OTHER FUNCTIONS - R&D BIOMEDICAL (BASIC RESEARCH)

肺癌是世界范围内癌症死亡的主要原因，80%的非小细胞肺癌(NSCLC)是由三个相互排斥的癌基因EGFR、KRAS和ALK(合计占所有非小细胞肺癌病例的30%-60%)引起的。致癌因素，如ROS1和RET融合和DEPDC1的过度表达已被确定为明显复发，共同构成高达~12%的NSCLC病例。临床前研究表明，ROS1驱动的癌症对小分子酪氨酸激酶抑制剂(TKI)以及Hsp90抑制剂非常敏感，这些抑制剂目前正由几家制药和生物技术公司开发。同样，在正在进行的I期和II期临床试验中，模糊的TKI疗法也用于非NSCLC RET和DEPDC1驱动的癌症，效果良好。这些试验应该会鼓励许多制药公司效仿，使用专门针对RET和DEPDC1驱动的非小细胞肺癌的疗法进行类似的临床试验。不幸的是，目前还没有得到监管部门批准的高通量商业诊断测试，可以可靠有效地诊断非小细胞肺癌患者的ROS1或RET融合或DEPDC1过度表达。我们建议完成基于定量聚合酶链式反应(QPCR)和荧光原位杂交(FISH)分析的综合小组的开发和验证，以共同用作基础广泛的非小细胞肺癌检测小组，对以前未确定但意义重大的可用现有疗法治疗的非小细胞肺癌患者进行分类。所有的验证都将通过最终测试一大批临床样本来确定临床实用性，以明确地证明合理的患者选择抑制剂治疗的统计学意义。然后，所有潜在的伴随诊断将进入与IVD合作伙伴的共同开发，将每种检测完全商业化，作为FDA批准的伴随诊断。

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.