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Targeting PKM2-InsP3R interaction to treat AML

靶向 PKM2-InsP3R 相互作用来治疗 AML

基本信息

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
项目类别：
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

项目摘要

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.