2-chloro-n(6)-(3-iodobenzyl)adenosine-5--n-methyluronamide and Carcinoma--Hepatocellular

The A(3) adenosine receptor (A(3)AR) is overexpressed in the tumor and in the peripheral blood mononuclear cells of patients with hepatocellular carcinoma (HCC). The orally active drug candidate CF102, an A(3)AR agonist, induces apoptosis of HCC cells via deregulation of the Wnt signaling pathway. In this open label phase I/II trial, the safety and clinical effects of CF102 were assessed in patients with advanced unresectable HCC.. The primary objectives of this trial were to examine the safety and pharmacokinetic (PK) behavior of CF102 given orally (1, 5, and 25 mg BID) in 28-day cycles. Evaluation of anti-tumor effects and the utilization of A(3)AR as a biological predictive marker of response to CF102 were the secondary objectives.. Eighteen patients received CF102-six at each dose level. No serious drug-related adverse events or dose-limiting toxicities were observed. CF102 demonstrated good oral bioavailability and linear PK behavior. Median overall survival in the study population, 67% of whom had received prior sorafenib, was 7.8 months, and for Child Pugh B patients (28%) it was 8.1 months. Stable disease by RECIST was observed in four patients for at least 4 months. CF102 maintained liver function over a 6-month period. A correlation between receptor overexpression levels at baseline and patients' overall survival was found. One of the patients who presented with skin nodules that were biopsy-proven to be HCC metastases prior to the trial showed complete metastasis regression during three months of treatment with CF102.. CF102 is safe and well-tolerated, showing favorable PK characteristics in Child Pugh A and B HCC patients, justifying further clinical development.

Topics: Adenosine; Adult; Aged; Apoptosis; Carcinoma, Hepatocellular; Child; Female; Humans; Leukocytes, Mononuclear; Liver Neoplasms; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Purinergic P1 Receptor Agonists; Receptor, Adenosine A3; Sorafenib; Wnt Signaling Pathway

The A3 adenosine receptor (A(3)AR) is highly expressed in tumors and was suggested as a target for cancer treatment. In this study, we show that A(3)AR is highly expressed in tumor tissues and in peripheral blood mononuclear cells (PBMCs) derived from patients with HCC, as well as from HCC tumor-bearing rats. The high expression level of the receptor was directly correlated to overexpression of NF-kappaB, known as a transcription factor of A(3)AR. CF102, a synthetic highly selective agonist to A(3)AR induced a marked dose response inhibition of tumor growth in N1S1 HCC tumor rats, via de-regulation of the NF-kappaB and the Wnt signal transduction pathways, resulting in apoptosis of tumor cells. Taken together, A(3)AR is highly expressed in tumors and PBMCs of HCC patients and tumor-bearing rats. CF102 induced apoptosis and tumor growth inhibition. These data suggest A(3)AR as a novel targeted therapy to treat HCC.

Topics: Adenosine; Adenosine A3 Receptor Agonists; Adult; Aged; Aged, 80 and over; Animals; Apoptosis; Blotting, Western; Carcinoma, Hepatocellular; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Liver Neoplasms; Male; Middle Aged; NF-kappa B; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A3; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Wnt Proteins