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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Available from: Klas G Wiman
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    • "These results indicate that fatostatin predominantly inhibited the SREBP metabolic pathways in PCa cells harboring mutant p53s. Reactivation of wild-type function in mutant p53 protein has been a major strategy for treating human cancer harboring mutant p53s such as small molecules, STIMA-1 [27] and APR-246 [28]. To determine the restoration of wtp53 by fatostatin, we performed qPCR analysis of wtp53 target genes [29, 30], including p21, p53R2, BAX and MDM2 in PC-3 R248W and DU145 cells. "
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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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    • "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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