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: 8451143
• 负责人: RONALD Jay KOENIG
• 金额: $ 50.43万
• 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/8451143
• 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（由申请人提供）：约 35% 的滤泡性甲状腺癌存在染色体易位，该染色体易位将配对盒基因 8 (PAX8) 与过氧化物酶体增殖物激活受体 γ 基因 (PPARG) 融合，导致产生称为 PPFP 的 PAX8-PPARG 融合蛋白。 PPFP 包含核受体 PPARG1 的完整序列，因此 PPFP 与 PPARG 响应基因和 PPARG 配体结合。我们创建了第一个这种癌症的转基因小鼠模型。该癌症具有局部侵袭性并形成肺转移。使用 PPARG 激动剂吡格列酮 (Pio) 治疗可缩小甲状腺，几乎控制大小并消除转移性疾病。最值得注意的是，这种治疗反应的特点是转分化型过程，其中剩余的甲状腺细胞产生大的脂滴并表达多种 PPARG 诱导的脂肪细胞基因。由于 PPARG 是脂肪生成的主要调节因子，这些结果表明，在 Pio 存在的情况下，PPFP 与 PPARG 非常相似。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作用有关。也就是说，甲状腺癌细胞获得成熟脂肪细胞表型的越多，它们保留的恶性表型就越少。在目标 1 中，我们将评估 PPFP 在小鼠模型中的致癌作用。有证据表明，在缺乏 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 致癌性的基础。因此，我们将测试PPARG的基因缺失是否在甲状腺癌的发展过程中模拟PPFP的表达。我们还将通过研究 PPFP 具有适当突变的小鼠来评估 PPFP 内的 PAX8 和 PPARG DNA 结合域是否重要。对组织学、基因表达和 DNA 结合的分析将深入了解 PPFP 调节的基因，这些基因有助于甲状腺癌的发生和进展。我们将使用非脂肪形成的 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。我们还将测试是否砷 三氧化二氮具有治疗作用，特别是与 Pio 结合使用。该假说源于观察到 PPFP + Pio 强烈诱导 AQP7，砷通过该通道蛋白进入细胞。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 甲状腺癌患者有治疗作用。主要终点是转移灶尺寸的减小。次要终点是测量未完全消退的转移灶的脂质含量，这是基于观察到用 Pio 治疗这种癌症的小鼠模型会导致存活的甲状腺细胞产生脂肪生成反应。其他次要终点包括血清甲状腺球蛋白的变化以及测试 Pio 诱导癌症吸收放射性碘的能力，然后根据需要进行放射性碘治疗。总体而言，这些研究将有助于阐明 PPFP 导致甲状腺癌的机制，并将有助于确定转基因小鼠模型和患者的新疗法。