OTHER FUNCTIONS - R&D BIOMEDICAL (BASIC RESEARCH)

其他功能-R

• 批准号: 8727411
• 负责人: DR. DAVID HOUT
• 金额: $ 149.94万
• 依托单位: INSIGHT GENETICS, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-20 至 2015-08-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8727411
• 关键词: Basic Science; Biological Assay; Cancer Detection; Cancer Etiology; Cancer Patient; Cancer cell line; Clinical; Clinical Trials; Companions; Development; Diagnosis; Diagnostic; Diagnostic tests; FDA approved; Fluorescent in Situ Hybridization; Genetic; KRAS2 gene; Malignant Neoplasms; Malignant neoplasm of lung; Mutation; Non-Small-Cell Lung Carcinoma; Oncogenic; Patient Selection; Pharmacologic Substance; Phase; Phase II Clinical Trials; Phosphotransferases; Polymerase Chain Reaction; ROS1 gene; Recurrence; Specimen; Testing; Therapeutic; Therapeutic Uses; Time; Tyrosine Kinase Inhibitor; Validation; base; cohort; commercialization; erbB Genes; inhibitor/antagonist; mortality; preclinical study; research and development; small molecule; sound

Lung cancer is the main cause of cancer mortality worldwide with 80% non-small cell lung cancer (NSCLC) in type and mainly driven by three mutually exclusive oncogenes, EGFR, KRAS and ALK (collectively between 30-60% of all NSCLC cases). Oncogenic drivers such as ROS1 and RET fusions and DEPDC1 over-expression have been identified as clearly recurrent, collectively constituting up to ~12% of all NSCLC cases. Preclinical studies have demonstrated ROS1-driven cancers to be exquisitely sensitive to small-molecule tyrosine kinase inhibitors (TKIs) as well as Hsp90 inhibitors that are now under development by several pharma and biotech firms. Similarly, ambiguous TKI treatments have also been used against non-NSCLC RET and DEPDC1 driven cancers in ongoing Phase I and Phase II clinical trials with good efficacy. These trials should encourage numerous pharmaceutical companies to follow suit and conduct similar clinical trials using therapeutics specifically targeting RET and DEPDC1-driven NSCLC. Unfortunately, no regulatory-approved, high-throughput commercial diagnostic tests are readily available to reliably and efficiently diagnose ROS1 or RET fusions nor DEPDC1 over expression in NSCLC patients. We propose to complete the development and validation of both a comprehensive panel of quantitative polymerase chain reaction (qPCR)-based assays and a fluorescence in situ hybridization (FISH) assay to collectively be used as a broad-based NSCLC detection panel to classify a previously unidentified, yet significant, cohort of NSCLC patients readily treatable with available therapeutics. All validations will establish clinical utility by ultimately testing a large cohort of clinical specimens to unequivocally demonstrate statistical significance for sound patient selection of inhibitor therapy. All potential companion diagnostics will then enter co-development with an IVD partner for full commercialization of each assay as a FDA-approved companion diagnostic.

肺癌是全球癌症死亡的主要原因，其中80%的非小细胞肺癌（NSCLC）主要由三种相互排斥的癌基因EGFR、KRAS和ALK（占所有NSCLC病例的30-60%）驱动。致癌驱动因素如ROS 1和RET融合以及DEPDC 1过表达已被确定为明显复发，合计占所有NSCLC病例的约12%。临床前研究表明，ROS 1驱动的癌症对小分子酪氨酸激酶抑制剂（TKI）以及目前正在由几家制药和生物技术公司开发的Hsp 90抑制剂非常敏感。类似地，在正在进行的I期和II期临床试验中，模糊TKI治疗也用于治疗非NSCLC RET和DEPDC 1驱动的癌症，疗效良好。这些试验应该鼓励许多制药公司效仿，并使用专门针对RET和DEPDC 1驱动的NSCLC的治疗方法进行类似的临床试验。不幸的是，没有监管机构批准的高通量商业诊断测试可以可靠有效地诊断NSCLC患者中的ROS 1或RET融合或DEPDC 1过表达。我们建议完成基于定量聚合酶链反应（qPCR）的检测试剂盒和荧光原位杂交（FISH）检测试剂盒的全面开发和验证，共同用作基础广泛的NSCLC检测试剂盒，以分类先前未识别但具有重要意义的NSCLC患者队列，这些患者可通过现有治疗方法轻松治疗。所有确认将通过最终检测大量临床样本来确定临床效用，以明确证明合理患者选择抑制剂治疗的统计学显著性。然后，所有潜在的伴随诊断将与IVD合作伙伴共同开发，以使每种检测试剂盒作为FDA批准的伴随诊断试剂完全商业化。