Targeting p53 in Vivo: A First-in-Human Study With p53-Targeting Compound APR-246 in Refractory Hematologic Malignancies and Prostate Cancer

Department of Hematology, M54, Karolinska University Hospital, 141 86 Stockholm, Sweden
Journal of Clinical Oncology (Impact Factor: 18.43). 09/2012; 30(29):3633-9. DOI: 10.1200/JCO.2011.40.7783
Source: PubMed


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.

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.

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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    • "PRIMA-1 was also shown to synergize with various chemotherapeutic agents to induce cancer cell death [77–79]. Due to its promising anticancer properties, PRIMA-1Met/APR246, a more potent derivative of the first generation drug, was developed and is currently in phase I/II clinical trials [80]. "
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    ABSTRACT: p53 abnormalities are regarded as an independent prognostic marker in multiple myeloma. Patients harbouring this genetic anomaly are commonly resistant to standard therapy. Thus, various p53 reactivating agents have been developed in order to restore its tumour suppressive abilities. Small molecular compounds, especially, have gained popularity in its efficacy against myeloma cells. For instance, promising preclinical results have steered both nutlin-3 and PRIMA-1 into phase I/II clinical trials. This review summarizes different modes of p53 inactivation in myeloma and highlights the current p53-based therapies that are being utilized in the clinic. Finally, we discuss the potential and promise that the novel small molecules possess for clinical application in improving the treatment outcome of myeloma.
    BioMed Research International 06/2014; 2014(4985):717919. DOI:10.1155/2014/717919 · 2.71 Impact Factor
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    • "Molecules that can reactivate cell death in p53-mutant cells in a p53-dependent manner have been selected based on their ability to either kill the cells (phenotypic screening) or bind to the mutated p53 protein and restore a functional p53 conformation (biochemical screening) [11,12]. Thus, several molecules, such as PRIMA, RITA and CP-31398, have been selected and will be evaluated in clinical trials [11-15]. RITA (Reactivating p53 and inducing tumor apoptosis) was isolated from a chemical library by its ability to kill the HCT116 cell line and spare its variant, HCT116 TP53-/-, that lacked p53 expression [16]. "
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    • "Three of twelve analyzed samples had p53 gene mutations with the remaining samples having wild-type status. The increase in p53 activity did not appear to correlate with p53 mutational status and further assessment of APR-246 needs to be made to assess its ability as a mutant reactivator [87]. "
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