Reference Detail

Ref Type

Journal Article

PMID

(28498808)

Authors

Chen H, Luo D, Zhang L, Lin X, Luo Q, Yi H, Wang J, Yan X, Li B, Chen Y, Liu X, Zhang H, Liu S, Qiu M, Yang D, Jiang N

Title

Restoration of p53 using the novel MDM2-p53 antagonist APG115 suppresses dedifferentiated papillary thyroid cancer cells.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Oncotarget			2017 Apr 24	43008-43022	Oncotarget

URL

Abstract Text

Dedifferentiated papillary thyroid cancer (DePTC) is characterized by aggressive growth, recurrence, distant metastasis, and resistance to radioactive iodine (RAI) therapy. DePTC is also accompanied by poor prognosis and high early-mortality. Nevertheless, most DePTC cells show intact p53 downstream functionality. In cells with wild-type p53, the murine double minute2 (MDM2) protein interacts with p53 and abrogates its activity. Inhibition of the MDM2-p53 interaction restores p53 activity and leads to cell cycle arrest and apoptosis. Restoring p53 function by inhibiting its interaction with p53 suppressors such as MDM2 is thus a promising therapeutic strategy for the treatment of DePTC. The novel MDM2-p53 interaction antagonist APG115 is an analogue of SAR405838, and is being tested in a phase I clinical trial. In this study, we evaluated the efficacy of APG115 as a single-agent to treat DePTC. APG115 diminished the viability of p53 wild-type DePTC cells and induced cell cycle arrest and apoptosis. In a human xenograft mouse model, APG115 elicited robust tumor regression and cell apoptosis. These data demonstrate that further research is warranted to determine whether APG115 can be used to effectively treat DePTC patients.

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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
APG-115	APG-115	1	4

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
APG-115		APG115\|APG 115\|Alrizomadlin	MDM2 Inhibitor 22	APG-115, a derivative of SAR405838, inhibits MDM2 and its interaction with p53, thereby stabilizing and activating wild-type p53, which may result in antitumor activity and also synergizes with PD-1 inhibitors (PMID: 28498808, PMID: 31779710).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
TP53 wild-type	thyroid gland papillary carcinoma	sensitive	APG-115	Preclinical - Cell line xenograft	Actionable	In a preclinical study, a TP53 wild-type dedifferentiated papillary thyroid carcinoma cell line treated with APG-115 demonstrated decreased cell viability and induction of cell cycle arrest and apoptosis in culture, and tumor growth suppression and tumor regression in xenograft models (PMID: 28498808).	28498808