):5408-12. View

Panagopoulos I, Hoglund M, Mertens F, Mandahl N, Mitelman F, Aman P . Fusion of the EWS and CHOP genes in myxoid liposarcoma. Oncogene. 1996; 12(3):489-94. View

Riggi N, Stamenkovic I . The Biology of Ewing sarcoma. Cancer Lett. 2007; 254(1):1-10. DOI: 10.1016/j.canlet.2006.12.009. View

10.

Kauer M, Ban J, Kofler R, Walker B, Davis S, Meltzer P . A molecular function map of Ewing's sarcoma. PLoS One. 2009; 4(4):e5415. PMC: 2671847. DOI: 10.1371/journal.pone.0005415. View

11.

Kovar H, Aryee D, Jug G, Henockl C, Schemper M, Delattre O . EWS/FLI-1 antagonists induce growth inhibition of Ewing tumor cells in vitro. Cell Growth Differ. 1996; 7(4):429-37. View

12.

Schneider-Stock R, RADIG K, Oda Y, Mellin W, Rys J, NIEZABITOWSKI A . p53 gene mutations in soft-tissue sarcomas--correlations with p53 immunohistochemistry and DNA ploidy. J Cancer Res Clin Oncol. 1997; 123(4):211-8. DOI: 10.1007/BF01240317. View

13.

Peter M, Couturier J, Pacquement H, Michon J, Thomas G, Magdelenat H . A new member of the ETS family fused to EWS in Ewing tumors. Oncogene. 1997; 14(10):1159-64. DOI: 10.1038/sj.onc.1200933. View

14.

Tolcher A, Sarantopoulos J, Patnaik A, Papadopoulos K, Lin C, Rodon J . Phase I, pharmacokinetic, and pharmacodynamic study of AMG 479, a fully human monoclonal antibody to insulin-like growth factor receptor 1. J Clin Oncol. 2009; 27(34):5800-7. DOI: 10.1200/JCO.2009.23.6745. View

15.

Wei G, Antonescu C, de Alava E, Leung D, Huvos A, Meyers P . Prognostic impact of INK4A deletion in Ewing sarcoma. Cancer. 2000; 89(4):793-9. DOI: 10.1002/1097-0142(20000815)89:4<793::aid-cncr11>3.0.co;2-m. View

16.

Kojima K, Konopleva M, Samudio I, Shikami M, Cabreira-Hansen M, McQueen T . MDM2 antagonists induce p53-dependent apoptosis in AML: implications for leukemia therapy. Blood. 2005; 106(9):3150-9. PMC: 1895324. DOI: 10.1182/blood-2005-02-0553. View

17.

Leach F, Tokino T, Meltzer P, Burrell M, Oliner J, Smith S . p53 Mutation and MDM2 amplification in human soft tissue sarcomas. Cancer Res. 1993; 53(10 Suppl):2231-4. View

18.

Hall K, Teneriello M, Taylor R, Lemon S, Ebina M, Linnoila R . Analysis of Ki-ras, p53, and MDM2 genes in uterine leiomyomas and leiomyosarcomas. Gynecol Oncol. 1997; 65(2):330-5. DOI: 10.1006/gyno.1997.4653. View

19.

Ozaki T, Paulussen M, Poremba C, Brinkschmidt C, Rerin J, Ahrens S . Genetic imbalances revealed by comparative genomic hybridization in Ewing tumors. Genes Chromosomes Cancer. 2001; 32(2):164-71. DOI: 10.1002/gcc.1178. View

20.

Ladanyi M . EWS-FLI1 and Ewing's sarcoma: recent molecular data and new insights. Cancer Biol Ther. 2002; 1(4):330-6. View