Non-genotoxic p53 activation as novel therapeutic concept for lymphoma

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The primary goal of this project is to improve treatment outcome and the cure rate of lymphoma, by introducing novel therapeutic strategies. The main therapeutic challenge in the treatment of lymphomas is the development of strategies that maximize the induction of lymphoma cell apoptosis before resistance to chemotherapy develops. p53 and Bcl-2 are the master switches that determine whether a stressed cell undergoes apoptosis, thus acting as tumor suppressors. We have recently reported that restoration of p53 activity by inhibiting the HDM2/p53 interaction utilizing non-genotoxic small molecule inhibitors (Nutlin 3a, Ml 63) induces apoptosis in CLL, lymphomas (Hodgkin's and Non-Hodgkin's), and in lymphoid and myeloid acute leukemias with unmutated p53. While these HDM2 inhibitors dramatically increase p53 levels which in turn initiate transcription of p53 targets, transcription-independent direct interactions of p53 with Bcl-2 family members do also occur. We reported striking synergisms of HDM2 inhibitors with conventional chemotherapeutic agents such as fludarabine, cytarabine and daunorubicin, and with MAPK inhibitors, which we found to regulate the subcellular distribution of p53 and to inhibit induction of anti-apoptotic p21. Bcl-2 and some of its anti-apoptotic family members are overexpressed in lymphomas, including CLL, and are potential inhibitors of p53 activation-induced mitochondrial apoptotic signaling. We and others have reported that functional inhibition of Bcl-2 by BH3-mimetics (e.g. ABT-737) induces mitochondrial apoptosis and synergizes with chemotherapy. However, we reported that ABT-737 does not bind to Mcl-1. In leukemias, Mcl-1 can be completely downregulated by MAPK (pERK) inhibition, resulting in unprecedented synergism with ABT-737 in inducing apoptosis. In Aim 1 we propose to identify the molecular determinants of apoptosis induced by non-genotoxic small molecule inhibitors of HDM2 (Nufiin 3a, Ml 63) in CLL and lymphoma cell lines and primary CLL/SLL cells. In Aim 2 we will determine mechanisms by which HDM2 inhibifion synergizes with BH3 mimefics, MAPK inhibitors and chemotherapy, and in Aim 3 we will conduct the first-in-man Phase 1 trial of a HDM2 inhibitor (Nufiin 3a analog R05045337) in CLL/SLL. These studies will provide rationale for the development of novel therapeufic strategies in lymphomas based on the non- genotoxic disruption of protein-protein interactions resulfing in activation of p53 signaling and inhibition of Bcl-2 function. RELEVANCE (See Instructions): CLL Is a largely incurablo leukemia with increasing incidence and novel therapeutic concepts are urgently needed. In this proposal, we will take advantage of the recent discovery that p53 is rarely mutated in CLL, but frequently inactivated by over-expressed HDM2. We have demonstrated that disrupfion of the MDM2 / p53 complex by Nufiin results in the non-genotoxic activafion of p53 signaling and apoptosis in CLL . Beyond mechanisfic studies of p53 acfivafion and inhibition of the second major anfi-apoptotic gene (Bcl-2), we will conduct the first human trial of Nutlin in man, with the goal of evaluafing this novel therapeufic concept in CLL.