Abstract 4560: Targeting chronic lymphocytic leukemia with p53 deficiency with phenethyl isothiocyanate

Abstract Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the United States and Europe. Despite recent advance in new therapeutic agents that have improved treatment outcomes, CLL remains incurable. CLL patients with loss of p53 due to unfavorable cytogenetic alterations such as chromosome 17p deletion often exhibit more malignant disease phenotype, are resistant to many standard therapeutic agents, and have poor clinical outcomes. Thus, finding effective treatment for CLL with p53 deficiency represents a significant challenge, and development new agents and therapeutic strategies to effectively kill CLL cells with loss of p53 function would have profound clinical implications in CLL treatment. We have recently created a mouse model with Tcl1-Tg:p53-/- genotype that resembles the aggressive human CLL disease with p53 deficiency (17p-deletion). We showed that leukemia cells isolated from this mouse model as well as primary human leukemia cells with 17p deletion isolated from CLL patients are resistant to standard anti-CLL agents. Because p53 plays important roles in regulation of apoptosis and in maintaining mitochondrial function/normal metabolism/redox homeostasis, we hypothesized that a loss of p53 function in CLL with 17p- or p53 mutations would on one hand lead to drug resistance and poor therapeutic response to conventional treatment, and would on the other hand also cause mitochondrial dysfunction and high ROS stress. Our study tested the possibility to use the high oxidative stress as a biochemical basis to effectively target the drug-resistant CLL cells with p53 deletion using redox-modulating strategy in vitro and in vivo. Our results showed that ROS-mediating strategies could overcome drug resistance of CLL cells with p53 deficiency, and was able to effectively eliminate fludarabine-resistant CLL cells using phenethyl isothiocyanate (PEITC), which induced rapid glutathione depletion and caused severe ROS accumulation leading to massive death of CLL cells in culture. Importantly, PEITC also exhibited promising in vivo therapeutic activity in the CLL mouse model as a single agent, leading to a significant prolongation of the mouse survival time. Since PEITC is a natural compound found in vegetables with very low toxicity to normal cells, the results of this study may have important therapeutic implications. Our study suggests that PEITC may potentially be used for clinical treatment of CLL with 17p deletion and improve the outcome of this subpopulation of CLL patients, who would otherwise refractory to standard therapeutics. Citation Format: Jinyun Liu, Gang Chen, Helen Pelicano. Targeting chronic lymphocytic leukemia with p53 deficiency with phenethyl isothiocyanate. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4560. doi:10.1158/1538-7445.AM2015-4560