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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 Cancer cell
Vol 29
Issue 1
Date 2016 Jan 11
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 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 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 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 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
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 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