A Targeted Combination Therapy Approach for AML

AML 的靶向联合治疗方法

• 批准号: 10047167
• 负责人: Dawn Elizabeth Barnes
• 金额: $ 15.6万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10047167
• 关键词: 3-Dimensional; ABCG2 gene; Acute Myelocytic Leukemia; Address; Adult; Adult Acute Myeloblastic Leukemia; Affinity; Apoptosis; Biomimetics; Blood; Bone Marrow; Bone Marrow Diseases; Cell Cycle Progression; Cell Death; Cell Density; Cell Line; Cells; Cellular Metabolic Process; Cessation of life; Chemotaxis; Childhood; Combined Modality Therapy; Cytotoxic Chemotherapy; Data; Development; Down-Regulation; Doxorubicin; Etoposide; Goals; Hematopoiesis; Homing; Human; In Vitro; Induction of Apoptosis; Integrins; Lead; Leukemic Cell; Leukocytes; Libraries; MERTK gene; Measures; Mediating; Mediator of activation protein; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Mus; Oncogenes; Pancytopenia; Patients; Phase I Clinical Trials; Pre-Clinical Model; Protein Kinase; Protein Tyrosine Kinase; Quality of life; ROCK1 gene; Receptor Protein-Tyrosine Kinases; Relapse; Resistance; Resistance development; Sampling; Signal Pathway; Spleen; Stream; Stromal Cells; Survival Rate; Testing; Therapeutic; Therapeutic Effect; Tissues; Toxic effect; Treatment Efficacy; Treatment Protocols; Work; Xenograft Model; Xenograft procedure; acute myeloid leukemia cell; burden of illness; chemokine; chemotherapy; drug efficacy; experimental study; fetal liver kinase-2; hematopoietic differentiation; improved; improved outcome; inhibitor/antagonist; innovation; kinase inhibitor; leukemia; leukemogenesis; metabolomics; molecular targeted therapies; mortality; mouse model; novel; older patient; outcome forecast; patient response; pediatric patients; pre-clinical; preclinical study; prevent; research clinical testing; response; rho; side effect; small hairpin RNA; small molecule; small molecule inhibitor; synergism; targeted treatment; therapeutic evaluation; therapeutic target; tumor

PROJECT SUMMARY/ ABSTRACT Treatment of acute myeloid leukemia (AML) has improved but five-year survival rates are still <60% for adult and pediatric patients. Current therapies are very toxic, can cause long-term side effects, and are often contraindicated for elderly patients. Our goal is to develop a molecularly-targeted therapy for AML with better efficacy and reduced toxicity. MERTK tyrosine kinase is ectopically expressed in >90% of pediatric and adult AML patient samples. MRX-2843 is a novel small molecule that inhibits MERTK and FLT3, a known therapeutic target in AML. MRX-2843 has robust activity in preclinical models and is currently in phase I clinical trials; however, the utility of molecularly-targeted monotherapies has been limited by development of resistance. Thus, we sought to identify signaling pathways that synergize with MRX-2843 to inhibit leukemia cell expansion. Using a kinase inhibitor library screen, we found synergistic interactions between MRX-2843 and RKI-1447, an inhibitor of rho-associated protein kinases (ROCK1 and ROCK2). ROCK1 down-regulation reduces leukocyte affinity for chemokines in the protective bone marrow niche and ROCK inhibition reduces expansion of AML blasts in patient sample cultures, induces AML cell death, and prolongs survival in murine AML models. MRX-2843/RKI-1447 combination therapy synergistically reduced AML cell expansion in vitro and these effects correlated with changes in cell cycle progression and induction of apoptosis. Preliminary data also suggest that ROCK1/2 inhibition can promote AML sensitivity to MRX-2843 in the bone marrow. We hypothesize that simultaneous inhibition of ROCK1/2 and MERTK/FLT3 will decrease disease burden and prolong survival, both alone and in combination with standard AML induction chemotherapy, in murine AML models. To test this idea, the impact of treatment with MRX-2843, GSK269962A, and/or chemotherapy will be determined in mice with human AML cell line and/or patient derived xenografts. To identify the targets important for therapeutic synergy, shRNA-expressing cell line derivatives (shMERTK, shROCK1, shROCK2, shCONTROL) will be tested in xenograft models in combination with MRX-2843, GSK269962A, or vehicle. To further evaluate the ability of the combination therapy to target bone marrow disease, the impact of treatment with MRX-2843 and/or GSK269962A will be determined using 3-dimensional biomimicry cultures derived from a panel of AML patient samples, which recapitulate many features of the normal bone marrow niche, including protection from chemotherapy, and provide a robust platform for therapeutic testing. Together these experiments will assess the utility of ROCK1/2 and MERTK/FLT3 inhibitor combination therapies for treatment of AML, provide important information about the efficacy and toxicity of the combination therapy in preclinical mouse models, and may lead to development of a powerful approach to treat AML more effectively and with less toxicity by 1) disrupting the protective interactions between bone marrow stromal cells and leukemic blasts and 2) inhibiting specific molecular targets to induce leukemia cell death.

项目摘要/摘要