Investigating HIF1-alpha Signaling to Identify Predictive Markers and Therapeutic Targets in Desmoid-Type Fibromatosis

研究 HIF1-α 信号传导以识别硬纤维瘤型纤维瘤病的预测标记物和治疗靶点

• 批准号: 10357768
• 负责人: Aimee Marie Crago
• 金额: $ 55.81万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10357768
• 关键词: Abdomen; Adriamycin PFS; Adult; Affect; Aggressive Fibromatosis; BAY 54-9085; Benefits and Risks; Binding; Biological Markers; Biology; Biopsy Specimen; CCND1 gene; CTNNB1 gene; Cell Proliferation; Cells; Cessation of life; Characteristics; Clinical; Complement Factor B; Contracture; Counseling; DNA Sequence Alteration; Data; Disease; Disease Progression; Gene Targeting; Genes; Growth; HIF1A gene; Hypoxia Inducible Factor; Immunohistochemistry; In Vitro; Individual; Intestines; Lead; Ligands; Limb structure; Link; Malignant Neoplasms; Mediating; Mesenchymal Cell Neoplasm; Molecular; Morbidity - disease rate; Mutation; Neoplasm Metastasis; Neoplasms; Oncogenic; Operative Surgical Procedures; Outcome; Pain; Pathway interactions; Patient-Focused Outcomes; Patients; Physicians; Platelet-Derived Growth Factor; Progression-Free Survivals; Proteins; Receptor Protein-Tyrosine Kinases; Recurrence; Regimen; Reproducibility; Research; Role; Signal Pathway; Signal Transduction; Symptoms; Systemic Therapy; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transcriptional Regulation; Variant; Widespread Disease; Work; adverse event risk; base; beta catenin; druggable target; factor A; gene product; genetic analysis; individual patient; inhibitor; insight; knock-down; middle age; new therapeutic target; outcome prediction; overexpression; pain symptom; patient prognosis; patient subsets; phase II trial; platelet-derived growth factor BB; potential biomarker; predictive marker; standard care; therapeutic target; tool; tumor; tumor growth; tumorigenesis

Desmoid-type fibromatosis is a mesenchymal tumor that does not progress to high-grade disease or metastasize. Surgery was the standard treatment for desmoids, but in patients with extensive disease, surgery can lead to complications as morbid as the tumors themselves, and ~30% of patients have local recurrence. For these and other reasons, active observation is prescribed to an increasingly large subset of patients with asymptomatic disease. Desmoid outcomes, however, are highly variable; under observation half of desmoids do not progress over two years and a subset will regress spontaneously, while other desmoids grow relentlessly. Locally aggressive tumors can cause severe symptoms: pain and contracture from desmoids in the extremities and intestinal fistulization and death from abdominal desmoids. Once present, symptoms can be difficult to reverse. Therefore, there is need for tools to predict outcome prior to recommending active observation. Nearly all desmoids contain CTNNB1 mutations that constitutively activate the gene product, β- catenin, but extensive genetic analyses have failed to identify any additional genetic alterations that may underlie variations in patient prognosis. This proposal builds upon preliminary results suggesting that β-catenin promotes desmoid oncogenesis through non-canonical downstream targets, including hypoxia-inducible factor α (HIF1α). Both HIF1α protein levels and desmoid cell proliferation are also increased by activated PDGFRβ, which may explain the fact that sorafenib, an inhibitor of PDGFRβ among other receptor tyrosine kinases, has activity in desmoids. Based on these and other preliminary data, we hypothesize that HIF1α mediates mitogenic signals from PDGFRβ in a manner dependent on activated β-catenin. We propose to investigate the role of this and other pathways in desmoid biology and to use the insight gained to identify and test potential biomarkers of desmoid tumor growth. In Aim 1, we seek to determine the roles of HIF1α and β-catenin in mediating PDGFRβ signaling and proliferation in desmoid cells. In Aim 2, we perform highly focused screens to identify additional genes and druggable pathways that are necessary for desmoid cell proliferation. We will then test whether they act upstream of a PDGFRβ/β-catenin/HIF1α axis or act independently of this axis. Finally, in Aim 3, we propose to use biopsy specimens, collected as part of a phase II trial, to examine whether desmoid progression during active observation can be predicted by markers from the PDGFRβ/β- catenin/HIF1α pathway or other pathways defined in Aims 1 and 2. We expect the proposed studies to identify biomarkers that will help clinicians to identify optimal therapeutic pathways for individual desmoid patients. In addition, by elucidating the molecular basis of oncogenesis in desmoids, this work may identify novel therapeutic targets for the disease. Because aberrant β-catenin activity can be observed in a wide range of neoplasms, our results may provide insight that affects our approach to other cancers as well.

脱乳突型纤维瘤病是一种间充质肿瘤，不发展为高级疾病或 转移。手术是对脱胶质细胞的标准治疗方法，但在患有广泛疾病的患者中 可能导致与肿瘤本身一样病态的并发症，并且约有30％的患者患有局部复发。 由于这些和其他原因，将主动观察处方为越来越多的患者 无症状疾病。但是，脱粘的结果是高度可变的。在观察一半下 不要在两年内进展，子集将赞助退缩，而其他脱木体则增长 无情。局部侵略性肿瘤会引起严重的症状：demoids的疼痛和染色 腹部甜点的四肢和肠刺和死亡。一旦存在，症状就可以 难以逆转。因此，需要工具在推荐活动之前预测结果 观察。几乎所有的脱粘体都包含CTNNB1突变，这些突变可组成性激活基因产物β- Catenin，但广泛的遗传分析未能鉴定出任何可能的遗传改变 患者预后的差异是基础。该提议建立在初步结果的基础上，表明β-catenin 通过非经典下游靶标促进脱粘性肿瘤发生，包括缺氧诱导因子 α（HIF1α）。激活的PDGFRβ，HIF1α蛋白水平和脱蛋白细胞增殖也增加了 这可能解释了索拉非尼（PDGFRβ的抑制剂）与其他受体酪氨酸激酶相比，索拉非尼具有 在脱木体中的活性。基于这些和其他初步数据，我们假设HIF1α培养基 来自PDGFRβ的有丝分裂信号的方式取决于活化的β-catenin。我们建议调查 该途径和其他途径在Desmoid生物学中的作用，并利用获得的见解来识别和测试潜力 脱蛋白肿瘤生长的生物标志物。在AIM 1中，我们寻求确定HIF1α和β-catenin在 介导脱粘细胞中的PDGFRβ信号传导和增殖。在AIM 2中，我们执行高度集中的屏幕 确定脱乳突细胞增殖所必需的其他基因和可吸毒的途径。我们将 然后测试它们是在PDGFRβ/β-catenin/hif1α轴上的上游作用还是独立于该轴的作用。 最后，在AIM 3中，我们建议使用作为II期试验的一部分收集的活检标本，以检查是否是否 PDGFRβ/β-的标记可以预测活跃观察过程中的脱蛋白进展 Catenin/HIF1α途径或目标1和2中定义的其他途径。我们希望拟议的研究能够识别 生物标志物将帮助临床医生鉴定单个脱乳突病患者的最佳治疗途径。 另外，通过阐明脱乳突中肿瘤发生的分子基础，这项工作可以识别出新的 该疾病的治疗靶标。因为可以在广泛的范围内观察到异常的β-catenin活性 肿瘤，我们的结果可能会提供洞察力，从而影响我们对其他癌症的方法。