Non-genotoxic p53 activation as novel therapeutic concept for lymphoma

非基因毒性 p53 激活作为淋巴瘤的新治疗概念

基本信息

  • 批准号:
    7715218
  • 负责人:
  • 金额:
    $ 6.8万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-09-01 至 2012-08-31
  • 项目状态:
    已结题

项目摘要

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.
本项目的主要目标是改善淋巴瘤的治疗效果和治愈率

项目成果

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MICHAEL ANDREEFF其他文献

MICHAEL ANDREEFF的其他文献

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{{ truncateString('MICHAEL ANDREEFF', 18)}}的其他基金

Therapeutic targeting of p53 reactivation-induced OXPHOS dependency and stress responses to overcome resistance to venetoclax/HMA in AML
治疗靶向 p53 重新激活诱导的 OXPHOS 依赖性和应激反应,以克服 AML 中对 Venetoclax/HMA 的耐药性
  • 批准号:
    10356325
  • 财政年份:
    2022
  • 资助金额:
    $ 6.8万
  • 项目类别:
Therapeutic targeting of p53 reactivation-induced OXPHOS dependency and stress responses to overcome resistance to venetoclax/HMA in AML
治疗靶向 p53 重新激活诱导的 OXPHOS 依赖性和应激反应,以克服 AML 中对 Venetoclax/HMA 的耐药性
  • 批准号:
    10550265
  • 财政年份:
    2022
  • 资助金额:
    $ 6.8万
  • 项目类别:
Ph1/2 Study of the Imipridone ONC201 for Treatment of AML IND125,203 (12/23/2014)
咪啶酮 ONC201 治疗 AML IND125,203 的 Ph1/2 研究 (12/23/2014)
  • 批准号:
    10663157
  • 财政年份:
    2019
  • 资助金额:
    $ 6.8万
  • 项目类别:
Ph1/2 Study of the Imipridone ONC201 for Treatment of AML IND125,203 (12/23/2014)
咪啶酮 ONC201 治疗 AML IND125,203 的 Ph1/2 研究 (12/23/2014)
  • 批准号:
    9806956
  • 财政年份:
    2019
  • 资助金额:
    $ 6.8万
  • 项目类别:
P53 Activation as Novel Therapeutic Strategy for Acute Myelogenous Leukemia
P53 激活作为急性髓性白血病的新治疗策略
  • 批准号:
    8499746
  • 财政年份:
    2013
  • 资助金额:
    $ 6.8万
  • 项目类别:
Combined inhibition of CXCR4 and FLT3-ITD signaling in acute myeloid leukemia
联合抑制急性髓系白血病中的 CXCR4 和 FLT3-ITD 信号传导
  • 批准号:
    7897533
  • 财政年份:
    2010
  • 资助金额:
    $ 6.8万
  • 项目类别:
Combined inhibition of CXCR4 and FLT3-ITD signaling in acute myeloid leukemia
联合抑制急性髓系白血病中的 CXCR4 和 FLT3-ITD 信号传导
  • 批准号:
    8056055
  • 财政年份:
    2010
  • 资助金额:
    $ 6.8万
  • 项目类别:
Targeting Microenvironment / Leukemia Cell Interactions in CML
CML 中的靶向微环境/白血病细胞相互作用
  • 批准号:
    8000073
  • 财政年份:
    2010
  • 资助金额:
    $ 6.8万
  • 项目类别:
Plerixafor/G-CSF with Sorafenib for Acute Myelogenous Leukemia with FLT3-ITD Muta
Plerixafor/G-CSF 联合索拉非尼治疗带有 FLT3-ITD Muta 的急性髓性白血病
  • 批准号:
    7936811
  • 财政年份:
    2009
  • 资助金额:
    $ 6.8万
  • 项目类别:
Plerixafor/G-CSF with Sorafenib for Acute Myelogenous Leukemia with FLT3-ITD Muta
Plerixafor/G-CSF 联合索拉非尼治疗带有 FLT3-ITD Muta 的急性髓性白血病
  • 批准号:
    8324135
  • 财政年份:
    2009
  • 资助金额:
    $ 6.8万
  • 项目类别:

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急性粒细胞白血病白血病干细胞动力学的计算分析
  • 批准号:
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  • 批准号:
    3556971
  • 财政年份:
    1980
  • 资助金额:
    $ 6.8万
  • 项目类别:
DETERMINANTS OF RESPONSE OF ACUTE MYELOCYTIC LEUKEMIA
急性粒细胞白血病反应的决定因素
  • 批准号:
    3556968
  • 财政年份:
    1980
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ERADICATION OF ACUTE MYELOCYTIC LEUKEMIA CELLS BY MAB THERAPY
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