In vivo therapy and mechanisms of PAX8-PPARgamma thyroid cancer

PAX8-PPARγ甲状腺癌的体内治疗及机制

• 批准号: 8628804
• 负责人: RONALD Jay KOENIG
• 金额: $ 48.11万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8628804
• 关键词: 2,4-thiazolidinedione; Acute Promyelocytic Leukemia; Adipocytes; Agonist; Arsenic; Arsenic Trioxide; Binding; Boxing; Cells; Chimeric Proteins; Chromosomal translocation; DNA Binding; DNA Binding Domain; DNA Sequence; Development; Disease; Follicular thyroid carcinoma; Gene Expression; Gene Fusion; Gene Targeting; Genes; Genetic; Growth; Histology; Invaded; Left; Ligands; Lipids; Lung; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of thyroid; Measurement; Measures; Metastatic/Recurrent; Michigan; Modeling; Mus; Mutation; Nature; Neoplasm Metastasis; Normal Cell; Nuclear Hormone Receptors; Nuclear Receptors; Oncogenic; Operative Surgical Procedures; PPAR gamma; PPARG gene; Papillary thyroid carcinoma; Patients; Peroxisome Proliferator-Activated Receptors; Phase II Clinical Trials; Phenotype; Phosphorylation; Pioglitazone; Process; Production; Property; Proteins; Proto-Oncogene Proteins c-akt; Radioactive Iodine; Serum; Signal Transduction; Site; Testing; Therapeutic; Therapeutic Effect; Thiazolidinediones; Thyroglobulin; Thyroid Gland; Thyroid carcinoma; Trachea; Transgenic Mice; Tumor Markers; Universities; Variant; X-Ray Computed Tomography; base; cancer cell; cancer therapy; gene induction; in vivo; insight; lipid biosynthesis; malignant phenotype; mouse model; novel; public health relevance; response; tumor; tumorigenesis; tumorigenic; uptake; water channel

DESCRIPTION (provided by applicant): Approximately 35% of follicular thyroid carcinomas harbor a chromosomal translocation that fuses paired box gene 8 (PAX8) with the peroxisome proliferator-activated receptor gamma gene (PPARG), resulting in production of a PAX8-PPARG fusion protein denoted PPFP. PPFP contains the full sequence of the nuclear receptor PPARG1, and hence PPFP binds to PPARGresponsive genes and to PPARG ligands. We have created the first transgenic mouse model of this cancer. The cancer is locally invasive and forms lung metastases. Treatment with the PPARG agonist pioglitazone (Pio) shrinks the thyroid almost to control size and eliminates metastatic disease. Most remarkably, this therapeutic response is characterized by a trans differentiation-type process whereby the remaining thyroid cells develop large lipid droplets and express a wide array of PPARG- inducible adipocyte genes. Since PPARG is the master regulator of adipogenesis, these results indicate that, in the presence of Pio, PPFP is strongly PPARG-like. We postulate that the anti-tumor action of Pio in PPFP cancers is tied to this adipocyte trans differentiation-like effect; i.e., the more the thyroi cancer cells acquire a mature adipocyte phenotype, the less they retain of their malignant phenotype. In Aim 1, we will evaluate the oncogenic action of PPFP in the mouse model. There is evidence that, in the absence of Pio, PPFP can inhibit PPARG induction of some target genes, and that inhibition of endogenous PPARG may underlie the oncogenic nature of PPFP. Therefore, we will test whether the genetic deletion of PPARG mimics the expression of PPFP in terms of the development of thyroid cancer. We also will assess whether both the PAX8 and PPARG DNA binding domains within PPFP are important by studying mice in which PPFP has appropriate mutations. Analyses of histology, gene expression and DNA binding will provide insight into the genes regulated by PPFP that contribute to the development and progression of thyroid cancer. We will use a non-adipogenic PPARg ligand to test whether the adipogenic nature of the Pio response is critical to its therapeutic effect. We also will test whether arsenic trioxide is therapeutic, especially in combination with Pio. This hypothesis derives from the observation that PPFP + Pio strongly induces AQP7, a channel protein through which arsenic enters cells. In Aim 2, we will perform a phase II clinical trial to determine whether Pio is therapeutic in patients with metastatic PPFP thyroid cancer not treatable by standard therapies. The primary endpoint will be a decrease in the size of metastases. A secondary endpoint will be measurement of lipid content of metastases that do not completely resolve, based upon the observation that treatment of our mouse model of this cancer with Pio results in an adipogenic response in the surviving thyroid cells. Other secondary endpoints include changes in serum thyroglobulin and testing the ability of Pio to induce radioiodine uptake in the cancer, followed b radioiodine therapy if indicated. Overall, these studies will help elucidate mechanisms through which PPFP contributes to thyroid cancer and will help identify novel therapies both in the transgenic mouse model and in patients.

描述（由申请方提供）：约35%的滤泡性甲状腺癌存在染色体易位，该易位融合了配对盒基因8（PAX 8）与过氧化物酶体增殖物激活受体γ基因（PPARG），导致产生PAX 8-PPARG融合蛋白（表示为PPFP）。PPFP含有核受体PPARG 1的全部序列，因此PPFP与PPARG应答基因和PPARG配体结合。我们已经建立了这种癌症的第一个转基因小鼠模型。癌症是局部浸润性的，并形成肺转移。用PPARG激动剂吡格列酮（Pio）治疗可以使甲状腺缩小到几乎控制大小并消除转移性疾病。最值得注意的是，这种治疗反应的特征在于转分化型过程，其中剩余的甲状腺细胞产生大的脂滴并表达广泛的PPARG诱导的脂肪细胞基因。由于PPARG是脂肪形成的主要调节剂，这些结果表明，在Pio的存在下，PPFP是强PPARG样的。我们假设Pio在PPFP癌症中的抗肿瘤作用与这种脂肪细胞转分化样效应有关;即，甲状腺癌细胞获得成熟脂肪细胞表型越多，它们保留的恶性表型就越少。在目的1中，我们将评估PPFP在小鼠模型中的致癌作用。有证据表明，在没有Pio的情况下，PPFP可以抑制PPARG对某些靶基因的诱导，并且内源性PPARG的抑制可能是PPFP的致癌性质的基础。因此，我们将测试PPARG的基因缺失是否模仿甲状腺癌发展方面的PPFP表达。我们还将通过研究PPFP具有适当突变的小鼠来评估PPFP内的PAX 8和PPARG DNA结合结构域是否重要。对组织学、基因表达和DNA结合的分析将提供对PPFP调控的基因的深入了解，这些基因有助于甲状腺癌的发展和进展。我们将使用非脂肪形成PPARg配体来测试Pio反应的脂肪形成性质是否对其治疗效果至关重要。我们还将测试砷是否 三氧化物是治疗性的，特别是与Pio组合。这一假设来自PPFP + Pio强烈诱导AQP 7的观察，AQP 7是砷进入细胞的通道蛋白。在目标2中，我们将进行一项II期临床试验，以确定Pio是否对标准疗法无法治疗的转移性PPFP甲状腺癌患者具有治疗作用。主要终点将是转移灶大小的减小。次要终点将是测量未完全消退的转移瘤的脂质含量，这是基于用Pio治疗这种癌症的小鼠模型导致存活甲状腺细胞中的脂肪形成反应的观察结果。其他次要终点包括血清甲状腺球蛋白的变化和检测Pio诱导癌症中放射性碘摄取的能力，如有指征，随后进行B放射性碘治疗。总的来说，这些研究将有助于阐明PPFP导致甲状腺癌的机制，并有助于在转基因小鼠模型和患者中确定新的治疗方法。