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Therapeutic resistance in leukemic cells: targeting BCL-2 family and autophagy

白血病细胞的治疗耐药：针对 BCL-2 家族和自噬

基本信息

批准号：
9763510
负责人：
Alexandru Almasan
金额：
$ 35.17万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
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：
2015-09-25 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9763510
关键词：
Address Amino Acids Apoptosis Apoptosis Regulation Gene Apoptotic Autophagocytosis B-Cell Leukemia B-Lymphocytes BCL1 Oncogene BCL2L11 gene Biological Biological Markers Biology Blood Platelets Cancer Patient Cell Death Cell Line Cell Survival Cell membrane Cells Chronic Lymphocytic Leukemia Clinic Clinical Coculture Techniques Combined Modality Therapy Data Development Drug Combinations Drug resistance Epigenetic Process Family Foundations Future Gene Expression Gene Family Glucose Impairment Intervention Knowledge Leukemic Cell MCL1 gene Malignant Neoplasms Malignant lymphoid neoplasm Mediating Methylation Molecular Oral Pathology Pathway interactions Patients Pharmacology Phosphorylation Post-Translational Protein Processing Process Prodrugs Protein Family Proteins Publishing Reagent Receptors, Antigen, B-Cell Regulation Resistance Resistance development Role Signal Pathway Signal Transduction Starvation Stromal Cells Suspensions Testing Therapeutic Therapeutic Agents Therapeutic Intervention Thrombocytopenia Time Toxic effect base chemotherapy clinical development clinically relevant clinically significant cohort drug development epigenetic regulation experimental study fludarabine genetic approach in vivo indexing individualized medicine innovation interest leukemia leukemia/lymphoma lymphoid neoplasm mimetics neoplastic cell new therapeutic target next generation sequencing novel predict clinical outcome predicting response prevent protein complex public health relevance research clinical testing resistance mechanism response small molecule inhibitor success targeted agent targeted treatment therapeutic target therapy outcome therapy resistant transcriptome treatment response tumor tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): Chronic lymphocytic leukemia (CLL) is heterogeneous clinically, reflecting functional alterations in multiple pathways, including apoptotic and B cell signaling. Novel targeted agents in late-stage development include PI3K and pro-apoptotic B cell leukemia/lymphoma 2 (BCL-2) homology 3 (BH3) mimetics. We have a long- standing interest in understanding the fundamental mechanisms for the response and resistance to BH3 mimetics and active agents, such as fludarabine. We have identified several determinants with biologic and clinical significance in the apoptotic response and resistance to these therapeutics, with the BCL-2 family proteins emerging as key regulators of cellular survival. We will address two critical therapy resistance mechanisms: impaired apoptosis and autophagy, processes in which the anti-apoptotic BCL-2 family is crucial, as supported by our published and preliminary data. We have developed an apoptotic index based on BCL-2 family gene expression that defines sensitivity to ABT-737 in CLL and have generated and characterized ABT- 737 and ABT-199-resistant cell lines. Increased MCL-1 expression in resistant cells was critical to preventing cell death, with the excess MCL-1 being associated with the BH3-only protein, BIM, or key autophagy regulators Beclin 1 and Beclin 2, which also contain a BH3 domain. ABT-199-resistant cells also developed high BCL-xL expression that is regulated epigenetically through miR377. Both miR377 and BCL-xL expression predicted clinical outcome in CLL and thus can provide new targets for intervention as well as biomarkers for therapy. Therapy-resistant cells were addicted to high basal autophagy that depended on Beclin 2, instead of Beclin 1, and AMPK, and surprisingly, also had high mTORC1 activity. Our central hypothesis is that responsiveness and resistance to CLL therapeutics are governed by the BCL-2 family proteins that regulate apoptosis and autophagy. We will perform experiments with leukemia cell lines and primary CLL patient cells after clinical therapy with ABT-199, cultured ex vivo in suspension or on stromal cells to mimic their interaction with their in vivo microenvironment. Our specific aims are: 1) To define the role of BCL-xL and MCL-1 in resistance to and sensitization to BH3 mimetics, 2) To define autophagy as a mechanism of resistance, and 3) To lay the foundations for optimizing the use of BCL-2 targeting agents by integrating gene expression data obtained from cell lines with that from patients treated in the clinic or ex vivo. Our likelihood of success is enhanced by the expertise of the PI in the BCL-2 family biology, apoptosis, and autophagy, M. Smith, B. Hill (Co-I) in CLL and lymphoid malignancies, E. Hsi (Co-I) in pathology, and A. Ting (Consultant) in methylation and next-generation sequencing. Understanding the critical BCL-2 family protein associations according to differing cell sensitivities will allow development of molecular and pharmacologic approaches for their effective targeting. By characterizing apoptotic and autophagy pathways in lymphoid malignancies, we seek to ultimately use them to predict response and thus personalize the selection of targeted therapeutic agents.