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

增强 Ph 样 B-ALL 治疗的联合策略

• 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
• 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' 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

 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.

 描述（由适用提供）：该提案重点介绍B细胞急性淋巴细胞白血病（B-ALL）。尽管过去几十年来的治愈率急剧提高，但B-all的一部分儿童的退休率仍然令人难以置信。这个“高风险”组的白血病包括由BCR-ABL酪氨酸激酶驱动的费城染色体阳性（pH+）病例，但大多数是pH值。由于类似的基因表达和酪氨酸激酶的激活，许多高风险的pH值B-ALL病例现在可以被指定为“ pH样” B-all。新兴数据表明，在青少年和年轻的成年患者中，类似pH的B-all也很普遍。重要的是，在用酪氨酸激酶抑制剂（TKIS）在体外和TKI治疗中，类似pH的白血病显示激酶信号降低，而TKI治疗抑制了异种移植模型中的疾病。这些发现为与pH样B-all中的患者特异性基因组病变相匹配的TKI临床测试提供了强大的理由。但是，许多癌症在许多癌症中都会发展出TKI耐药性，强调需要针对其他生存机制。使用成人pH+ B-all的异种移植模型，我们报告了第二代ATP竞争性抑制剂与针对BCR-ABL癌基因的TKI协同作用。将MTOR激酶抑制剂（TOR-KIS）与TKI相结合，甚至在对BCR-ABL激酶抑制剂固有抗性的肿瘤中，也比单独TKI或TKI加雷霉素更大程度地导致白血病消退。 MTOR激酶抑制剂在治疗剂量时耐受性良好。由于TKI/TOR-KI组合在pH+ B-ALL异种移植物中效果很好，因此我们认为类似的组合在类似pH的B-all中也有效。该项目将检验这一假设，目的是获得概念证明数据，支持TKI和TOR-KIS的临床试验儿童，青少年和具有pH样B-All的年轻人的临床试验。我们将使用合作者提供的类似pH的B-All Xenographichics中的单元格来实现这一目标。第一个具体目的是评估双途径抑制对XenographogrogrogriconPH样白血病样品的有效性。终点将是骨髓中白血病细胞的百分比，以及白血病与正常骨髓细胞群体中的循环细胞的一部分。第二个具体目的是测试组合处理是否比单个治疗更深刻地抑制B-all细胞中的存活信号传导。我们将通过对从异种移植小鼠的骨髓获得的细胞的磷酸流分析进行部分解决。我们还将验证一种新兴技术Cytof，以对处理小鼠的骨髓中B-ALL细胞中的磷酸蛋白酶进行多参数分析。这些研究可能导致新的方法，以防止在高危B-ALL和生物标志物中退休以监测对治疗的反应。