PHIP as a Biomarker of Triple-Negative Melanoma

PHIP 作为三阴性黑色素瘤的生物标志物

• 批准号: 8696725
• 负责人: MOHAMMED KASHANI-SABET
• 金额: $ 42.48万
• 依托单位: CALIFORNIA PACIFIC MED CTR RES INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-09 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8696725
• 关键词: Attention; BRAF gene; Biological; Biological Markers; Cell Line; Classification; Complementary DNA; Cutaneous Melanoma; Development; Distant Metastasis; Down-Regulation; Fluorescent in Situ Hybridization; Gene Proteins; Human; Laboratories; Mediating; Mediator of activation protein; Melanoma Cell; Molecular; Mus; Mutation; Neoplasm Metastasis; PH Domain; PTEN gene; Patients; Play; Population; Prognostic Factor; Prognostic Marker; Protein Overexpression; Proteins; Public Health; Role; Staging; Ulcer; base; cohort; disease classification; inhibitor/antagonist; lymph nodes; melanoma; mutant; novel; outcome forecast; overexpression; prognostic; progression marker; protein expression; public health relevance; small hairpin RNA; small molecule; therapy development; tumor

DESCRIPTION (provided by applicant): Recent studies performed in our laboratory have identified novel roles for the pleckstrin homology domain interacting protein (PHIP) gene as a marker and mediator of melanoma progression. Increased PHIP levels were an independent predictor of melanoma survival. PHIP was activated in triple-negative melanomas (harboring wild type BRAF, NRAS and PTEN), thereby helping to characterize this poorly understood molecular subset of melanoma. In addition, shRNA-mediated down regulation of PHIP significantly suppressed the invasiveness and metastatic potential of both murine and human melanoma, including in triple-negative melanoma cell lines. In this proposal, we plan to confirm the important role played by PHIP as a biomarker for melanoma and its role as a mediator of melanoma progression. Our specific aims are: (1) to validate the prognostic role of PHIP in melanoma. We will assess the prognostic role of PHIP in a distinct cohort of 250 patients with primary melanoma amassed from a different population. We will determine PHIP levels using both immunohistochemical analysis and fluorescence in situ hybridization and correlate PHIP levels with survival. We will also assess PHIP levels in 200 melanoma metastases. This aim will validate the prognostic impact of PHIP in melanoma, and determine its role as a melanoma progression marker. (2) To assess the role of PHIP in the molecular classification of melanoma. We will examine the 450 melanomas with documented PHIP levels for the most commonly acquired mutations in melanoma, including BRAF, NRAS, and PTEN. This aim will serve to identify the molecular subtypes of melanoma with activated PHIP levels. It will also determine the proportion of triple-negative melanomas that have activated PHIP levels. (3) To validate the functional role of PHIP in the progression of human melanoma. We will examine the role of PHIP in mediating human melanoma progression. We will assess the consequences of both shRNA-mediated PHIP knockdown as well as PHIP overexpression in the progression of early-passage human melanoma cultures with defined BRAF mutational status. If successful, these studies will validate the role of PHIP as a novel molecular prognostic factor for melanoma and establish its utility in the molecular classification of this disease. Finally, they will validate he functional role of PHIP in melanoma progression, establishing it as a viable target for therapy.

描述（由申请人提供）：我们实验室最近进行的研究已经确定了 pleckstrin 同源结构域相互作用蛋白 (PHIP) 基因作为黑色素瘤进展的标记和介质的新作用。 PHIP 水平升高是黑色素瘤存活的独立预测因子。 PHIP 在三阴性黑色素瘤（含有野生型 BRAF、NRAS 和 PTEN）中被激活，从而有助于表征这一人们知之甚少的黑色素瘤分子亚型。此外，shRNA介导的PHIP下调显着抑制了小鼠和人类黑色素瘤的侵袭性和转移潜力，包括三阴性黑色素瘤细胞系。在本提案中，我们计划确认 PHIP 作为黑色素瘤生物标志物所发挥的重要作用及其作为黑色素瘤进展介质的作用。我们的具体目标是：(1) 验证 PHIP 在黑色素瘤中的预后作用。我们将评估 PHIP 在来自不同人群的 250 名原发性黑色素瘤患者的独特队列中的预后作用。我们将使用免疫组织化学分析和荧光原位杂交来确定 PHIP 水平，并将 PHIP 水平与生存相关联。我们还将评估 200 个黑色素瘤转移灶中的 PHIP 水平。该目标将验证 PHIP 对黑色素瘤的预后影响，并确定其作为黑色素瘤进展标志物的作用。 (2)评估PHIP在黑色素瘤分子分类中的作用。我们将检查 450 个记录有 PHIP 水平的黑色素瘤中最常见的黑色素瘤突变，包括 BRAF、NRAS 和 PTEN。这一目标将有助于识别具有激活 PHIP 水平的黑色素瘤的分子亚型。它还将确定激活 PHIP 水平的三阴性黑色素瘤的比例。 (3)验证PHIP在人类黑色素瘤进展中的功能作用。我们将研究 PHIP 在介导人类黑色素瘤进展中的作用。我们将评估 shRNA 介导的 PHIP 敲低以及 PHIP 过表达对具有明确 BRAF 突变状态的早期传代人类黑色素瘤培养物进展的影响。如果成功，这些研究将验证 PHIP 作为黑色素瘤新型分子预后因素的作用，并确立其在该疾病分子分类中的实用性。最后，他们将验证 PHIP 在黑色素瘤进展中的功能作用，将其确立为可行的治疗靶点。