Our work on this grant is based on the hypothesis that malignant cells have retained the capacity to undergo terminal differentiation and that therapeutic agents can be developed to effectively induce that response. Our initial studies with phorbol esters and other activators of protein kinase C (PKC) demonstrated the importance of reactive oxygen species (ROS) in induction of the terminally differentiated myeloid phenotype. The clinical development of PKC activators has been limited by toxicity. In this regard, we showed that the CDDO triterpenoids also increase ROS and thereby induce differentiation and apoptosis of malignant cells. We are completing a Phase I trial of the CDDO C-28 methyl ester (CDDO-Me) and will be performing Phase II trials of this agent for patients with hematologic malignancies. What is needed now, at least in part, is a better understanding of how CDDO-Me disrupts redox balance and induces terminal differentiation in the laboratory and in patients receiving this agent. Our preliminary data indicate that CDDO-Me downregulates the Nrf2 transcription factor and thereby increases ROS by decreasing enzymatic effectors of the major antioxidant systems. In turn, inhibition of thioredoxin activates ASK1, an upstream effector of the JNK and p38 MAPK pathways. Our preliminary data also indicate that CDDO-Me induces sustained activation of JNK and p38 MAPK by oxidation of other effectors that regulate these pathways. Our hypothesis is that the sustained activation of JNK/p38 MAPK is responsible for integrating differentiation with apoptosis through a c-Abl- and caspase-8-dependent pathway. Other work has indicated that the MUC1 oncoprotein, which is aberrantly expressed by diverse hematologic malignancies, blocks ROS-induced differentiation and death. Consequently, our hypothesis is that a better understanding of how MUC1 affects CDDO-Me-induced signaling will be of importance to the clinical development of these agents.
The Specific Aims are: 1) To define the mechanisms responsible for CDDO-Me-induced disruption of redox balance;2) To assess the effects of CDDO-Me-induced disruption of redox balance on regulation of the JNK, p38 MAPK and STAT3 signaling pathways;3) To define the signaling pathways that regulate CDDO-Me- induced differentiation and apoptosis;4) To determine whether CDDO-Me-induced terminal differentiation is attenuated by the MUC1 oncoprotein;and 5) To assess the pharmacodynamic and biologic effects of CDDO- Me in Phase II trials for the treatment of patients with hematologic malignancies.
Hematologic malignancies, such as myeloid leukemia and multiple myeloma, are incurable in most patients. Our research on terminal differentiation of malignant hematopoietic cells has provided new insights for the treatment of these diseases. The proposed work will expand our understanding of how agents that disrupt redox balance induce terminal differentiation in the laboratory and in patients on clinical trials.
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