Targeted Inhibition in Leukemia

白血病的靶向抑制

• 批准号: 10212981
• 负责人: Jose A Cancelas
• 金额: $ 46.56万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-08 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10212981
• 关键词: Acute Myelocytic Leukemia; Adult; Allosteric Site; Apoptosis; Applications Grants; B-Cell Acute Lymphoblastic Leukemia; B-cell precursor acute lymphoblastic leukemia cell; Binding; Binding Sites; Biochemical Genetics; Biological Markers; Biophysics; Breast; Cancer Model; Cell Death; Cells; Cessation of life; Chemoresistance; Childhood; Childhood Acute Lymphocytic Leukemia; Childhood Acute Myeloid Leukemia; Clinic; Data; Development; Disease; Dose; Drug Binding Site; Drug Kinetics; Drug Targeting; Exhibits; Genes; Genetic; Glioblastoma; Goals; Growth; Guanine; Guanine Nucleotide Exchange Factors; Hematopoiesis; Human; Immunophenotyping; Immunotherapy; In Vitro; Intervention; Leukemia Acute Lymphoblastic Chemotherapy; Leukemic Cell; MAP Kinase Gene; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Mediator of activation protein; Metallothionein; Methodology; Modeling; Molecular; Molecular Conformation; Molecular Target; Monomeric GTP-Binding Proteins; Neoplasms; Oncogenes; Oncogenic; Oncology; Pathway interactions; Patients; Ph+ ALL; Pharmaceutical Preparations; Pharmacodynamics; Phase I Clinical Trials; Philadelphia; Prognosis; Property; Proteins; Proto-Oncogene Proteins c-abl; Public Health; Relapse; Research; Resistance; Role; Salvage Therapy; Signal Pathway; Signal Transduction; Site; Site-Directed Mutagenesis; Small GTPase Activators; Solid Neoplasm; Structure; Testing; Therapeutic; Toxic effect; Translating; Transplantation; Tyrosine Kinase Inhibitor; Xenograft procedure; addiction; analog; base; bcr-abl Fusion Proteins; cancer stem cell; chemical group; chemotherapy; combinatorial; cytotoxic; drug efficacy; genetic approach; human disease; human model; in vitro Assay; in vivo; inhibitor/antagonist; leukemia; leukemic stem cell; malignant breast neoplasm; malignant stomach neoplasm; mouse model; non-oncogenic; novel; novel therapeutics; overexpression; patient derived xenograft model; preclinical safety; prevent; refractory cancer; repository; small molecule; small molecule inhibitor; stem; stem cells; therapeutically effective; tumor

ABSTRACT We have identified the first in vivo and in vitro small molecule inhibitor of Vav3, a signaling hub that is overex- pressed in many cancers and an activator of the small GTPase Rac. Rac is a major mediator of oncogenic and non-oncogenic addiction in cancer stem/progenitor cells. At low dose, our inhibitor eliminates TKI-resistance in vivo, prolongs the survival of a mouse model of pre-B-ALL, and eradicates cancer stem cell propagation in a model of mouse serial transplantation. It induces apoptosis of primary pediatric Philadelphia-positive (Ph+) and Ph-like B-ALL and chemotherapy-resistant RAM immunophenotype primary pediatric AML cells. It specifically targets leukemic cells while sparing normal hematopoiesis in vivo and shows no toxicity. In addition, it is active in oncogenic Ras xenografts mouse models of human solid tumors. Given this broad activity and the wide in- volvement of Vav3 and Rac in human disease, it is likely that our inhibitor will be efficacious in several human cancers resistant to current therapies. Even though we focus on Ph+ B-cell acute lymphoblastic leukemia (Ph+ B-ALL) as a simpler cancer model to validate the mechanism of action of our inhibitor, we will test its efficacy in models of pediatric TKI-resistant B- ALL and AML. Despite the introduction of ABL tyrosine kinase inhibitor (TKI) therapy and more recently highly- toxic immunotherapies, Ph+ B-ALL and AML remain poor prognosis diseases, especially in adults, as a result of frequent relapse and resistance to current therapies. The long-term goal of this grant application is a multidrug approach consisting of a TKI and our drug or an optimized derivative as a new therapy for ALL and AML without the toxicity associated with current salvage therapy approaches. We postulate that multitarget approaches in ALL and AML are necessary to prevent resistance to single-agent TKI therapy. Based on our preliminary data, we hypothesize that our drug increases death of leukemia initiating and propa- gating cells and overcomes TKI-resistance by targeting Vav3. The goal of the proposed research is to (1) validate the Vav3/Rac signaling axis as our drug’s target using biochemical and genetic approaches and determine in vivo implications; (2) to identify our drug’s binding site on Vav3 using biophysical, structural, and genetic ap- proaches, and validate the site using site-directed mutagenesis. Finally, (3) we will take advantage of the CCHMC Oncology Leukemia/Solid Tumor Repository to test our drug’s efficacy in PDX models of chemotherapy- resistant pediatric ALL and AML alone and in combination with existing TKI approaches and validate metallothi- onein as a biomarker. If successful, we would like to see our drug, or a more potent analog, move into pre-clinical safety analysis and potentially into a Phase I clinical trial in ALL and AML resistant to TKI therapies. Allosteric targeting of the Vav3 autoinhibited conformation as proposed here could be generalized to other ‘undruggable’ protein-protein interfaces.!

摘要