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Targeting p53 in Vivo: A First-in-Human Study With p53-Targeting Compound APR-246 in Refractory Hematologic Malignancies and Prostate Cancer
Open accessAbstract
Purpose: APR-246 (PRIMA-1MET) is a novel drug that restores transcriptional activity of unfolded wild-type or mutant p53. The main aims of this first-in-human trial were to determine maximum-tolerated dose (MTD), safety, dose-limiting toxicities (DLTs), and pharmacokinetics (PK) of APR-246. Patients and Methods: APR-246 was administered as a 2-hour intravenous infusion once per day for 4 consecutive days in 22 patients with hematologic malignancies and prostate cancer. Acute myeloid leukemia (AML; n = 7) and prostate cancer (n = 7) were the most frequent diagnoses. Starting dose was 2 mg/kg with dose escalations up to 90 mg/kg. Results: MTD was defined as 60 mg/kg. The drug was well tolerated, and the most common adverse effects were fatigue, dizziness, headache, and confusion. DLTs were increased ALT/AST (n = 1), dizziness, confusion, and sensory disturbances (n = 2). PK showed little interindividual variation and were neither dose nor time dependent; terminal half-life was 4 to 5 hours. Tumor cells showed cell cycle arrest, increased apoptosis, and upregulation of p53 target genes in several patients. Global gene expression analysis revealed changes in genes regulating proliferation and cell death. One patient with AML who had a p53 core domain mutation showed a reduction of blast percentage from 46% to 26% in the bone marrow, and one patient with non-Hodgkin's lymphoma with a p53 splice site mutation showed a minor response. Conclusion: We conclude that APR-246 is safe at predicted therapeutic plasma levels, shows a favorable pharmacokinetic profile, and can induce p53-dependent biologic effects in tumor cells in vivo.
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“Adverse events were similar to those reported for azacitidine or eprenetapopt monotherapy, with the most common grade ≥ 3 adverse events being febrile neutropenia (33%), leukopenia (29%), and neutropenia (29%).”
From Eprenetapopt (APR-246) and Azacitidine in TP53 -Mutant Myelodysplastic Syndromes (2021) · cites this paper as [25]
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“In a phase I study including patients with AML, eprenetapopt monotherapy demonstrated clinical activity with corresponding activation of p53-dependent pathways.25,26”
From Eprenetapopt (APR-246) and Azacitidine in TP53 -Mutant Myelodysplastic Syndromes (2021) · cites this paper as [25]
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2 retracted
Erratum: PRIMA-1Met induces mitochondrial apoptosis through activation of caspase-2
Shen, J., Vakifahmetoglu, H., Stridh, H., Zhivotovsky, B., & Wiman, K. G. (2016) · Oncogene · doi:10.1038/onc.2016.210 · Cited by 54
Self-citationRetractedPRIMA-1MET induces mitochondrial apoptosis through activation of caspase-2
Shen, J., Vakifahmetoglu, H., Stridh, H., Zhivotovsky, B., & Wiman, K. G. (2008) · Oncogene · doi:10.1038/onc.2008.249 · Cited by 52
Self-citationRetractedTumor suppressor p53 is a direct transcriptional activator of the human bax gene
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Blinded by the Light: The Growing Complexity of p53
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Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas
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Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound
Bykov, V. J. N., Issaeva, N., Shilov, A., Hultcrantz, M., Pugacheva, E., Chumakov, P., Bergman, J., Wiman, K. G., & Selivanova, G. (2002) · Nature Medicine · doi:10.1038/nm0302-282 · Cited by 1,067
Self-citationAwakening guardian angels: drugging the p53 pathway
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PRIMA-1 reactivates mutant p53 by covalent binding to the core domain
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Self-citationTranslating p53 into the clinic
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Shaping Genetic Alterations in Human Cancer: The p53 Mutation Paradigm
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Self-citationPharmacologic activation of p53 elicits Bax-dependent apoptosis in the absence of transcription
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PRIMA-1MET synergizes with cisplatin to induce tumor cell apoptosis
Bykov, V. J. N., Zache, N., Stridh, H., Westman, J., Bergman, J., Selivanova, G., & Wiman, K. G. (2005) · Oncogene · doi:10.1038/sj.onc.1208419 · Cited by 252
Self-citationApoptotic volume decrease and the incredible shrinking cell
Bortner, C. D., & Cidlowski, J. A. (2002) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401126 · Cited by 237
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Self-citationAli, D., Jönsson‐Videsäter, K., Deneberg, S., Bengtzén, S., Nahi, H., Paul, C., & Lehmann, S. (2010) · European Journal Of Haematology · doi:10.1111/j.1600-0609.2010.01557.x · Cited by 70
Self-citationPRIMA‐1 induces apoptosis in acute myeloid leukaemia cells with p53 gene deletion
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Self-citationEffects of PRIMA‐1 on chronic lymphocytic leukaemia cells with and without hemizygous p53 deletion
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Self-citationMutated and non‐mutated TP53 as targets in the treatment of leukaemia
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PRIMA-1 induces apoptosis by inhibiting JNK signaling but promoting the activation of Bax
Wang, T., Lee, K., Rehman, A., & Daoud, S. S. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.11.006 · Cited by 41
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Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer
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mCSM: Predicting the effects of mutations in proteins using graph-based signatures
Pires, D. E. V., Ascher, D. B., & Blundell, T. L. (2014) · Bioinformatics · doi:10.1093/bioinformatics/btt691 · Cited by 1,066
Targeting p53 pathways: mechanisms, structures, and advances in therapy
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Targeting mutant p53 for efficient cancer therapy
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Metadata
- Authors
- Lehmann, S., Bykov, V. J. N., Ali, D., Andrén, O., Cherif, H., Tidefelt, U., Uggla, B., Yachnin, J., Juliusson, G., Moshfegh, A., Paul, C., Wiman, K. G., & Andersson, P.-O.
- Affiliations
- Karolinska University Hospital (SE)
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2012-10-10
- Volume
- 30
- Issue
- 29
- Pages
- 3633-3639
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2142765738
- Cited by
- 406
- References
- 21
- Citations by year
- 2026: 8 · 2025: 20 · 2024: 14 · 2023: 27 · 2022: 27 · 2021: 42 · 2020: 38 · 2019: 43 · 2018: 38 · 2017: 30 · 2016: 36 · 2015: 26 · 2014: 37 · 2013: 17 · 2012: 2
- FWCI
- 12.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- APR-246, PRIMA-1MET, p53 reactivation, mutant p53, acute myeloid leukemia, non-Hodgkin lymphoma, prostate cancer, hematologic malignancies, maximum tolerated dose, dose-limiting toxicity, pharmacokinetics, cell cycle arrest, apoptosis, global gene expression
- MeSH terms
- Aged, Aged, 80 and over, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Humans, Infusions, Intravenous, Male, Middle Aged, Pharmacogenetics, Prospective Studies, Prostatic Neoplasms, Quinuclidines, Risk Factors, Sensitivity and Specificity, Tumor Cells, Cultured, Genes, p53, Treatment Outcome, Hematologic Neoplasms, Maximum Tolerated Dose, Molecular Targeted Therapy, Patient Safety
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