Targeting FGFR4, RAS, and PAX3-FOXO1 gene in Rhabdomyosarcoma

横纹肌肉瘤中靶向 FGFR4、RAS 和 PAX3-FOXO1 基因

• 批准号: 10702449
• 负责人: Javed Khan
• 金额: $ 102.52万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10702449
• 关键词: Age; Alveolar; Amino Acids; Antibodies; Antibody-drug conjugates; Apert-Crouzon syndrome; Biology; Cancer Biology; Childhood Soft Tissue Sarcoma; Chromosomal translocation; Chromosome 13; Clinical Trials Design; Code; Colon Carcinoma; Development; Diagnosis; Disease; Embryonal Rhabdomyosarcoma; Endometrial Carcinoma; Epigenetic Process; Event; FGFR1 gene; FGFR2 gene; FGFR3 gene; FGFR4 gene; FOXO1A gene; Fibroblast Growth Factor Receptor Family Gene; Fibroblast Growth Factor Receptors; Gene Expression Profiling; Gene Family; Genes; Genetic Polymorphism; Genome; Genomics; Germ-Line Mutation; Glioblastoma; Goals; Growth; Growth Factor Receptor Genes; Histologic; Human; Lead; Loss of Heterozygosity; Malignant Neoplasms; Malignant neoplasm of lung; Manuscripts; Molecular; Monoclonal Antibodies; Mutate; Mutation; Natural Products; Oncogenes; Oncogenic; Outcome; PAX3 gene; Pathway interactions; Patients; Pattern; Pfeiffer Syndrome; Phenotype; Process; Prognosis; Proteins; Publishing; Reagent; Receptor Protein-Tyrosine Kinases; Reporting; Rhabdomyosarcoma; Site; Somatic Mutation; Testing; Tumor Biology; angiogenesis; cell motility; chimeric antigen receptor; diagnostic biomarker; efficacy testing; epigenome; fusion gene; hypochondroplasia; improved; in vivo; inhibiting antibody; inhibitor; insight; interest; mRNA Expression; malignant breast neoplasm; member; mouse model; neoplastic cell; new therapeutic target; novel strategies; older patient; paralogous gene; sarcoma; small molecule inhibitor; targeted treatment; tumor; tumor progression

Rhabdomyosarcoma (RMS) is a rare pediatric soft tissue sarcoma typically classified as either alveolar (ARMS) or embryonal histological subtypes. ARMS is observed in older patients and is associated with a chromosomal translocation creating a fusion gene involving FOXO1A on chromosome 13 and members of the PAX gene family. Embryonal RMS is characterized by a younger age at diagnosis, loss of heterozygosity and altered patterns of genomic imprinting1. An important determinant of poor long term survival for all RMS histological subtypes is the presence of metastatic disease. Factors contributing to tumor progression and metastatic disease are not well understood. Analysis of gene expression patterns have led to improved accuracy of tumor identification and advances in sarcoma biology, particularly new insights into possible mechanisms of metastatic regulators. We and others have previously reported that FGFR4, a receptor tyrosine kinase (RTK) member of the fibroblast growth factor receptor (FGFR) gene family, is highly expressed in RMS and mRNA expression correlates with protein levels. These observations suggest that FGFR4 could be a tumor specific diagnostic marker and/or a determinant of tumor biology. In other human cancers, the presence of a common polymorphism in the coding region (FGFR4 G388R) is associated with increased tumor cell motility and prognosis in patients with sarcomas, colon or breast cancer. The FGFR genes are of great interest in cancer biology because they regulate essential processes including cellular survival, motility, development, and angiogenesis. Comparison of the FGFR coding regions indicates segments of high amino acid conservation in FGFR1, FGFR2, FGFR3, and FGFR4. Germline mutations in these paralogs have been described for several rare, highly penetrant Medelian disorders including Crouzon syndrome, Pfeiffer syndrome, and hypochondroplasia. Somatic mutations at the same sites of paralologs have been observed within the FGFR TK domains in glioblastoma multiforme, breast cancer, lung cancer and endometrial carcinoma. These observations lead us to hypothesize that FGFR4 activation, perhaps by somatic mutational events, could be critical to the oncogenic process in RMS, sarcomas, or other cancers. Furthermore, FGFR4 over activity could be associated with advanced stage disease and poor outcome. We have now published a manuscript that confirms that activating FGFR4 mutations occur in 7.5% or RMS and that over expression is associated with a more aggressive phenotype. Our group has also recently performed a comprehensive genomic analysis of the rhabdomyosarcoma genome and found that RAS pathway genes are mutated in 50% of fusion negative rhabdomyosarcoma. Finally we are dedicating considerable efforts in characterizing the molecular, epigentic and functional effects of the PAX3/7- FOXO1 fusion oncogene, and developing novel strategies to target the epigenome of fusion positive rhabdomyosarcoma, including a natural product screen. We are therefore developing new therapies targeting FGFR4, RAS and the fusion gene in rhabdomyosarcoma.

横纹肌肉瘤（RMS）是一种罕见的小儿软组织肉瘤，通常被归类为肺泡（臂）或胚胎组织学亚型。在老年患者中观察到了手臂，并且与染色体易位有关，从而在13号染色体上产生涉及FoxO1a的融合基因和PAX基因家族成员。胚胎RMS的特征是诊断时年龄较小，杂合性丧失和基因组印记的模式改变。所有RMS组织学亚型的长期生存不良的重要决定因素是转移性疾病的存在。尚不清楚导致肿瘤进展和转移性疾病的因素。基因表达模式的分析导致肿瘤鉴定和肉瘤生物学的进步的准确性提高，尤其是对转移性调节剂可能机制的新见解。我们和其他人先前已经报道说，成纤维细胞生长因子受体（FGFR）基因家族的受体酪氨酸激酶（RTK）成员FGFR4在RMS中高度表达，mRNA表达与蛋白质水平相关。 这些观察结果表明，FGFR4可能是肿瘤特异性诊断标记和/或肿瘤生物学决定因素。在其他人类癌症中，编码区（FGFR4 G388R）中存在常见的多态性与肉瘤，结肠或乳腺癌患者的肿瘤细胞运动和预后的增加有关。 FGFR基因对癌症生物学具有极大的兴趣，因为它们调节了基本过程，包括细胞存活，运动，发育和血管生成。 FGFR编码区的比较表明FGFR1，FGFR2，FGFR3和FGFR4中高氨基酸保护的段。这些旁系同源物中的种系突变已被描述为几种罕见的高度渗透性中间疾病，包括克鲁宗综合征，pfeiffer综合征和下软骨质。在胶质母细胞瘤多形，乳腺癌，肺癌和子宫内膜癌的FGFR TK结构域中，已经观察到了同一动物学位点的体细胞突变。这些观察结果使我们假设FGFR4激活可能是通过躯体突变事件的激活对于RMS，肉瘤或其他癌症的致癌过程至关重要。此外，FGFR4的活动可能与晚期舞台疾病和不良预后有关。现在，我们发表了一份手稿，该手稿确认激活FGFR4突变发生在7.5％或RMS中，并且表达过度与更具侵略性的表型有关。我们的小组最近还对横纹肌肉瘤基因组进行了全面的基因组分析，发现RAS途径基因在50％的融合横纹肌肉瘤中突变。最后，我们正在为表征PAX3/7- FOXO1融合Oncogene的分子，表观和功能效应的分子，表观和功能效应，并制定新的策略来瞄准融合融合阳性横纹肌肉瘤的表观组，包括自然产品筛选。因此，我们正在开发针对横纹肌肉瘤中FGFR4，RAS和融合基因的新疗法。