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（由申请人提供）：本提案重点关注 B 细胞急性淋巴细胞白血病 (B-ALL)。尽管过去几十年治愈率急剧上升，但一部分 B-ALL 儿童的复发率仍然高得令人无法接受。这一“高危”群体中的白血病包括由 BCR-ABL 酪氨酸激酶驱动的费城染色体阳性 (Ph+) 病例，但大多数为 Ph- 阴性。由于相似的基因表达和酪氨酸激酶激活，许多高危 Ph 阴性 B-ALL 病例现在可被指定为“Ph 样”B-ALL。新数据表明，Ph 样 B-ALL 在青少年和年轻成年患者中也很常见。重要的是，Ph 样白血病在体外用酪氨酸激酶抑制剂 (TKI) 治疗后表现出激酶信号传导减少，并且 TKI 治疗可抑制异种移植模型中的疾病。这些发现为与 Ph 样 B-ALL 患者特异性基因组病变相匹配的 TKI 临床测试奠定了强有力的基础。然而，许多癌症都会出现 TKI 耐药性，这强调需要针对其他生存机制。使用成人 Ph+ B-ALL 异种移植模型，我们报道了第二代 mTOR ATP 竞争性抑制剂与靶向 BCR-ABL 癌基因的 TKI 协同作用。与单独使用 TKI 或 TKI 加雷帕霉素相比，mTOR 激酶抑制剂 (TOR-KI) 与 TKI 联合使用可以更大程度地使白血病消退，甚至在对 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具有良好的耐受性。由于 TKI/TOR-KI 组合在 Ph+ B-ALL 异种移植物中效果良好，因此我们相信类似的组合对于 Ph 样 B-ALL 也将有效。该项目将测试这一假设，目的是获得概念验证数据，支持 TKI 加 TOR-KI 在患有 Ph 样 B-ALL 的儿童、青少年和年轻人中进行的临床试验。我们将使用来自合作者提供的已建立的 Ph 样 B-ALL 异种移植物的细胞来实现这一目标。第一个具体目标是评估双途径抑制对异种移植 Ph 样白血病样本的功效。终点将是骨髓中白血病细胞的百分比，以及白血病中循环细胞相对于正常骨髓细胞群的分数。第二个具体目标是测试联合治疗是否比单一治疗更能抑制 B-ALL 细胞的生存信号。我们将通过对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。我们还将验证一项新兴技术 CYTOF，用于对来自治疗小鼠骨髓的 B-ALL 细胞中的磷酸蛋白质组进行多参数分析。这些研究可能会带来预防高危 B-ALL 复发的新方法和监测治疗反应的生物标志物。