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(申请人提供)：本方案重点针对B细胞急性淋巴细胞性白血病(B-ALL)。尽管在过去的几十年里治愈率有了戏剧性的增长，但B-ALL的一部分儿童的复发率仍然高得令人无法接受。这一“高危”人群中的白血病包括由bcr-abl酪氨酸激酶导致的费城染色体阳性(Ph+)病例，但大多数是Ph阴性。由于相似的基因表达和酪氨酸激酶的激活，许多高危Ph阴性的B-ALL病例现在可以被指定为“Ph-like”B-ALL。新出现的数据表明，类似Ph的B-ALL在青少年和年轻成人患者中也很普遍。重要的是，在体外用酪氨酸激酶抑制剂(TKI)治疗的Ph样白血病表现出激酶信号的减少，而TKI治疗在异种移植模型中抑制了疾病。这些发现为临床测试与Ph样B-ALL患者特定基因组病变相匹配的TKI奠定了坚实的基础。然而，TKI耐药性在许多癌症中发生，强调了针对额外的生存机制的必要性。利用成人Ph+B-ALL异种移植模型，我们已经报道了第二代ATP竞争性mTOR抑制剂与靶向bcr-abl癌基因的TKI具有协同作用。联合应用mTOR激酶抑制剂(TOR-KI)和TKI可导致白血病的消退程度高于单独使用TKI或TKI加雷帕霉素，即使在对BCR-ABL激酶抑制剂具有内在耐药性的肿瘤中也是如此。MTOR激酶抑制剂在治疗剂量下耐受性良好。由于TKI/TOR-KI组合在Ph+B-ALL异种移植中效果良好，我们相信类似的组合将在Ph-样B-ALL中有效。该项目将测试这一假设，目的是获得概念验证数据，支持在患有Ph样B-ALL的儿童、青少年和年轻人中进行TKI加TOR-KI的临床试验。我们将使用合作者提供的已建立的Ph样B-ALL异种移植的细胞来实现这一目标。第一个具体目的是评估双途径抑制对异种移植的Ph样白血病样本的疗效。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循环细胞的比例。第二个具体目标是测试联合治疗是否比单一治疗更深刻地抑制B-ALL细胞中的生存信号。我们将通过对从异种移植小鼠骨髓中获得的细胞进行磷流分析来部分解决这个问题。我们还将验证一项名为CyTOF的新兴技术，用于对治疗小鼠骨髓中B-ALL细胞的磷酸蛋白质组进行多参数分析。这些研究可能导致预防高危B-ALL复发的新方法，以及监测治疗反应的生物标记物。