Reference Detail

Ref Type

Journal Article

PMID

(26748848)

Authors

Soragni A, Janzen DM, Johnson LM, Lindgren AG, Thai-Quynh Nguyen A, Tiourin E, Soriaga AB, Lu J, Jiang L, Faull KF, Pellegrini M, Memarzadeh S, Eisenberg DS

Title

A Designed Inhibitor of p53 Aggregation Rescues p53 Tumor Suppression in Ovarian Carcinomas.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer cell	29	1	2016 Jan 11	90-103	Cancer Cell

URL

Abstract Text

Half of all human cancers lose p53 function by missense mutations, with an unknown fraction of these containing p53 in a self-aggregated amyloid-like state. Here we show that a cell-penetrating peptide, ReACp53, designed to inhibit p53 amyloid formation, rescues p53 function in cancer cell lines and in organoids derived from high-grade serous ovarian carcinomas (HGSOC), an aggressive cancer characterized by ubiquitous p53 mutations. Rescued p53 behaves similarly to its wild-type counterpart in regulating target genes, reducing cell proliferation and increasing cell death. Intraperitoneal administration decreases tumor proliferation and shrinks xenografts in vivo. Our data show the effectiveness of targeting a specific aggregation defect of p53 and its potential applicability to HGSOCs.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
ReACp53	ReACp53	8	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
ReACp53			p53 Activator 11	ReACp53 is a peptide that inhibits Tp53 aggregation, resulting in reactivation of Tp53 pathway signaling in Tp53-mutant cells, and potentially resulting in increased tumor cell death (PMID: 26748848, PMID: 31471556)

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
TP53	I251S	missense	unknown	TP53 I251S lies within the DNA-binding domain of the Tp53 protein (PMID: 22713868). I251S confers similar sensitivity to mutant Tp53-targeted therapeutics compared to cells with characterized Tp53 mutations in culture (PMID: 26748848), however, has not been biochemically characterized and therefore, its effect on Tp53 protein function is unknown.
TP53	Y327L	missense	unknown	TP53 Y327L (also referred to as Y326L) lies within the tetramerization domain of the Tp53 protein (PMID: 15510160). Y327L confers similar sensitivity to mutant Tp53-targeted therapeutics compared to cells with characterized Tp53 mutations in culture (PMID: 26748848), however, has not been biochemically characterized and therefore, its effect on Tp53 function is unknown.

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
TP53 inact mut	ovarian carcinoma	sensitive	ReACp53	Preclinical	Actionable	In a preclinical study, ReACp53 induced cell death and decreased proliferation of ovarian carcinoma cells harboring TP53 mutations in culture, but did not effect viability of ovarian carcinoma cells with wild-type TP53 (PMID: 26748848).	26748848
TP53 R175H	Advanced Solid Tumor	sensitive	ReACp53	Preclinical	Actionable	In a preclinical study, treatment with ReACp53 induced cell death in primary human uterine fibroblasts expressing TP53 R175H in culture (PMID: 26748848).	26748848
TP53 R175H	head and neck cancer	sensitive	ReACp53	Preclinical	Actionable	In a preclinical study, ReACp53 induced cell death and decreased proliferation of head and neck carcinoma cells harboring TP53 R175H in culture (PMID: 26748848).	26748848
TP53 loss	ovarian cancer	no benefit	ReACp53	Preclinical	Actionable	In a preclincial study, ReACp53 did not induce cell death in ovarian cancer cells with loss of TP53 in culture (PMID: 26748848).	26748848
TP53 Y234C	ovarian carcinoma	sensitive	ReACp53	Preclinical	Actionable	In a preclinical study, ReACp53 induced cell death in human primary ovarian carcinoma cells harboring TP53 Y234C in culture (PMID: 26748848).	26748848
TP53 I195* TP53 R248Q	ovarian carcinoma	sensitive	ReACp53	Preclinical	Actionable	In a preclinical study, ReACp53 induced cell death and decreased proliferation of human primary ovarian carcinoma cells harboring both TP53 I195* and TP53 R248Q in culture (PMID: 26748848).	26748848
TP53 Y327L	ovarian carcinoma	sensitive	ReACp53	Preclinical	Actionable	In a preclinical study, ReACp53 induced cell death in human primary ovarian carcinoma cells harboring TP53 Y327L in culture (PMID: 26748848).	26748848
TP53 R248Q	ovarian cancer	sensitive	ReACp53	Preclinical - Pdx & cell culture	Actionable	In a preclinical study, ReACp53 rescued p53 activity and decreased viability of ovarian cancer cells harboring TP53 R248Q in culture, and induced tumor regression in patient-derived ovarian cancer xenograft models harboring TP53 R248Q (PMID: 26748848).	26748848