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: 9036341
• 负责人: RONALD Jay KOENIG
• 金额: $ 49.6万
• 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/9036341
• 关键词: 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 Targeting; Genes; Genetic; Growth; Health; Histology; Invaded; Left; Ligands; Lipids; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of thyroid; Measurement; Measures; Metastatic Neoplasm to the Lung; Metastatic/Recurrent; Michigan; Modeling; Mus; Mutation; Nature; Neoplasm Metastasis; Normal Cell; Nuclear Hormone Receptors; Nuclear Receptors; Oncogenic; Operative Surgical Procedures; PPAR gamma; 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; in vivo; insight; lipid biosynthesis; malignant phenotype; mouse model; novel therapeutics; radioiodine therapy; response; transdifferentiation; treatment 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-PPARγ fusion protein denoted PPFP. PPFP contains the full sequence of the nuclear receptor PPARγ1, and hence PPFP binds to PPAR-responsive genes and to PPARγ ligands. We have created the first transgenic mouse model of this cancer. The cancer is locally invasive and forms lung metastases. Treatment with the PPARγ 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 PPARγ- inducible adipocyte genes. Since PPARγ is the master regulator of adipogenesis, these results indicate that, in the presence of Pio, PPFP is strongly PPARγ-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 PPARγ induction of some target genes, and that inhibition of endogenous PPARγ may underlie the oncogenic nature of PPFP. Therefore, we will test whether the genetic deletion of PPARγ 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 PPARγ 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（由适用提供）：大约35％的卵泡甲状腺癌携带染色体易位，该染色体易位，将配对的盒子基因8（PAX8）与过氧化物体增殖物激活受体伽马基因（PPARG）融合在一起，从而导致PAX8-PPPARγFusionfifusion Protein deNoteSppppppppppppppppppppppppppp。 PPFP包含核受体PPARγ1的完整序列，因此PPFP与PPAR反应基因和PPARγ配体结合。我们创建了该癌症的第一个转基因小鼠模型。癌症是局部侵入性的，形成肺转移。用PPARγ激动剂吡格列酮（PIO）治疗几乎可以控制甲状腺以控制大小并消除转移性疾病。最值得注意的是，该理论响应的特征是跨分化型过程，其余的甲状腺细胞会产生大脂质液滴并表达广泛的PPARγ-诱导脂肪细胞基因。由于PPARγ是脂肪形成的主要调节剂，因此这些结果表明，在PIO存在下，PPFP具有强烈的PPARγ样。我们假设PIO在PPFP癌症中的抗肿瘤作用与这种脂肪细胞跨分化样效应有关。即，甲状腺癌细胞获得成熟的脂肪细胞表型的越多，其恶性表型的保留就越少。在AIM 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可以抑制某些靶基因的PPARγ诱导，并且内源性PPARγ的抑制可能是PPFP的致癌性质。因此，我们将测试PPARγ的遗传缺失是否模仿甲状腺癌的发展中PPFP的表达。我们还将评估PPFP中PAX8和PPARG DNA结合结构域是否通过研究PPFP具有适当突变的小鼠是否很重要。组织学，基因表达和DNA结合的分析将为由PPFP调节的基因提供洞察，这些基因有助于甲状腺癌的发展和进展。我们将使用非辅助PPARγ配体来测试PIO反应的成生性对于其治疗作用至关重要。我们还将测试是否砷 三氧化物是治疗性的，尤其是与PIO结合使用。该假设来自于观察到PPFP + PIO强烈诱导AQP7，AQP7是一种通道蛋白，砷通过该蛋白进入细胞。在AIM 2中，我们将进行II期临床试验，以确定PIO在转移性PPFP甲状腺癌患者中是否具有治疗性，不受标准疗法治疗。主要终点将减少转移的大小。次要终点将是基于观察到，使用PIO对我们的小鼠模型的处理导致存活甲状腺细胞的掺杂反应，将测量未完全解决的转移酶的脂质含量。其他次要终点包括血清甲状腺球蛋白的变化以及测试PIO在癌症中诱导放射性碘摄取的能力，如有指示，b放射性药物治疗。总体而言，这些研究将有助于阐明PPFP促进甲状腺癌的机制，并将有助于在转基因小鼠模型和患者中鉴定新的疗法。