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: 10576913
• 负责人: Aimee Marie Crago
• 金额: $ 54.69万
• 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/10576913
• 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; Contracture; Counseling; DNA Sequence Alteration; Data; Disease; Disease Progression; Genes; Growth; HIF1A gene; Hypoxia Inducible Factor; Immunohistochemistry; In Vitro; Individual; Intestines; 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; Proliferating; Proteins; Receptor Protein-Tyrosine Kinases; Recommendation; 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; alpha catenin; beta catenin; biomarker identification; druggable target; gene product; genetic analysis; individual patient; inhibitor; insight; knock-down; middle age; new therapeutic target; outcome prediction; overexpression; 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.

硬纤维瘤型纤维瘤病是一种间叶性肿瘤，不会进展为高级疾病或 手术是硬纤维瘤的标准治疗方法，但对于病变广泛的患者，则需要手术治疗。 可导致与肿瘤本身一样严重的并发症，约 30% 的患者会出现局部复发。 由于这些和其他原因，越来越多的患者需要积极观察 然而，半数硬纤维瘤的观察结果差异很大； 两年内不会进展，一部分会自发消退，而其他硬纤维会生长 局部侵袭性肿瘤会导致严重的症状：硬纤维瘤引起的疼痛和挛缩。 一旦出现四肢和肠道瘘管，腹部硬纤维瘤就会导致死亡。 因此，在建议采取积极措施之前需要有工具来预测结果。 观察发现，几乎所有硬纤维都含有 CTNNB1 突变，该突变持续激活基因产物 β-。 连环蛋白，但广泛的遗传分析未能发现任何其他可能的遗传改变 该提议建立在β-连环蛋白初步结果的基础上。 通过非典型下游靶点（包括缺氧诱导因子）促进硬纤维瘤发生 激活的 PDGFRβ 也会增加 HIF1α 蛋白水平和硬纤维细胞增殖， 这可能解释了索拉非尼（PDGFRβ 和其他受体酪氨酸激酶中的一种抑制剂）具有以下作用： 基于这些和其他初步数据，我们发现 HIF1α 介导。 PDGFRβ 的促有丝分裂信号以依赖于活化的 β-连环蛋白的方式进行。 该途径和其他途径在硬纤维生物学中的作用，并利用获得的见解来识别和测试潜力 在目标 1 中，我们试图确定 HIF1α 和 β-连环蛋白在硬纤维瘤生长中的作用。 在目标 2 中，我们进行了高度集中的筛选以介导硬纤维细胞中的 PDGFRβ 信号传导和增殖。 我们将确定硬纤维细胞增殖所需的其他基因和药物途径。 然后测试它们是在 PDGFRβ/β-连环蛋白/HIF1α 轴上游起作用还是独立于该轴起作用。 最后，在目标 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来检查是否 积极观察期间的硬纤维进展可以通过 PDGFRβ/β- 的标记物来预测 连环蛋白/HIF1α 通路或目标 1 和 2 中定义的其他通路。我们希望拟议的研究能够确定 生物标志物将帮助忠诚者确定个体硬纤维瘤患者的最佳治疗途径。 此外，通过阐明硬纤维瘤发生的分子基础，这项工作可能会发现新的 因为在多种情况下都可以观察到异常的 β-连环蛋白活性。 肿瘤，我们的结果可能会提供影响我们治疗其他癌症的方法的见解。