Blood-based detection of BRAF DNA as a biomarker in metastatic melanoma patients

基于血液的 BRAF DNA 检测作为转移性黑色素瘤患者的生物标志物

• 批准号: 8028544
• 负责人: DAVID POLSKY
• 金额: $ 18.38万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-23 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8028544
• 关键词: Accounting; Age of Onset; Animal Model; BRAF gene; Biological Assay; Biological Markers; Biopsy; Biopsy Specimen; Blood; Blood specimen; Cell Proliferation; Cessation of life; Clinical; Clinical Markers; Clinical Trials; Colon Carcinoma; Critical Pathways; DNA; Data; Decision Making; Detection; Development; Diagnostic; Disease; Disease Marker; Disease Progression; Distant; Early Diagnosis; Effectiveness; Enrollment; Evaluation; Generations; Genotype; Goals; Image; Imatinib; In Vitro; Individual; Lactate Dehydrogenase; MEKs; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant neoplasm of thyroid; Medicine; Metastatic Melanoma; Methodology; Mitogen-Activated Protein Kinases; Molecular; Monitor; Mutation; Neoplasm Metastasis; Oncogenes; Outcome; Patient Care; Patients; Protein-Serine-Threonine Kinases; Proteins; Proto-Oncogene Proteins B-raf; Radiation; Recurrence; Role; Sensitivity and Specificity; Serological; Serum; Solid Neoplasm; Specimen; Staging; Survival Rate; Testing; Therapeutic; Therapeutic Agents; United States; base; clinical practice; cost; disorder risk; experience; follow-up; high risk; improved; inhibitor/antagonist; innovation; malignant breast neoplasm; melanoma; member; mutant; neoplastic cell; research study; response; small molecule; standard measure; tool; tumor; years of life lost

DESCRIPTION (provided by applicant): Melanoma remains a highly morbid disease in the United States. With a relatively young age of onset, the toll of melanoma in terms of "life-years lost" is second only to breast cancer among the major solid tumor malignancies. Despite advances in early detection, the number of deaths from melanoma has continued to rise. Current treatment options for metastatic melanoma are largely ineffective with dismal 5-year survival rates of only 3%-14%% for distant metastatic disease (stage IV). In addition, the only commonly used serologic marker of disease activity in the US, serum lactate dehydrogenase, has a poor sensitivity to detect disease progression leading clinicians to rely on expensive imaging studies to monitor disease. Overall, the annual estimated cost of treating melanoma in the United States is over $3.1 billion. Beginning in 2002 activating mutations in the serine-threonine kinase BRAF were identified at high rates in primary and metastatic melanoma, and subsequent in-vitro and animal model experiments demonstrated BRAF to be an oncogene in melanoma. The V600E substitution is a mutation hotspot, accounting for greater than 90% of the mutations identified in melanoma. In mid 2009 preliminary results from a clinical trial of PLX4032, a second generation small molecule inhibitor of the BRAFV600E protein, showed responses in the majority of patients carrying the BRAF V600E mutation. Currently, enrollment into clinical trials with PLX4032 is restricted to patients in whom a tumor biopsy can be obtained, and in which the mutation is detected. Based on our clinical trial experience, tumor genotyping currently takes 1-2 weeks or longer if there are difficulties obtaining a metastatic tumor specimen for genotyping. In addition, we and others have found that multiple metastases from individual patients may be discordant for the BRAF mutation (i.e. one tumor is mutant, a second tumor from the same patient is wild-type). Genotyping of a single tumor biopsy from individual patients, therefore, may inadvertently render some patients ineligible for a BRAF inhibitor who might otherwise derive benefit. To overcome these limitations we have developed a rapid, highly sensitive approach to detect mutant BRAF DNA in patient blood samples. Our Preliminary Data demonstrate that this approach is feasible in melanoma patients, as the results of blood-based testing are highly associated with the BRAF genotype of the tumor. The current proposal seeks to further optimize our methodology, and rigorously demonstrate its utility as a molecular diagnostic tool. In addition, we will test the utility of blood-based detection of BRAF DNA as a biomarker of disease activity. Using a blood sample to genotype a patient's solid tumor is a highly innovative approach in cancer medicine and has potential to change clinical practice not only in melanoma but also in the care of patients with other solid tumors such as thyroid, colon, ovarian and lung cancers which have significant rates of BRAF mutation. PUBLIC HEALTH RELEVANCE: Recently, a mechanism-based therapeutic agent targeting the mutant BRAF kinase has shown effectiveness in metastatic melanoma patients whose tumors have the mutation. We have developed a rapid, highly sensitive approach to detect mutant BRAF DNA in patient blood samples. The current proposal seeks to rigorously demonstrate the clinical utility of these assays as molecular diagnostic tools that have the potential to change the clinical practice in melanoma and potentially in other solid tumors in which mechanism-based therapies may be applied.

描述（由申请人提供）：黑色素瘤在美国仍然是一种高度病态的疾病。由于发病年龄相对较轻，黑色素瘤在主要实体肿瘤恶性肿瘤中的“生命年损失”仅次于乳腺癌。尽管在早期检测方面取得了进展，但黑色素瘤的死亡人数仍在继续上升。目前转移性黑色素瘤的治疗选择在很大程度上是无效的，对于远处转移性疾病（IV期），5年生存率仅为3%-14%。此外，美国唯一常用的疾病活动性血清学标志物血清乳酸脱氢酶检测疾病进展的灵敏度较差，导致临床医生依赖昂贵的影像学研究来监测疾病。总体而言，在美国治疗黑色素瘤的年度估计费用超过31亿美元。从2002年开始，在原发性和转移性黑色素瘤中以高比率鉴定丝氨酸-苏氨酸激酶BRAF中的激活突变，随后的体外和动物模型实验证明BRAF是黑色素瘤中的致癌基因。V600 E取代是突变热点，占黑色素瘤中发现的突变的90%以上。在2009年中期，来自PLX 4032（BRAFV 600 E蛋白的第二代小分子抑制剂）的临床试验的初步结果显示，在大多数携带BRAFV 600 E突变的患者中有反应。目前，PLX 4032临床试验的招募仅限于可以获得肿瘤活检并且检测到突变的患者。根据我们的临床试验经验，如果难以获得用于基因分型的转移性肿瘤标本，肿瘤基因分型目前需要1-2周或更长时间。此外，我们和其他人发现，来自个体患者的多个转移瘤可能与BRAF突变不一致（即一个肿瘤是突变型，来自同一患者的第二个肿瘤是野生型）。因此，对个体患者的单个肿瘤活检进行基因分型可能会无意中使一些患者不适合接受BRAF抑制剂治疗，否则这些患者可能会获益。为了克服这些局限性，我们开发了一种快速、高灵敏度的方法来检测患者血液样品中的突变BRAF DNA。我们的初步数据表明，这种方法在黑色素瘤患者中是可行的，因为血液检测的结果与肿瘤的BRAF基因型高度相关。目前的建议旨在进一步优化我们的方法，并严格证明其作为分子诊断工具的实用性。此外，我们将测试BRAF DNA作为疾病活动性生物标志物的血液检测的实用性。使用血液样本对患者的实体瘤进行基因分型是癌症医学中的一种高度创新的方法，并且不仅有可能改变黑色素瘤的临床实践，而且有可能改变具有显著BRAF突变率的其他实体瘤（如甲状腺癌、结肠癌、卵巢癌和肺癌）患者的护理。 公共卫生关系：最近，靶向突变型BRAF激酶的基于机制的治疗剂已经在其肿瘤具有突变的转移性黑素瘤患者中显示出有效性。我们已经开发了一种快速，高灵敏度的方法来检测患者血液样本中的突变BRAF DNA。目前的提案旨在严格证明这些检测作为分子诊断工具的临床实用性，这些工具有可能改变黑色素瘤的临床实践，并可能改变其他实体瘤的临床实践，其中可能应用基于机制的治疗。