Diversity Supplement for Molecular Predictive Testing in Ocular Melanoma

眼部黑色素瘤分子预测测试的多样性补充

• 批准号: 10220448
• 负责人: JAMES WILLIAM HARBOUR
• 金额: $ 3.91万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10220448
• 关键词: Adjuvant Therapy; Asses; Benign; Biological Markers; Blood specimen; Cessation of life; Disease; Funding; Gene Expression Profile; Grant; Industry Standard; Malignant - descriptor; Measurable; Melanocytic Neoplasm; Messenger RNA; Metastatic to; MicroRNAs; Micrometastasis; Molecular; Mutation; Ocular Melanoma; Patients; Primary Neoplasm; Research; Risk; Systemic Therapy; Testing; Uveal Melanoma; base; high risk; improved; innovation; malignant neoplasm of eye; patient stratification; personalized genomic medicine; predictive test; prognostic; prognostic assays; prognostic value; programs; prospective

Project Summary Uveal melanoma (UM) is a highly aggressive eye cancer that leads to metastatic death in up to half of patients. UM has a propensity to undergo early micrometastasis prior to treatment of the primary tumor, with later emergence of overt metastatic disease. Consequently, there has been no measurable improvement in survival over the past half century. The overall objective of our research program is to improve survival by developing highly accurate prognostic tests, based on biomarkers we discovered in the lab. In this proposal, we propose to (1) stratify patients with high-risk medium and large UMs to adjuvant therapy and increased metastatic surveillance, and (2) stratify patients with high-risk small UMs to early preemptive treatment of the primary tumor. During previous funding periods, we developed a highly innovative UM gene expression profile-based prognostic test (UM-GEP) that has been commercialized and is now used by a majority of centers in the US and beyond, to asses metastatic risk and make management decisions. Despite being recognized as the first- in-class industry standard in the field, there is a critical need to further improve its prognostic accuracy. We have since discovered new prognostically significant mutations in BAP1 and SF3B1 and a new mRNA biomarker (PRAME) that will set a new standard for prognostic accuracy, while also guiding the choice of systemic therapy. In this competitive renewal, we propose (1) to perform a landmark prospective 28-center study to optimize and validate these new biomarkers to expand the prognostic ability of the UM-GEP test and guide the choice of systemic therapy, and (2) to develop a ground breaking new prognostic test based on circulating exosomal microRNA profiling performed on routine blood samples, which will greatly expand the number of patients with benign and malignant uveal melanocytic tumors who will directly benefit from this personalized genomic medicine approach. 7

项目摘要 葡萄膜黑色素瘤（UM）是一种高度侵袭性的眼癌，导致多达一半的患者转移性死亡。 UM在原发性肿瘤治疗前有发生早期微转移的倾向， 出现明显的转移性疾病。因此，在生存率方面没有可衡量的改善， 在过去的半个世纪。我们研究计划的总体目标是通过开发 基于我们在实验室发现的生物标志物的高度准确的预后测试。在本提案中，我们建议 （1）将高风险中型和大型UM患者分层接受辅助治疗， 监测，和（2）分层高风险的小UM患者的早期先发制人的治疗的主要 肿瘤在之前的资助期间，我们开发了一种高度创新的基于UM基因表达谱的 预后检测（UM-GEP）已商业化，目前在美国的大多数中心使用 以及其他方面，评估转移风险并做出管理决策。尽管被认为是第一个- 在该领域的同类行业标准中，迫切需要进一步提高其预测准确性。我们 此后，他们在BAP 1和SF 3B 1中发现了新的具有重要意义的突变， 生物标志物（PRAME）将为预后准确性设定新的标准，同时也指导 全身治疗在本次竞争性更新中，我们建议（1）进行一项具有里程碑意义的前瞻性28中心研究 优化和验证这些新生物标志物的研究，以扩大UM-GEP测试的预后能力， 指导系统治疗的选择，（2）开发一种突破性的新的预后测试， 在常规血液样本上进行的循环外泌体microRNA分析，这将极大地扩展 良性和恶性葡萄膜黑色素细胞肿瘤患者的数量将直接受益于此 个性化的基因组医学方法。 7

项目成果

Epigenetic reprogramming of melanoma cells by vitamin C treatment.

通过维生素C治疗对黑色素瘤细胞的表观遗传重编程。

• DOI: 10.1186/s13148-015-0087-z
• 发表时间: 2015
• 期刊: Clinical epigenetics
• 影响因子: 5.7
• 作者: Gustafson CB;Yang C;Dickson KM;Shao H;Van Booven D;Harbour JW;Liu ZJ;Wang G
• 通讯作者: Wang G

PRAME as an Independent Biomarker for Metastasis in Uveal Melanoma.

• DOI: 10.1158/1078-0432.ccr-15-2071
• 发表时间: 2016-03-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Field MG;Decatur CL;Kurtenbach S;Gezgin G;van der Velden PA;Jager MJ;Kozak KN;Harbour JW
• 通讯作者: Harbour JW

Intraocular Dissemination of Uveal Melanoma Cells Following Radiotherapy: Evolving Management Over the Past Decade.

放射治疗后葡萄膜黑色素瘤细胞的眼内播散：过去十年管理的演变。

• DOI: 10.3928/23258160-20190905-06
• 发表时间: 2019
• 期刊: Ophthalmic surgery, lasers & imaging retina
• 作者: Paez-Escamilla,Manuel;Walter,ScottD;Mohsenin,Amir;Decatur,ChristinaL;Harocopos,GeorgeJ;Dubovy,Sander;Harbour,JWilliam
• 通讯作者: Harbour,JWilliam

Gene Expression Profiling and PRAME Status Versus Tumor-Node-Metastasis Staging for Prognostication in Uveal Melanoma.

• DOI: 10.1016/j.ajo.2018.07.045
• 发表时间: 2018-11
• 期刊: American journal of ophthalmology
• 影响因子: 4.2
• 作者: Cai L;Paez-Escamilla M;Walter SD;Tarlan B;Decatur CL;Perez BM;Harbour JW
• 通讯作者: Harbour JW

ChIPprimersDB: a public repository of verified qPCR primers for chromatin immunoprecipitation (ChIP).

• DOI: 10.1093/nar/gky813
• 发表时间: 2019-01-08
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Kurtenbach S;Reddy R;Harbour JW
• 通讯作者: Harbour JW