Molecular Predictive Testing in Ocular Melanoma

眼部黑色素瘤的分子预测测试

• 批准号: 7250878
• 负责人: JAMES WILLIAM HARBOUR
• 金额: $ 21.54万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7250878
• 关键词: Address; Biological Assay; Biological Markers; Biopsy Specimen; Cause of Death; Cells; Cessation of life; Class; Clinical; Clinical Pathology; Condition; Data; Development; Diagnosis; Disease; Distant; Early identification; Excision; Eye; Eye Neoplasms; Future; Gene Expression; Gene Expression Profile; Individual; Institutes; Laboratories; Lead; Malignant Neoplasms; Melanoma Cell; Microarray Analysis; Microscopic; Modeling; Molecular; Neoplasm Metastasis; Numbers; Ocular Melanoma; Organ; Paraffin Embedding; Patient Care; Patients; Pattern; Primary Neoplasm; Prognostic Marker; Prophylactic treatment; Purpose; Reproducibility; Research Personnel; Resistance; Risk; Sampling; Special Equipment; Specimen; Staging; Staining method; Stains; Testing; Time; Tumor Burden; Tumor Tissue; Validation; Work; base; cancer therapy; cohort; follow-up; improved; insight; intracellular protein transport; metastatic process; neoplastic cell; novel therapeutics; prognostic; programs; prophylactic; protein localization location; research and development; research study; small molecule; therapeutic target; therapy resistant; tumor; tumor progression

DESCRIPTION (provided by applicant): Most cancer deaths are caused by metastasis to distant organs, and treatment is usually ineffective if withheld until metastasis is clinically detectable. Fortunately, recent work in several cancers has shown that molecular information obtained from the primary tumor can predict metastatic risk, thereby permitting prophylactic treatment of high-risk patients at an early stage of metastasis. Ocular melanoma provides an ideal model for developing and validating such a preemptive strategy. Up to 50% of ocular melanoma patients die of metastasis despite successful treatment of the primary eye tumor, indicating that most patients who die of metastasis have microscopic, undetectable metastatic disease prior to ocular treatment. Metastatic disease usually goes undetected for 2-5 years after diagnosis and treatment of the primary ocular tumor, which allows the metastatic tumor cells to undergo up to 30 doublings, resulting in a large tumor burden of genetically deregulated cells that are highly resistant to treatment. Consequently, by the time metastatic disease is detected, death inexorably occurs within 5-7 months. Ocular melanoma cells are likely to be sensitive to many new molecular therapies, if treatment could be instituted earlier in the metastatic process. These observations suggest that early identification of high-risk patients and prophylactic treatment for presumptive metastatic disease may improve survival. Unfortunately, there are currently no biomarkers for ocular melanoma that are sufficiently accurate and/or practical to identify high-risk patients. To address this deficiency, we developed a gene expression profile that identifies high-risk patients with far greater accuracy than previous prognostic indicators. Conversion of this RNA-based assay to an immunohistochemical (IHC) platform is critical for continued development of this discovery. An IHC platform would be practical for routine clinical use, and it would allow the assay to be validated using archival tumors. Here, we propose experiments to identify and validate lead IHC markers in two independent tumor sets, then to evaluate the predictive accuracy of the IHC-based assay in a large patient cohort from the Collaborative Ocular Melanoma Study. These studies are likely to impact patient care by identifying high-risk patients, providing a framework for testing prophylactic therapies, revealing new therapeutic targets and offering new mechanistic insights into cancer progression.

描述（由申请人提供）：大多数癌症死亡是由转移到远处器官引起的，如果在临床上可检测到转移之前停止治疗，通常是无效的。幸运的是，最近在几种癌症中的研究表明，从原发性肿瘤中获得的分子信息可以预测转移风险，从而允许在转移的早期阶段对高危患者进行预防性治疗。眼黑色素瘤为开发和验证这种先发制人的策略提供了一个理想的模型。尽管原发性眼部肿瘤治疗成功，但高达50%的眼部黑色素瘤患者死于转移，这表明大多数死于转移的患者在眼部治疗之前患有显微镜下不可检测的转移性疾病。转移性疾病通常在原发性眼部肿瘤的诊断和治疗后2-5年内未被检测到，这使得转移性肿瘤细胞经历多达30次倍增，导致对治疗具有高度抗性的基因失调细胞的大肿瘤负荷。因此，当检测到转移性疾病时，死亡不可避免地在5-7个月内发生。眼黑色素瘤细胞可能对许多新的分子疗法敏感，如果治疗可以在转移过程中更早开始。这些观察结果表明，早期识别高危患者和预防性治疗可能会提高生存率。不幸的是，目前还没有足够准确和/或实用的眼黑色素瘤生物标志物来识别高风险患者。为了解决这一缺陷，我们开发了一种基因表达谱，该基因表达谱识别高风险患者的准确性远远高于以前的预后指标。将这种基于RNA的检测方法转换为免疫组织化学（IHC）平台对于这一发现的持续发展至关重要。IHC平台对于常规临床使用将是实用的，并且它将允许使用存档肿瘤来验证测定。在这里，我们提出了在两个独立的肿瘤组中鉴定和验证主要IHC标志物的实验，然后在来自眼黑色素瘤协作研究的大型患者队列中评估基于IHC的测定的预测准确性。这些研究可能会通过识别高风险患者、提供测试预防性疗法的框架、揭示新的治疗靶点并提供对癌症进展的新机制见解来影响患者护理。