Targeting Kinase Inhibitor Induced Signaling Plasticity in Patients with Ph-Like ALL

针对 Ph 样 ALL 患者中激酶抑制剂诱导的信号可塑性

基本信息

批准号：
10584455
负责人：
Christian Hurtz
金额：
$ 19.31万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-04 至 2023-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10584455
关键词：
ABL1 gene Acute Lymphocytic Leukemia Adult Age Animals Apoptosis B cell differentiation B-Cell Activation B-Cell Acute Lymphoblastic Leukemia B-Cell Antigen Receptor B-cell precursor acute lymphoblastic leukemia cell Bioinformatics Biology Breast Cancer Patient CHEK1 gene Cell Death Cell Differentiation Induction Cell Line Cell Proliferation Cell Survival Cells Cellular Stress Cessation of life Child Complex Critical Pathways Cytokine Receptors DNA DNA Damage DNA Double Strand Break Dasatinib Data Development Down-Regulation Drug resistance Enzyme Induction Enzymes Gene Expression Gene Expression Profile Genetic Genetic Heterogeneity Goals Heterochromatin Human In Vitro JAK1 gene JAK2 gene Lesion Leukemic Cell Mediating Molecular Mus Mutate Mutation Oncogenes Oncogenic PI3K/AKT PIK3CG gene PTPN6 gene Patient-Focused Outcomes Patients Ph+ ALL Philadelphia Chromosome Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Pre-Clinical Model Proliferating Proto-Oncogene Proteins c-akt Receptor Signaling Relapse Research Sampling Signal Induction Signal Pathway Signal Transduction Signaling Molecule Source Stat5 protein Techniques Testing Therapeutic Toxic effect Training Treatment Protocols Uncertainty V(D)J Recombination acute lymphoblastic leukemia cell addiction cell type chemotherapy clinical translation cytokine cytotoxicity defined contribution endonuclease experimental study flexibility high risk human disease improved improved outcome in vivo inhibitor innovation kinase inhibitor leukemia leukemia treatment loss of function mortality mouse model novel therapeutic intervention patient derived xenograft model pharmacologic pre-clinical preclinical study prevent protective pathway relapse prevention relapse risk repaired response src-Family Kinases success synergism targeted treatment therapeutic target therapeutically effective translational study treatment strategy

项目摘要

Project Summary Major scientific and therapeutic advances have improved outcomes of patients with B-cell acute lymphoblastic leukemia (B-ALL) over the last four decades. Addition of ABL1 kinase inhibitors to chemotherapy has significantly improved relapse-free and overall survival of children and adults with the Philadelphia chromosome positive (Ph+) ALL subtype. This great treatment success has been attributed to oncogenic addiction of Ph+ leukemias to BCR-ABL1-driven signaling and the ability of ABL1 kinase inhibitors to induce profound cytotoxicity. Philadelphia chromosome-like (Ph-like) ALL is an analogous high-risk leukemia subtype driven by various non- BCR-ABL1 genetic lesions that similarly activate oncogenic kinase signaling. Ph-like B-ALL occurs in 15-40% of children and adults with B-ALL and is associated with a particularly high risk of relapse and death. We identified constitutively activated JAK2/STAT5, PI3K and B cell receptor-like (BCR) signaling in CRLF2-rearranged Ph-like ALL, which can be abrogated with JAK1/2 (ruxolitinib), PI3Kδ (idelalisib), and SRC (dasatinib) inhibition in vitro and in vivo in preclinical models. However, while the triple inhibition results in complete cell death in vitro and significant decrease of the leukemia burden of mice, we doubt that this treatment strategy is clinically translatable for patients given potential for appreciable toxicity. We thus focused on discovering vulnerabilities induced by JAK2-kinase inhibition and identified i) high activity of SGK1, a molecule known to induce drug resistance to PI3K inhibitors in PI3Kα-mutated breast cancer patients, ii) complete inactivity and downregulation of PTPN6, a phosphatase known to downregulate JAK2, PI3K, and BCR signaling, and iii) accumulation of DNA damage with JAK2 inhibition. We hypothesized that activation of SGK1 and inactivation of PTPN6 are required mechanisms to overcome JAK2 inhibitor-induced signaling inhibition. Strikingly, our preliminary data demonstrated that targeting activated SGK1 in JAK2 inhibitor treated samples results in potent in vitro cell death. Furthermore, we hypothesized that the JAK2-inhibitor induced DNA-damage is mediated by the RAG endonuclease complex, which is activated during B cell differentiation to form the BCR. It has been shown that JAK2/STAT5 signaling is downregulated in differentiating B cells to induce a proliferation arrest, which prevents cells from dying from apoptosis during V(D)J recombination. Our preliminary data demonstrate that we can exploit this conserved mechanism by targeting the DNA-damage response molecule CHK1 in JAK2 inhibitor treated Ph-like ALL cells, which may result in massive leukemic cell death due to accumulation of unrepaired DNA damage. The proposed study aims to uncover previously unknown mechanisms of drug resistance and to characterize the underlying biology of Ph-like B-ALL cells to ultimately establish preclinical treatment protocols with the goal to prevent relapse and to cure patients with Ph-like B-ALL.

项目概要重大科学和治疗进展改善了 B 细胞急性淋巴细胞白血病患者的预后过去四十年来，在化疗中添加 ABL1 激酶抑制剂已显着改善了白血病 (B-ALL) 的发病率。提高费城染色体阳性儿童和成人的无复发率和总体生存率 (Ph+) ALL 亚型这一巨大的治疗成功归功于 Ph+ 白血病的致癌成瘾。 BCR-ABL1 驱动的信号传导以及 ABL1 激酶抑制剂诱导深度细胞毒性的能力。费城染色体样（Ph 样）ALL 是一种类似的高危白血病亚型，由各种非- BCR-ABL1 基因损伤同样会激活致癌激酶信号传导，15-40% 的 B-ALL 发生这种情况。我们发现患有 B-ALL 的儿童和成人与复发和死亡的风险特别高有关。 CRLF2 重排 Ph 样中组成型激活的 JAK2/STAT5、PI3K 和 B 细胞受体样 (BCR) 信号传导 ALL，可以在体外通过 JAK1/2 (ruxolitinib)、PI3Kδ (idelalisib) 和 SRC (dasatinib) 抑制来消除然而，三重抑制会导致体外和体内的细胞完全死亡。小鼠的白血病负担显着降低，我们怀疑这种治疗策略是否可以临床转化因此，我们专注于发现潜在的明显毒性的患者。 JAK2 激酶抑制并鉴定出 i) SGK1 的高活性，这是一种已知可诱导耐药性的分子 PI3Kα 突变乳腺癌患者中的 PI3K 抑制剂，ii) PTPN6 完全失活和下调，a 已知磷酸酶可下调 JAK2、PI3K 和 BCR 信号传导，以及 iii) DNA 损伤的积累我们发现 SGK1 的激活和 PTPN6 的失活是必需的机制。令人惊讶的是，我们的初步数据表明，在 JAK2 抑制剂处理的样品中靶向激活的 SGK1 会导致有效的体外细胞死亡。研究发现 JAK2 抑制剂诱导的 DNA 损伤是由 RAG 核酸内切酶复合物介导的， JAK2/STAT5 信号在 B 细胞分化过程中被激活，形成 BCR。下调分化 B 细胞以诱导增殖停滞，从而防止细胞死亡我们的初步数据表明我们可以利用这种保守性。通过靶向 JAK2 抑制剂处理的 Ph 样 ALL 细胞中的 DNA 损伤反应分子 CHK1 的机制，由于未修复的 DNA 损伤的积累，这可能会导致大量白血病细胞死亡。研究旨在揭示以前未知的耐药机制并表征潜在的耐药性 Ph 样 B-ALL 细胞的生物学，最终建立临床前治疗方案，目标是预防复发并治愈 Ph 样 B-ALL 患者。