Reference Detail

Ref Type

Journal Article

PMID

(27179933)

Authors

Fransson Å, Glaessgen D, Alfredsson J, Wiman KG, Bajalica-Lagercrantz S, Mohell N

Title

Strong synergy with APR-246 and DNA-damaging drugs in primary cancer cells from patients with TP53 mutant High-Grade Serous ovarian cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of ovarian research	9	1	2016 May 14	27	J Ovarian Res

URL

Abstract Text

Mutation in the tumor suppressor gene TP53 is an early event in the development of high-grade serous (HGS) ovarian cancer and is identified in more than 96 % of HGS cancer patients. APR-246 (PRIMA-1(MET)) is the first clinical-stage compound that reactivates mutant p53 protein by refolding it to wild type conformation, thus inducing apoptosis. APR-246 has been tested as monotherapy in a Phase I/IIa clinical study in hematological malignancies and prostate cancer with promising results, and a Phase Ib/II study in combination with platinum-based therapy in ovarian cancer is ongoing. In the present study, we investigated the anticancer effects of APR-246 in combination with conventional chemotherapy in primary cancer cells isolated from ascitic fluid from 10 ovarian, fallopian tube, or peritoneal cancer patients, 8 of which had HGS cancer.Cell viability was assessed with fluorometric microculture cytotoxicity assay (FMCA) and Combination Index was calculated using the Additive model. p53 status was determined by Sanger sequencing and single strand conformation analysis, and p53 protein expression by western blotting.We observed strong synergy with APR-246 and cisplatin in all tumor samples carrying a TP53 missense mutation, while synergistic or additive effects were found in cells with wild type or TP53 nonsense mutations. Strong synergy was also observed with carboplatin or doxorubicin. Moreover, APR-246 sensitized TP53 mutant primary ovarian cancer cells, isolated from a clinically platinum-resistant patient, to cisplatin; the IC50 value of cisplatin decreased 3.6 fold from 6.5 to 1.8 μM in the presence of clinically relevant concentration of APR-246.These results suggest that combination treatment with APR-246 and DNA-damaging drugs could significantly improve the treatment of patients with TP53 mutant HGS cancer, and thus provide strong support for the ongoing clinical study with APR-246 in combination with carboplatin and pegylated liposomal doxorubicin in patients with recurrent HGS cancer.

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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

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
TP53	L111Q	missense	unknown	TP53 L111Q lies within the DNA-binding domain of the Tp53 protein (PMID: 22713868). L111Q has been identified in the scientific literature (PMID: 27179933, PMID: 25471132, PMID: 29386642), but has not been biochemically characterized and therefore, its effect on Tp53 protein function is unknown (PubMed, Feb 2024).
TP53	Y163H	missense	unknown	TP53 Y163H lies within the DNA-binding domain of the Tp53 protein (PMID: 22713868). Y163H has been identified in the scientific literature (PMID: 27179933, PMID: 17764544, PMID: 28245875), but has not been biochemically characterized and therefore, its effect on Tp53 protein function is unknown (PubMed, Feb 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
TP53 Y163H	ovarian cancer	sensitive	APR-246 + Cisplatin	Preclinical - Patient cell culture	Actionable	In a preclinical study, the combination of APR-246 and Platinol (cisplatin) resulted in strong synergism, thereby reducing cell viability in patient derived ovarian cancer cells harboring TP53 Y163H in culture (PMID: 27179933).	27179933
TP53 P151H	ovarian cancer	sensitive	APR-246 + Cisplatin	Preclinical - Patient cell culture	Actionable	In a preclinical study, the combination of APR-246 and Platinol (cisplatin) resulted in strong synergism, thereby reducing cell viability in patient derived ovarian cancer cells harboring TP53 P151H in culture (PMID: 27179933).	27179933
TP53 C238F	fallopian tube cancer	sensitive	APR-246 + Cisplatin	Preclinical - Patient cell culture	Actionable	In a preclinical study, the combination of APR-246 and Platinol (cisplatin) resulted in strong synergism, thereby reducing cell viability in patient derived fallopian tube cancer cells harboring TP53 C238F in culture (PMID: 27179933).	27179933
TP53 P278R	ovarian cancer	sensitive	APR-246 + Cisplatin	Preclinical - Patient cell culture	Actionable	In a preclinical study, the combination of APR-246 and Platinol (cisplatin) resulted in strong synergism, thereby reducing cell viability in patient derived ovarian cancer cells harboring TP53 P278R in culture (PMID: 27179933).	27179933
TP53 C135Y	peritoneum cancer	sensitive	APR-246 + Cisplatin	Preclinical - Patient cell culture	Actionable	In a preclinical study, the combination of APR-246 and Platinol (cisplatin) resulted in strong synergism, thereby reducing cell viability in patient derived peritoneum cancer cells harboring TP53 C135Y in culture (PMID: 27179933).	27179933
TP53 L111Q	ovarian cancer	sensitive	APR-246 + Cisplatin	Preclinical - Patient cell culture	Actionable	In a preclinical study, the combination of APR-246 and Platinol (cisplatin) resulted in strong synergism, thereby reducing cell viability in patient derived ovarian cancer cells harboring TP53 L111Q in culture (PMID: 27179933).	27179933
TP53 R280K	ovarian cancer	sensitive	APR-246 + Cisplatin	Preclinical - Patient cell culture	Actionable	In a preclinical study, the combination of APR-246 and Platinol (cisplatin) worked synergistically in culture, resulting in reduced cell viability in patient derived ovarian cancer cells harboring TP53 R280K (PMID: 27179933).	27179933