Understanding the impact that tumor representative oxygen tension has on phosphotyrosine-dependent signaling networks in solid tumors

了解肿瘤代表性氧张力对实体瘤中磷酸酪氨酸依赖性信号网络的影响

• 批准号: 10765139
• 负责人: Benjamin Jacob Mayro
• 金额: $ 8.91万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10765139
• 关键词: 2-tyrosine; ABL1 gene; ABL2 gene; Ablation; Animal Model; Biological; Brain; Cell Hypoxia; Cells; Cellular biology; Characteristics; Clinical Trials; Dasatinib; Data; Dependence; Development; Disseminated Malignant Neoplasm; Doctor of Philosophy; Environment; FDA approved; Fellowship; Foundations; Future; Genetic Transcription; Gleevec; HSF1; Hypoxia; Impairment; In Vitro; Intervention; Investigation; Luciferases; Lung Adenocarcinoma; Malignant Neoplasms; Manuscripts; Mass Spectrum Analysis; Mediating; Metastatic malignant neoplasm to brain; Modality; Nature; Neoplasm Metastasis; Oxygen; Patient-Focused Outcomes; Patients; Phosphoric Monoester Hydrolases; Phosphotransferases; Phosphotyrosine; Play; Postdoctoral Fellow; Principal Investigator; Protein Tyrosine Kinase; Protein Tyrosine Phosphatase; Proteins; Proto-Oncogene Proteins c-abl; Reporter; Reporting; Research; Research Project Grants; Resistance; Role; Sampling; Signal Pathway; Signal Transduction; Solid Neoplasm; Technology; Therapeutic; Time; Training; Translating; Trastuzumab; Tumor-Associated Process; Tyrosine Kinase Inhibitor; Tyrosine Phosphorylation; Work; anticancer research; autocrine; brain parenchyma; cancer cell; cancer therapy; career; effective therapy; efficacious treatment; high-throughput drug screening; improved; in vivo; inhibitor; leukemia; lung cancer cell; lung colonization; molecular targeted therapies; oxidation; pharmacologic; pre-clinical; pre-doctoral; preclinical study; programs; response; restraint; skills; small molecule; targeted treatment; trait; transcription factor; tumor; tumor hypoxia; tumor microenvironment; tumor progression; ubiquitin-protein ligase

PROJECT SUMMARY/ ABSTRACT The perturbation of phospho-tyrosine mediated signaling networks is an essential occurrence during the multistep process of tumor development and progression. As a result, the components of these phospho-tyrosine signaling networks, especially tyrosine kinases, have been shown to be a key reservoir of actionable molecular targets for the treatment of cancer. In recent years, it has been revealed that the tumor microenvironment plays a critical role in modulating the signaling pathways that govern tumor progression and metastasis. The features of a tumor's microenvironment have been shown to produce unique sensitivities and resistances to different treatment modalities. One major aspect of the tumor microenvironment which is often overlooked in preclinical studies is oxygen tension. This proposal seeks to understand the impact that oxygen tension has on phosphotyrosine-dependent signaling networks in solid tumors, and how the resultant vulnerabilities can be targeted to improve patient outcome. In Aim 1.1 (prior studies), we sought to identify alterations in signaling networks that occur when lung cancer cells colonize the brain, a hypoxic environment. We showed that brain- metastatic lung cancer cells elevate and have an increased dependence on a non-canonical HSF1-E2F transcriptional program for survival. Importantly, we identified that this transcriptional program is targetable through treatment with allosteric ABL2 tyrosine kinase inhibitors. In Aim 1.2 (proposed studies), using a small molecule screen, I have identified previously unrecognized modulators of the cellular response to hypoxia, a tumor microenvironment feature associated with increased metastasis and lower overall survival in patients with solid tumors. The top uncharacterized hit was the FDA-approved ABL1/2 tyrosine kinase inhibitor Dasatinib and my preliminary investigation has shown that the ABL kinases are critical regulators of HIF-1α protein stability. I will continue mechanistic investigation of the ABL- HIF-1α axis in vitro and in vivo. Finally, in Aim 2 (post-doctoral studies), I will focus on understanding the impact that tumor representative- oxygen tension has on protein tyrosine phosphatase activity. Extensive investigation has demonstrated that tumor hypoxia induces activation of phospho-tyrosine signaling networks, but current work has almost exclusively focused on the role of tyrosine kinases. I show that hypoxia induces inhibitory oxidation of protein tyrosine phosphatases (PTPs). Using mass- spectrometry based approaches, I will identify the oxidized- PTP landscape (ox-PTPome) of tumor samples and cancer cells at oxygen levels observed in tumors. Further, since PTPs restrain cellular signaling, I will employ high-throughput drug screening technologies in vitro to identify emergent sensitivities due to the loss of PTP activity that would not have been captured in the numerous normoxically (tumor-unrepresentative oxygen level) performed screens. Overall, the focus of my career is to understand how the different characteristics of the tumor microenvironment, such as hypoxia, modulates the signaling networks co-opted by cancer cells and translate this to the identification of biological mechanisms that may be amenable to therapeutic exploitation.

项目概要/摘要 磷酸酪氨酸介导的信号网络的扰动是在 肿瘤发生和进展的多步骤过程。结果，这些磷酸酪氨酸的成分 信号网络，特别是酪氨酸激酶，已被证明是可操作分子的关键储存库 癌症治疗的目标。近年来，研究发现肿瘤微环境在 在调节控制肿瘤进展和转移的信号通路中发挥关键作用。特点 肿瘤微环境的变化已被证明对不同的肿瘤产生独特的敏感性和抵抗力。 治疗方式。肿瘤微环境的一个主要方面在临床前研究中经常被忽视 研究的是氧张力。该提案旨在了解氧张力对 实体瘤中磷酸酪氨酸依赖性信号网络，以及由此产生的脆弱性如何 旨在改善患者的治疗效果。在目标 1.1（之前的研究）中，我们试图识别信号传导的改变 当肺癌细胞在大脑（一个缺氧环境）中定植时，就会出现这种网络。我们展示了大脑—— 转移性肺癌细胞对非典型 HSF1-E2F 的依赖性升高 生存的转录程序。重要的是，我们发现这个转录程序是有针对性的 通过变构 ABL2 酪氨酸激酶抑制剂治疗。在目标 1.2（拟议的研究）中，使用小型 通过分子筛选，我发现了以前未被识别的细胞对缺氧反应的调节剂， 肿瘤微环境特征与患者转移增加和总生存率降低相关 实体瘤。最不知名的热门药物是 FDA 批准的 ABL1/2 酪氨酸激酶抑制剂达沙替尼 (Dasatinib) 和 我的初步研究表明 ABL 激酶是 HIF-1α 蛋白稳定性的关键调节因子。我 将继续对 ABL-HIF-1α 轴的体外和体内机制进行研究。最后，在目标2（博士后 研究），我将重点了解肿瘤代表——氧张力对蛋白质的影响 酪氨酸磷酸酶活性。广泛的研究表明肿瘤缺氧会诱导激活 磷酸酪氨酸信号网络，但目前的工作几乎完全集中于酪氨酸的作用 激酶。我发现缺氧会诱导蛋白酪氨酸磷酸酶 (PTP) 的抑制性氧化。使用质量 基于光谱测定的方法，我将识别肿瘤样本的氧化 PTP 景观 (ox-PTPome) 和 在肿瘤中观察到的氧气水平下的癌细胞。此外，由于 PTP 抑制细胞信号传导，我将采用 体外高通量药物筛选技术，用于识别由于 PTP 丢失而出现的紧急敏感性 在大量含氧量正常（肿瘤不具有代表性的氧水平）中无法捕获的活性 执行的屏幕。总的来说，我职业生涯的重点是了解肿瘤的不同特征如何 微环境，例如缺氧，调节癌细胞选择的信号网络并翻译 这有助于确定可能适合治疗利用的生物机制。