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.

韧带样型纤维瘤病是一种间叶性肿瘤，不会进展为高级别疾病， 转移手术是硬纤维瘤的标准治疗方法，但对于广泛病变的患者， 可导致与肿瘤本身一样病态的并发症，约30%的患者局部复发。 由于这些和其他原因，对越来越多的患有以下疾病的患者子集进行积极观察 无症状的疾病。然而，硬纤维瘤的结果是高度可变的;根据观察， 两年内不进展，一个子集将自发消退，而其他韧带样瘤生长 无情地局部侵袭性肿瘤可引起严重症状： 四肢和肠瘘以及腹部硬纤维瘤导致的死亡。一旦出现症状， 很难逆转。因此，需要在推荐活性药物之前预测结果的工具。 观察.几乎所有的韧带样瘤都含有CTNNB 1突变，该突变组成性激活基因产物β- 连环蛋白，但广泛的遗传分析未能确定任何额外的遗传变异， 是患者预后变化的基础。这一建议建立在初步结果的基础上，表明β-连环蛋白 通过非经典下游靶点促进硬纤维瘤发生，包括缺氧诱导因子 α（HIF 1 α）。活化的PDGFRβ也会增加HIF 1 α蛋白水平和硬纤维瘤细胞增殖， 这可能解释了索拉非尼，一种PDGFRβ抑制剂和其他受体酪氨酸激酶， 韧带活动。基于这些和其他的初步数据，我们假设HIF 1 α介导 以依赖于活化的β-连环蛋白的方式从PDGFRβ产生促有丝分裂信号。我们建议调查 这一途径和其他途径在硬纤维瘤生物学中的作用，并利用所获得的见解来识别和测试潜在的 硬纤维瘤生长的生物标志物。在目的1中，我们试图确定HIF 1 α和β-catenin的作用， 介导PDGFRβ信号传导和硬纤维瘤细胞增殖。在Aim 2中，我们执行高度集中的屏幕， 确定额外的基因和药物途径是必要的硬纤维瘤细胞增殖。我们将 然后检测它们是否作用于PDGFRβ/β-catenin/HIF 1 α轴的上游或独立于该轴发挥作用。 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 主动观察期间硬纤维瘤进展可通过PDGFRβ/β- 连环蛋白/HIF 1 α通路或目的1和2中定义的其他通路。我们希望拟议的研究能够确定 这些生物标志物将帮助临床医生为个体硬纤维瘤患者确定最佳治疗途径。在 此外，通过阐明韧带样瘤发生的分子基础，本研究可能发现新的 疾病的治疗目标。由于β-连环蛋白的异常活性可以在很大范围内观察到， 肿瘤，我们的结果可能会提供影响我们对其他癌症的方法的见解。