Harnessing p27 for Prognostication of Pediatric Osteosarcoma

利用 p27 预测小儿骨肉瘤

• 批准号: 8416484
• 负责人: Tsz-Kwong Man
• 金额: $ 29.38万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8416484
• 关键词: Acute Myelocytic Leukemia; Adult; Area; Autoantibodies; Biological Assay; Biological Markers; Breast Carcinoma; CDKN1B gene; CDKN1C gene; Cancer Patient; Cell Line; Cells; Child; Childhood Osteosarcoma; Children' s Oncology Group; Clinical; Comb animal structure; Data; Detection; Development; Diagnosis; Genomics; Goals; Human; Immunohistochemistry; Laboratories; Lead; Literature; Malignant - descriptor; Malignant Bone Neoplasm; Malignant Neoplasms; Malignant neoplasm of pancreas; Medicine; Metastatic Osteosarcoma; Methods; Molecular; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; Ovarian Carcinoma; Pathology; Pathway interactions; Patients; Pediatric Hospitals; Pharmaceutical Preparations; Phosphorylation; Prognostic Factor; Prognostic Marker; Protein Array; Protein Family; Proteins; Proteomics; Proto-Oncogene Proteins c-akt; RHOA gene; Risk; Sampling; Sampling Studies; Series; Serum; Survival Rate; Testing; Texas; Time; Treatment Protocols; Tumor Suppressor Proteins; Validation; base; cell motility; chemotherapy; clinical risk; cyclin-dependent kinase inhibitor 1B; density; follow-up; high risk; human FRAP1 protein; imaging modality; improved; member; minimally invasive; mutant; novel; osteosarcoma; outcome forecast; prevent; prognostic; protein expression; public health relevance; tumor; young adult

DESCRIPTION (provided by applicant): Osteosarcoma is the most common malignant tumor in children and young adults. Despite the use of surgery and multi-drug chemotherapy, the survival rate of osteosarcoma patients has not improved in the past three decades. Personalized medicine holds the promise of improving the treatment of cancer patients; however, it relies on an accurate way to predict clinical risks before treatment initiation. In osteosarcoma, the only prognostic factor at the time of diagnosis is the detection of metastasis by conventional low-sensitive imaging methods. We reason that the development of a molecular prognostic biomarker will facilitate personalized medicine, so that an alternative or a targeted therapy can be used to improve the outcome of the high-risk patients, while the low-risk patients would be spared from unnecessary chemotherapy. A vast amount of literature has shown that the tumor suppressor p27 can be used to predict prognosis in various adult cancers, such as breast carcinomas, acute myelogenous leukemia, pancreatic cancer and ovarian carcinomas. Our laboratory has demonstrated that p27 is mislocalized in metastatic osteosarcoma cell lines and frequently in human osteosarcoma cases. Functional studies have further shown that cytoplasmic p27 can promote the motility and invasiveness of osteosarcoma cells. In addition, we have demonstrated that the p27 autoantibody is elevated in metastatic osteosarcoma patients using high-density protein arrays. Based on these observations, we hypothesize that p27, which is a prognostic biomarker in adult cancers, can be used to prognosticate pediatric osteosarcoma. To test this hypothesis, we propose four Specific Aims. First, we will correlate the protein expression and subcellular localization of p27 with metastasis and survival information in two series of osteosarcoma cases. Second, we will integrate the p27 results with other related prognostic biomarkers to test if we can increase the prognostic significance of the detection. Third, we will develop a novel Luminex-based assay for the p27 autoantibody to validate if it correlates with the outcomes of osteosarcoma patients using pre-treatment serum samples collected from the Children's Oncology Group. Lastly, we will perform genomic and targeted proteomic analyses of a panel of p27 mutants that have been generated in our laboratory to identify novel p27-related biomarkers. These candidate biomarkers will be validated using the data generated from our SPECS and TARGET consortia. All the biomarker results will be compared with the existing prognostic factor, i.e. metastasis, to test the clinical utility of the biomarkers. The long-term goal of this study is to develop a biomarker approach for the prognostication of osteosarcoma patients at the time of diagnosis that is more accurate than the conventional approaches. It would facilitate the development of personalized medicine and, hence, improve the survival of osteosarcoma patients. Completion of the proposed study is a critical step to achieve this goal. Furthermore, since p27 has been implicated in other cancers, the results obtained from this study will have a larger impact on the field of cancer biomarkers.

描述（申请人提供）：骨肉瘤是儿童和年轻人最常见的恶性肿瘤。尽管使用手术和多药化疗，在过去的三十年里，骨肉瘤患者的存活率并没有提高。个性化医疗有望改善癌症患者的治疗；然而，它依赖于在治疗开始前准确预测临床风险的方法。在骨肉瘤中，诊断时唯一的预后因素是通过传统的低灵敏度成像方法检测转移。我们认为，分子预后生物标志物的开发将促进个性化医疗，从而可以使用替代或靶向治疗来改善高危患者的预后，而低风险患者则可以避免不必要的化疗。大量文献表明，肿瘤抑制因子p27可用于预测各种成人癌症的预后，如乳腺癌、急性髓性白血病、胰腺癌、卵巢癌等。我们的实验室已经证明p27在转移性骨肉瘤细胞系中错误定位，并且经常在人骨肉瘤病例中错误定位。功能研究进一步表明，胞质p27可促进骨肉瘤细胞的运动和侵袭性。此外，我们已经证明p27自身抗体在转移性骨肉瘤患者中使用高密度蛋白阵列升高。基于这些观察结果，我们假设p27作为成人癌症的预后生物标志物，可以用于预测儿童骨肉瘤。为了验证这一假设，我们提出了四个具体目标。首先，我们将在两组骨肉瘤病例中将p27的蛋白表达和亚细胞定位与转移和生存信息联系起来。其次，我们将整合p27结果与其他相关的预后生物标志物，以测试我们是否可以增加检测的预后意义。第三，我们将开发一种新的基于luminex的p27自身抗体检测方法，以验证其是否与骨肉瘤患者的预后相关，该方法使用从儿童肿瘤组收集的治疗前血清样本。最后，我们将对实验室中产生的一组p27突变体进行基因组学和靶向蛋白质组学分析，以鉴定新的p27相关生物标志物。这些候选生物标志物将使用我们的SPECS和TARGET联盟生成的数据进行验证。所有的生物标志物结果将与现有的预后因素（即转移）进行比较，以检验临床疗效