PISARRO: A EUTROC phase 1b study of APR-246 with carboplatin (C) and pegylated liposomal doxorubicin (PLD) in relapsed platinum-sensitive high grade serous ovarian cancer (HGSOC)

Basu, Bristi; Gourley, C.; Gabra, Hani; Vergote, I.; Brenton, James D.; Abrahmsén, Lars; Smith, Austin M.; Euler, Mikael von; Green, J.A.

doi:10.1093/annonc/mdw368.29

Cited by 8 publications

(10 citation statements)

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“…APR-246 was tested in a phase 1 trial in patients with relapsed platinum sensitive HGSC in combination with carboplatin and PLD. This trial showed a 78% response rate and tolerable side effects profile, with dizziness being the most common adverse event (AE) attributed to APR-246 [ 193 ]. A phase 2 trial of APR-246 and PLD was conducted in platinum resistant HGSC, but the results have not yet been published [ 194 ].…”

Section: P53 As a Target For Eoc Therapymentioning

confidence: 99%

Mutated p53 in HGSC—From a Common Mutation to a Target for Therapy

Saleh

Perets

2021

Cancers

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Mutations in tumor suppressor gene TP53, encoding for the p53 protein, are the most ubiquitous genetic variation in human ovarian HGSC, the most prevalent and lethal histologic subtype of epithelial ovarian cancer (EOC). The majority of TP53 mutations are missense mutations, leading to loss of tumor suppressive function of p53 and gain of new oncogenic functions. This review presents the clinical relevance of TP53 mutations in HGSC, elaborating on several recently identified upstream regulators of mutant p53 that control its expression and downstream target genes that mediate its roles in the disease. TP53 mutations are the earliest genetic alterations during HGSC pathogenesis, and we summarize current information related to p53 function in the pathogenesis of HGSC. The role of p53 is cell autonomous, and in the interaction between cancer cells and its microenvironment. We discuss the reduction in p53 expression levels in tumor associated fibroblasts that promotes cancer progression, and the role of mutated p53 in the interaction between the tumor and its microenvironment. Lastly, we discuss the potential of TP53 mutations to serve as diagnostic biomarkers and detail some more advanced efforts to use mutated p53 as a therapeutic target in HGSC.

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Section: P53 As a Target For Eoc Therapymentioning

confidence: 99%

Mutated p53 in HGSC—From a Common Mutation to a Target for Therapy

Saleh

Perets

2021

Cancers

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“…S2F). These results indicate that diagnostic identification of CIP2A low status in human recurrent OvCa tumors could have predictive potential for these patients regarding clinical responsiveness to APR-246 currently in clinical development (18,19).…”

Section: Low Cip2a Expression Confers Ovca Cell Apr-246 Hypersensitivmentioning

confidence: 82%

“…1A). APR-246 (Eprenetapopt) has been studied in clinical trial in OvCa (19), and it showed promising clinical activity in a recent phase II trial in acute myeloid leukemia (AML) (18).…”

Section: Resultsmentioning

confidence: 99%

Ovarian cancers with low CIP2A tumor expression constitute an APR-246 sensitive disease subtype

Cvrljevic

Butt

Huhtinen

et al. 2021

Preprint

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Identification of ovarian cancer (OvCa) patient subpopulations with increased sensitivity to targeted therapies could offer significant clinical benefit. We report that 22% of the high grade OvCa tumors at diagnosis express CIP2A oncoprotein at low levels. CIP2Alow OvCa tumors have significantly lower likelihood of disease relapse after standard chemotherapy, but yet a portion of relapsed tumors retain their CIP2Alow phenotype. We further discover that reactive oxygen species (ROS) inducing compound APR-246 (PRIMA-1Met/Eprenetapopt), currently in clinical development, preferentially kill CIP2Alow OvCa cells across multiple chemotherapy resistant cell lines. Consistent with CIP2Alow OvCa subtype in humans, CIP2A is dispensable for development of MISIIR-TAg-driven mouse OvCa tumors. Nevertheless, CIP2A deficient OvCa tumor cells from MISIIR-TAg mice displayed APR-246 hypersensitivity both in vitro and in vivo. Mechanistically, the lack of CIP2A expression hypersensitizes the OvCa cells to APR-246 by inhibition of NF-kB activity. Accordingly, combination of APR-246 and Nf-kB inhibitor compounds strongly synergized in killing of CIP2A positive OvCa cells. Collectively, we discover low CIP2A expression as a vulnerability for APR-246 in OvCa. The results warrant consideration of clinical testing of APR-246 for CIP2Alow OvCa tumor subtype patients, and reveal CIP2A as a candidate APR-246 combination therapy target.

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“…Furthermore, as platinum compounds are the most active agents against this subtype, there are strong arguments for prioritizing development in this tumor. The phase Ib part of the study of APR-246 has shown combination with standard dose of carboplatin and liposomal doxorubicin is feasible with encouraging RECIST and CA125 response (GCIG) and progression-free survival [21]. Of 21 evaluable patients by RECIST1.1, 3 had a confirmed complete response, 10 a confirmed partial response and 8 stable disease.…”

mentioning

confidence: 99%

“…Several lines of evidence suggest that restoration of p53 may enhance the activity of DNA damaging agents and radiation treatment, which is known to elevate p53 activation signals. APR-246, based on preclinical data showing synergistic effects of the combination with cisplatin or doxorubicin, and potentiation of either drug [30], is being evaluated in combination with carboplatin and liposomal doxorubicin, an established second line regimen in HGSOC [21]. In vitro studies have also confirmed synergy with PARP inhibitors, which may further aid development in the 50% of HGSOC which harbor DNA-repair defects [20,31].…”

mentioning

confidence: 99%