Targeting PKM2-InsP3R interaction to treat AML

靶向 PKM2-InsP3R 相互作用来治疗 AML

• 批准号: 9104123
• 负责人: CLARK W DISTELHORST
• 金额: $ 22.23万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-02 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9104123
• 关键词: ATP Synthesis Pathway; Acute Myelocytic Leukemia; Acute leukemia; Address; Affect; Animal Model; Apoptosis; Autophagocytosis; Binding; Binding Sites; Biological Assay; Biological Markers; Bone Marrow; Ca(2+)-Transporting ATPase; Cell Death; Cell Death Induction; Cell Extracts; Cell Line; Cell Proliferation; Cell Survival; Cells; Cessation of life; Development; Doctor of Philosophy; Endoplasmic Reticulum; Enzymes; Goals; Health; Hematologic Neoplasms; Hematopoietic; Homeostasis; Human; Image; Inositol; Investigation; Ions; Laboratories; Lead; Link; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Measures; Mediating; Metabolic; Methods; Mitochondria; Modeling; Morbidity - disease rate; Necrosis; Normal Cell; Patients; Pattern; Peptides; Play; Process; Protein Isoforms; Proteomics; Pump; Pyruvate Kinase; Reporting; Research; Research Personnel; Research Proposals; Respiration; Role; Sampling; Signal Transduction; Sum; Testing; Therapeutic; Time; Treatment Efficacy; Work; age group; base; cancer cell; cancer type; chemotherapeutic agent; digital imaging; efficacy testing; experience; human disease; inhibitor/antagonist; insight; interest; killings; leukemia; leukemia treatment; mortality; mouse model; new therapeutic target; novel; novel strategies; novel therapeutic intervention; pre-clinical; preclinical study; protein protein interaction; receptor; research study; response; skills; synthetic peptide; targeted treatment; theories; treatment strategy; tumor metabolism; uptake

 DESCRIPTION (provided by applicant): Acute myelogenous leukemia (AML) is the most common acute leukemia. It occurs in all age groups and produces considerable morbidity and mortality. Advances in treating AML are much less than experienced in other hematologic malignancies. Therefore, we are in desperate need of novel therapeutic approaches for AML. This proposal initiates investigation into a completely novel targeted therapeutic approach for AML, based on our recent discovery that the cancer-related M2 isoform of the ATP-producing enzyme pyruvate kinase (PKM2) interacts with the inositol 1,4,5-trisphosphate receptor (InsP3R), an InsP3-gated Ca2+ channel located on the endoplasmic reticulum (ER). Our theory is that this interaction generates compartmentalized glycolytic ATP synthesis that supports ER Ca2+ uptake via ER-associated Ca2+-ATPase pumps and regulates InsP3R-mediated Ca2+ release from the ER. To test this theory we developed a peptide inhibitor of PKM2-InsP3R interaction, which we refer to as PKM2- DP (PKM2-Displacing Peptide). We find that treating AML cell lines and primary AML cells from patient samples with TAT-PKM2-DP causes high amplitude sustained Ca2+ elevation, inducing cell death. This observation indicates that PKM2-InsP3R interaction supports AML cell survival, suggesting that PKM2- InsP3R interaction may be an effective target for AML treatment. Therefore, this proposal will further elucidate the pro-survival function of PKM2-InsP3R interaction and initiate pre-clinical studies using an orthotopic mouse model of human AML to test the therapeutic efficacy of targeting PKM2-InsP3R interaction for AML treatment. In sum, research outlined in this proposal will both generate novel insight into the role of PKM2 in cancer and lead to development of a new therapeutic approach for AML that may also extend to other malignancies.

 描述（由申请人提供）：急性髓性白血病（AML）是最常见的急性白血病。它发生在所有年龄组，并产生相当大的发病率和死亡率。治疗AML的进展远低于其他血液恶性肿瘤。因此，我们迫切需要新的AML治疗方法。该提案启动了对AML的全新靶向治疗方法的研究，该研究基于我们最近发现的癌症相关的ATP产生酶丙酮酸激酶（PKM 2）的M2亚型与位于内质网（ER）上的肌醇1，4，5-三磷酸受体（InsP 3R）相互作用。我们的理论是，这种相互作用产生区室化的糖酵解ATP合成，通过ER相关的Ca 2 +-ATP酶泵支持ER Ca 2+摄取，并调节InsP 3R介导的Ca 2+从ER释放。为了测试这一理论，我们开发了PKM 2-InsP 3R相互作用的肽抑制剂，我们将其称为PKM 2- DP（PKM 2-置换肽）。我们发现用TAT-PKM 2-DP处理来自患者样品的AML细胞系和原代AML细胞引起高幅度持续的Ca 2+升高，诱导细胞死亡。这一观察结果表明PKM 2-InsP 3R相互作用支持AML细胞存活，表明PKM 2-InsP 3R相互作用可能是AML治疗的有效靶标。因此，该提案将进一步阐明PKM 2-InsP 3R相互作用的促生存功能，并使用人AML的原位小鼠模型启动临床前研究，以测试靶向PKM 2-InsP 3R相互作用用于AML治疗的治疗功效。总之，本提案中概述的研究将对PKM 2在癌症中的作用产生新的见解，并导致开发一种新的AML治疗方法，该方法也可能扩展到其他恶性肿瘤。