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.

项目摘要/摘要 磷酸酪氨酸介导的信号网络的扰动是在 肿瘤发育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，尤其是酪氨酸激酶，已被证明是可操作的分子的关键库 治疗癌症的靶标。近年来，已经揭示了肿瘤微环境的发挥 在调节控制肿瘤进展和转移的信号通路方面的关键作用。功能 肿瘤的微环境已显示出具有独特的灵敏度和对不同的抗性 治疗方式。肿瘤微环境的一个主要方面，在临床前经常被忽略 研究是氧气张力。该提议旨在了解氧气张力对 实体瘤中的磷酸酪氨酸依赖性信号网络，以及结果漏洞如何 针对改善患者结果的目标。在AIM 1.1（先前的研究）中，我们感觉到信号传导的变化 当肺癌细胞定居大脑时发生的网络是一种低氧环境。我们表明大脑 转移性肺癌细胞升高，对非经典HSF1-E2F的依赖性增加 生存的转录计划。重要的是，我们确定此转录程序是可定位的 通过使用变构ABL2酪氨酸激酶抑制剂治疗。在AIM 1.2（拟议的研究）中，使用一个小 分子屏幕，我已经确定了先前未识别的细胞反应调节剂，A 肿瘤微环境特征与转移增加和降低的总体生存率有关 实体瘤。最高的未表征是FDA批准的ABL1/2酪氨酸激酶抑制剂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剂。我 将继续在体外和体内对ABL-HIF-1α轴进行机械研究。最后，在AIM 2（博士后 研究），我将专注于理解肿瘤的氧气张力对蛋白质的影响 酪氨酸磷酸酶活性。广泛的研究表明，肿瘤缺氧会影响活性 磷酸 - 酪氨酸信号网络的数据，但是当前的工作几乎完全集中在酪氨酸的作用上 激酶。我表明，缺氧会诱导蛋白质酪氨酸磷酸酶（PTPS）的抑制氧化。使用质量 - 基于光谱的方法，我将确定肿瘤样品的氧化PTP景观（OX-PTPOME）和 在肿瘤中观察到的氧气水平的癌细胞。此外，由于PTP限制了细胞信号，我将采用 体外的高通量药物筛查技术，由于PTP的损失而识别出现的敏感性 在众多正常毒性中不会捕获的活性（肿瘤无代表性的氧气） 执行的屏幕。总体而言，我职业的重点是了解肿瘤的不同特征如何 微环境（例如缺氧）调节由癌细胞选择的信号网络并翻译 这是鉴定可能适合治疗剥削的生物学机制。