Abstract B59: Preliminary clinical experiences of Phortress: Putative role for c-MET inhibition in antitumor activity

Abstract

Abstract Experimental antitumor agent Phortress elicits selective activity in vitro and in vivo in human breast, ovarian and renal carcinoma models via a novel mechanism(s) of action. Prodrug Phortress [2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203) lysylamide dihydrochloride] liberates 5F 203 in the presence of cancer cells in vitro, and in plasma in vivo. 5F 203 is a potent aryl hydrocarbon receptor (AhR) ligand, resulting in induction of cyp1a1 transcription. CYP1A1-catalyzed biotransformation of 5F 203 to electrophilic species in sensitive tumor cells leads to cell death. Preclinical toxicokinetic studies in two rodent species led to a clinical starting dose of 3 mg/m2 Phortress. Three and six patients have received 3 mg/m2 and 4.25 mg/m2 Phortress respectively, by intravenous injection over a 15 minute period on day 1 of consecutive 21 day cycles. Phortress was generally well tolerated. Drug-related adverse reactions include fatigue and headache/arthralgia. In four patients, indications of stable disease have been achieved. One patient with colorectal carcinoma received nine 3 mg/m2 cycles before fatigue led to withdrawal. A mesothelioma patient received twelve 3 mg/m2 cycles; treatment was stopped after lung function tests revealed decreased TLco associated with disease progression. Two patients with renal cell carcinoma received four and sixteen 4.25 mg/m2 Phortress cycles before progressive disease led to withdrawal from trial. Germline and somatic mutations in the MET oncogene encoding transmembrane hepatocyte growth factor receptor tyrosine kinase (HGFTK) are thought to play a key role in the pathophysiology of hereditary and sporadic renal cell carcinoma (RCC). Indeed, aberrant MET activation has been detected in many carcinomas including breast, ovary, gastric and metastatic colon, promoting aggressive invasive growth through stimulation of cell migration, and inhibition of apoptosis. MET-dependent signaling includes the Ras-Raf-Mek-Erk and PI3K-Akt cascades. Downregulation (85% and 69%) of MET (HGFTK) activity has been observed in protein isolated from MCF-7 and MDA 468 breast cancer cells treated for 24 h with 1 M 5F 203; downstream of MET, inhibition of Erk, MapK, Mek kinase activity was observed. Samples were subjected to antibody microarray which tracked phosphorylation status of cell signalling proteins that regulate cell proliferation, stress and apoptosis. In scratch wound assays, 5F 203 (0.1 M) impeded renal TK10 as well as MCF-7 and MDA 468 cell motility. Inhibition of MET signaling may afford an important 5F 203 target. Further translational research will more comprehensively elucidate mechanisms of action of Phortress. Such studies may ultimately guide patient selection and predict tumor response. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B59.