Pre-Clinical Studies of PEITC as a Novel Agent for Treatment of CLL
Peng Huang, M.D., Ph.D.
University of Texas M. D. Anderson Cancer Center
Abstract:
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the United States and Europe. Although significant progress has been made in clinical treatment of this disease, many CLL cells, especially those with certain genetic abnormalities, are resistant to the currently available chemotherapeutic agents such as fludarabine and cyclophosphamide. This imposes a major challenge in clinical treatment of CLL, and underscores the urgent need to identify and develop new agents for effective treatment of refractory CLL. The main goal of this study is to test the therapeutic potential of a natural compound known as β-phenethyl isothiocyanate (PEITC) for treatment of CLL. Our previous studies showed that CLL cells isolated from patients, especially those in advanced disease stages, exhibit increased stress of reactive oxygen species (ROS) and are vulnerable to compounds that cause further ROS accumulation in the cells.
More recent work further showed that PEITC preferentially kills malignant cells with ROS stress through a ROS-mediated mechanism. Based on these observations, we propose to test the hypothesis that the increase in ROS generation in CLL cells may renders them highly sensitive to PEITC, whereas normal lymphocytes with low ROS output are less vulnerable to this compound, which can be developed as an effective and selective agent for treatment of CLL, especially for those in advance disease stage and resistant to other drugs. Specifically, we will compare the cytotoxic activity of PEITC in CLL cells that are either sensitive or resistant to fludarabine, and test the possibility that primary CLL cells from patients in advanced stages refractory to fludarabine-based therapy still remain highly sensitive to PEITC due to their increased ROS generation.
The cause-effect relationship between ROS stress and drug sensitivity will be examined. We will also develop mechanism-based drug combination strategies to enhance the therapeutic activity of PEITC against CLL cells. The main purpose is to identify proper agents for combination with PEITC to obtain optimal activity. The therapeutic activity of PEITC, alone or in combination with other drugs, will be further evaluated in an animal model that mimic human CLL disease. We anticipate that this study will provide important information on the in vitro and in vivo activity of PEICT against CLL, and serve as a basis for the future design of clinical trials to use PEITC for treatment of CLL patients.