In cancer treatment, the key is to focus on cancer-specific targets and thereby reduce side effects. Along this line, we are interested in exploring the possibility of using certain anthraquinone analogs to target MDM2 and/or MDM4 for the development of cancer treatment options. This revised application is based on extensive preliminary results examining certain anthraquinone analogs, which specifically inhibit the interactions between MDM2 and MDM4 and thus increase the level of p53, which in turn results in apoptosis of cancer cells. Initial animal studies with an acute lymphoblastic leukemia (ALL) mouse model indicated cure at the 1-year point (the duration of the experiments) after only two weeks of treatment, while all mice without treatment died within 45 days as expected. Preliminary studies also suggest that the identified compounds show minimal or no toxicity to normal cells, and in animal studies including pathological studies of heart, kidney, and liver, presumably due to the fact that levels of MDM2 and MDM4 are only elevated in cancer, not normal cells. In this application, we plan to understand and validate the mechanism(s) and examine the feasibility of inhibiting MDM2-MDM4 interaction as a way to develop cancer therapeutics. We plan to use acute lymphoblastic leukemia (ALL) as a model because of our extensive experience in this area.
Specific Aims i nclude (1) study the structure-activity relationship (SAR) of the anthraquinone analogs with regard to their ability to induce apoptosis;(2) define the molecular mechanism(s) of action of anthraquinone analogs;and (3) further ascertain the potential of developing anthraquinone analogs as viable candidates for ALL treatment using animal models. Upon completion of the proposed work, we hope to have (1) fully demonstrated the feasibility of targeting MDM2-MDM4 interactions as a way to develop new anticancer agents;(2) defined the molecular mechanism and structure-activity relationship for this class of anthraquinones, (3) fully established animal models for further preclinical evaluation, and (4) possibly identified viable candidates for preclinical GLP/GMP work in preparation for future clinical studies.
|Zhang, Hailong; Gu, Lubing; Liu, Tao et al. (2014) Inhibition of MDM2 by nilotinib contributes to cytotoxicity in both Philadelphia-positive and negative acute lymphoblastic leukemia. PLoS One 9:e100960|