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Your search keyword '"Corrales Benitez, M"' showing total 3 results
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3 results on '"Corrales Benitez, M"'

1. A thiol-bound drug reservoir enhances APR-246-induced mutant p53 tumor cell death

Author

Ceder, S, Eriksson, SE, Cheteh, EH, Dawar, S, Corrales Benitez, M, Bykov, VJN, Fujihara, KM, Grandin, M, Li, X, Ramm, S, Behrenbruch, C, Simpson, KJ, Hollande, F, Abrahmsen, L, Clemons, NJ, Wiman, KG, Ceder, S, Eriksson, SE, Cheteh, EH, Dawar, S, Corrales Benitez, M, Bykov, VJN, Fujihara, KM, Grandin, M, Li, X, Ramm, S, Behrenbruch, C, Simpson, KJ, Hollande, F, Abrahmsen, L, Clemons, NJ, and Wiman, KG

Abstract

The tumor suppressor gene TP53 is the most frequently mutated gene in cancer. The compound APR-246 (PRIMA-1Met/Eprenetapopt) is converted to methylene quinuclidinone (MQ) that targets mutant p53 protein and perturbs cellular antioxidant balance. APR-246 is currently tested in a phase III clinical trial in myelodysplastic syndrome (MDS). By in vitro, ex vivo, and in vivo models, we show that combined treatment with APR-246 and inhibitors of efflux pump MRP1/ABCC1 results in synergistic tumor cell death, which is more pronounced in TP53 mutant cells. This is associated with altered cellular thiol status and increased intracellular glutathione-conjugated MQ (GS-MQ). Due to the reversibility of MQ conjugation, GS-MQ forms an intracellular drug reservoir that increases availability of MQ for targeting mutant p53. Our study shows that redox homeostasis is a critical determinant of the response to mutant p53-targeted cancer therapy.

Published
2021

2. SLC7A11 Is a Superior Determinant of APR-246 (Eprenetapopt) Response than TP53 Mutation Status.

Author

Fujihara KM, Corrales Benitez M, Cabalag CS, Zhang BZ, Ko HS, Liu DS, Simpson KJ, Haupt Y, Lipton L, Haupt S, Phillips WA, and Clemons NJ

Subjects
Amino Acid Transport System y+ genetics, Apoptosis, Biomarkers, Tumor genetics, Cell Proliferation, Cisplatin administration & dosage, Esophageal Neoplasms drug therapy, Esophageal Neoplasms genetics, Esophageal Neoplasms metabolism, Fluorouracil administration & dosage, Humans, Metabolome, Prognosis, Proteome, Quinuclidines administration & dosage, Transcriptome, Tumor Cells, Cultured, Amino Acid Transport System y+ metabolism, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Biomarkers, Tumor metabolism, Esophageal Neoplasms pathology, Gene Expression Regulation, Neoplastic drug effects, Mutation, Tumor Suppressor Protein p53 genetics
Abstract

APR-246 (eprenetapopt) is in clinical development with a focus on hematologic malignancies and is promoted as a mutant-p53 reactivation therapy. Currently, the detection of at least one TP53 mutation is an inclusion criterion for patient selection into most APR-246 clinical trials. Preliminary results from our phase Ib/II clinical trial investigating APR-246 combined with doublet chemotherapy [cisplatin and 5-fluorouracil (5-FU)] in metastatic esophageal cancer, together with previous preclinical studies, indicate that TP53 mutation status alone may not be a sufficient biomarker for APR-246 response. This study aims to identify a robust biomarker for response to APR-246. Correlation analysis of the PRIMA-1 activity (lead compound to APR-246) with mutational status, gene expression, protein expression, and metabolite abundance across over 700 cancer cell lines (CCL) was performed. Functional validation and a boutique siRNA screen of over 850 redox-related genes were also conducted. TP53 mutation status was not consistently predictive of response to APR-246. The expression of SLC7A11, the cystine/glutamate transporter, was identified as a superior determinant of response to APR-246. Genetic regulators of SLC7A11, including ATF4, MDM2, wild-type p53, and c-Myc, were confirmed to also regulate cancer-cell sensitivity to APR-246. In conclusion, SLC7A11 expression is a broadly applicable determinant of sensitivity to APR-246 across cancer and should be utilized as the key predictive biomarker to stratify patients for future clinical investigation of APR-246., (©2021 American Association for Cancer Research.)

Published
2021
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3. A thiol-bound drug reservoir enhances APR-246-induced mutant p53 tumor cell death.

Author

Ceder S, Eriksson SE, Cheteh EH, Dawar S, Corrales Benitez M, Bykov VJN, Fujihara KM, Grandin M, Li X, Ramm S, Behrenbruch C, Simpson KJ, Hollande F, Abrahmsen L, Clemons NJ, and Wiman KG

Subjects
Cell Death, Cell Line, Tumor, Humans, Mutation, Quinuclidines, Sulfhydryl Compounds, Tumor Suppressor Protein p53 genetics, Neoplasms drug therapy, Pharmaceutical Preparations
Abstract

The tumor suppressor gene TP53 is the most frequently mutated gene in cancer. The compound APR-246 (PRIMA-1Met/Eprenetapopt) is converted to methylene quinuclidinone (MQ) that targets mutant p53 protein and perturbs cellular antioxidant balance. APR-246 is currently tested in a phase III clinical trial in myelodysplastic syndrome (MDS). By in vitro, ex vivo, and in vivo models, we show that combined treatment with APR-246 and inhibitors of efflux pump MRP1/ABCC1 results in synergistic tumor cell death, which is more pronounced in TP53 mutant cells. This is associated with altered cellular thiol status and increased intracellular glutathione-conjugated MQ (GS-MQ). Due to the reversibility of MQ conjugation, GS-MQ forms an intracellular drug reservoir that increases availability of MQ for targeting mutant p53. Our study shows that redox homeostasis is a critical determinant of the response to mutant p53-targeted cancer therapy., (© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)

Published
2021
Full Text
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