Li-Fraumeni Syndrome Disease Model: A Platform to Develop Precision Cancer Therapy Targeting Oncogenic p53

Ruoji Zhou; An Xu; Julian Gingold; Louise C Strong; Ruiying Zhao; Dung-Fang Lee

doi:10.1016/j.tips.2017.07.004

Li-Fraumeni Syndrome Disease Model: A Platform to Develop Precision Cancer Therapy Targeting Oncogenic p53

Trends Pharmacol Sci. 2017 Oct;38(10):908-927. doi: 10.1016/j.tips.2017.07.004. Epub 2017 Aug 14.

Authors

Ruoji Zhou¹, An Xu², Julian Gingold³, Louise C Strong⁴, Ruiying Zhao⁵, Dung-Fang Lee⁶

Affiliations

¹ Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA; These authors contributed equally to this work.
² Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; These authors contributed equally to this work.
³ Women's Health Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; These authors contributed equally to this work.
⁴ Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁵ Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA. Electronic address: [email protected].
⁶ Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA; Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Center for Precision Health, School of Biomedical Informatics and School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA. Electronic address: [email protected].

Abstract

Li-Fraumeni syndrome (LFS) is a rare hereditary autosomal dominant cancer disorder. Germline mutations in TP53, the gene encoding p53, are responsible for most cases of LFS. TP53 is also the most commonly mutated gene in human cancers. Because inhibition of mutant p53 is considered to be a promising therapeutic strategy to treat these diseases, LFS provides a perfect genetic model to study p53 mutation-associated malignancies as well as to screen potential compounds targeting oncogenic p53. In this review we briefly summarize the biology of LFS and current understanding of the oncogenic functions of mutant p53 in cancer development. We discuss the strengths and limitations of current LFS disease models, and touch on existing compounds targeting oncogenic p53 and in vitro clinical trials to develop new ones. Finally, we discuss how recently developed methodologies can be integrated into the LFS induced pluripotent stem cell (iPSC) platform to develop precision cancer therapy.

Keywords: Li–Fraumeni Syndrome; disease model; drug screening and development; in vitro clinical trial; mutant p53 gain of function; pluripotent stem cells.

Publication types

Review
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Disease Models, Animal
Drug Screening Assays, Antitumor
Genes, p53*
Germ-Line Mutation
Humans
Induced Pluripotent Stem Cells / drug effects
Induced Pluripotent Stem Cells / pathology
Li-Fraumeni Syndrome / drug therapy*
Li-Fraumeni Syndrome / genetics*
Li-Fraumeni Syndrome / pathology
Neoplasms / drug therapy*
Neoplasms / genetics*
Neoplasms / pathology
Precision Medicine

Abstract

Publication types

MeSH terms

Grants and funding