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Combination strategies to enhance therapy for Ph-like B-ALL

增强 Ph 样 B-ALL 治疗的联合策略

基本信息

批准号：
8912208
负责人：
DAVID Alexander FRUMAN
金额：
$ 25.67万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
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：
2015-03-09 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8912208
关键词：
ABL1 gene Address Adolescent and Young Adult Adult B-Cell Acute Lymphoblastic Leukemia Biological Biological Markers Bone Marrow Bone Marrow Cells Cell Cycle Cell Line Cells Chemicals Child Childhood Childhood Leukemia Clinical Clinical Trials Collaborations Combined Modality Therapy Cues Cytokine Receptors Cytometry Dana-Farber Cancer Institute Data Development Disease Dose Drug Combinations Emerging Technologies Enzymes Feedback Gene Activation Gene Expression Generations Genes Genomics Goals Growth Growth Factor Human In Vitro JAK2 gene Laboratories Lead Lesion Malignant Neoplasms Measures Metabolism Modeling Monitor Mus Mutation Nutrient Oncogene Proteins Oncogenes Oncogenic Oranges Outcome Output PDGFRB gene Pathway interactions Patients Pediatric Hospitals Pediatric Oncology Group Philadelphia Philadelphia Chromosome Phosphorylation Phosphotransferases Population Protein Tyrosine Kinase Receptor Signaling Refractory Relapse Reporting Resistance Resistance development Saint Jude Children&apos s Research Hospital Sampling Signal Pathway Signal Transduction Signal Transduction Pathway Sirolimus Technology Testing Therapeutic Translating Treatment Efficacy Tyrosine Kinase Inhibitor Work Xenograft Model Xenograft procedure base bcr-abl Fusion Proteins bone marrow xenograft cancer cell cell growth cytokine high risk inhibitor/antagonist kinase inhibitor leukemia mTOR protein novel strategies prevent protein complex public health relevance research clinical testing response therapy resistant tumor

项目摘要

DESCRIPTION (provided by applicant): This proposal focuses on B-cell acute lymphoblastic leukemia (B-ALL). Despite a dramatic increase in cure rates over the past decades, a subset of children with B-ALL continues to have unacceptably high rates of relapse. Leukemias in this "high-risk" group include Philadelphia chromosome positive (Ph+) cases driven by the BCR-ABL tyrosine kinase, but the majority are Ph- negative. Many high-risk Ph-negative B-ALL cases can now be designated as "Ph-like" B-ALL due to similar gene expression and activation of tyrosine kinases. Emerging data indicate that Ph-like B-ALL is also prevalent in adolescent and young adult patients. Importantly, Ph-like leukemias show decreased kinase signaling upon treatment with tyrosine kinase inhibitors (TKIs) in vitro and TKI treatment suppresses disease in xenograft models. These findings establish strong rationale for clinical testing of TKIs matched to patient-specific genomic lesions in Ph-like B-ALL. However, TKI resistance develops in many cancers, emphasizing the need to target additional survival mechanisms. Using xenograft models of adult Ph+ B-ALL we have reported that second generation, ATP- competitive inhibitors of mTOR work in synergy with TKIs targeting the BCR-ABL oncogene. Combining mTOR kinase inhibitors (TOR-KIs) with TKIs causes regression of leukemia to a greater extent than TKI alone or TKI plus rapamycin, even in tumors with intrinsic resistance to BCR-ABL kinase inhibitors. mTOR kinase inhibitors are well tolerated at therapeutic doses. Because the TKI/TOR-KI combination works well in Ph+ B-ALL xenografts, we believe similar combinations will be effective in Ph-like B-ALL. This project will test this hypothesis, with the goal of obtaining proof-of- concept data supporting clinical trials of TKI plus TOR-KIs in children, adolescents and young adults with Ph-like B-ALL. We will accomplish this objective using cells from established Ph-like B-ALL xenografts, provided by collaborators. The first specific aim is to evaluate the efficacy of dual pathway inhibition on xenografted Ph-like leukemia samples. Endpoints will be percent leukemia cells in the bone marrow, and fraction of cycling cells in the leukemia versus normal bone marrow cell populations. The second specific aim is to test whether the combination treatments suppress survival signaling in B-ALL cells more profoundly than single treatments. We will address this in part through phosphoflow analysis of cells obtained from bone marrow of xenografted mice. We will also validate an emerging technology, CYTOF, for multiparameter analysis of the phosphoproteome in B-ALL cells from bone marrow of treated mice. These studies may lead to new approaches to prevent relapse in high-risk B-ALL and biomarkers to monitor response to therapy.