MOLECULAR SIGNATURES FOR OUTCOME PREDICTION AND THERAPEUTIC TARGETING IN ALL

描述(申请人提供)：虽然大多数被诊断为急性淋巴细胞白血病(ALL)的儿童现在通过现代治疗方案获得了长期生存，但超过20%的儿童复发或死于耐药疾病。因此，所有这些仍然是儿童癌症死亡的主要原因。被诊断为“高危”急性淋巴细胞白血病的儿童尤其如此，占所有病例的30%；患有急性淋巴细胞白血病的青少年和成人的预后也很差。从&gt；900高危ALL病例的全面分子分析中，我们获得并验证了预测ALL无复发生存(RFs)的基因表达特征(“分类器”)，我们发现了新的潜在遗传异常(IKAR0S/IKZF1、JAK和CRLF2突变或基因组重排)，可作为这种疾病的新诊断和治疗靶点。我们现在建议将这些基于RNA和DNA的分子签名转化为强大的临床诊断工具；在一个新的队列&GT；500高危ALL患者中完成以这种方式测量的签名的验证，并开发用于改进HSK分类、结果预测和治疗靶向的新算法；并在下一代COG试验中前瞻性地测试这些签名。我们的目标是：1)将我们基于微阵列的基因表达分类器改进为最终的一组预测基因，并将这种多分析特征的定量测量转换到一个强大的临床诊断平台(ABI TaqMan(R)自动化、定量RT-PCR卡)；2)在与新定义的预后分子异常(涉及IKAROS、JAK、CRLF2)和已知风险因素(如最小残留疾病)相关的500例高危ALL病例的独立队列中，验证该分类器的预测能力，以开发用于风险分类和治疗靶向的新分子算法；3)在2011年开始的下一代COG临床试验中前瞻性地测试新的分子签名和风险算法的预测能力，该试验将产生3000名患有高危ALL的儿童；以及4)确定这些分类器、分子签名和风险算法在青少年和年轻人、所有患者队列以及老年人中的预测效用，所有这些都将由成人NCI合作小组进行临床试验。

DESCRIPTION (provided by applicant): While the majority of children diagnosed with acute lymphoblastic leukemia (ALL) now achieve long term survival on contemporary treatment regimens, more than 20% relapse or die of resistant disease. ALL thus remains the leading cause of cancer death in children. This is particularly true for children diagnosed with 'high-risk" ALL, accounting for 30% of all cases; outcomes also remain poor in adolescents and adults with ALL. From comprehensive molecular analyses of >900 high-risk ALL cases, we have derived and validated gene expression signatures ("classifiers") predictive of relapse-free survival (RFS) in ALL and we have discovered novel underlying genetic abnormalities (IKAR0S/IKZF1, JAK, and CRLF2 mutations or genomic rearrangements) that serve as new diagnostic and therapeutic targets for this disease. We now propose to translate these RNA and DNA-based molecular signatures into robust clinical diagnostic tools; complete the validation of the signatures measured in this fashion in a new cohort >500 high-risk ALL patients and develop new algorithms for improved hsk classification, outcome prediction, and therapeutic targeting; and, prospectively test these signatures in the next generation of COG trials. Our aims are to: 1) refine our microarray-based gene expression classifiers to a final set of predictive genes and translate the quantitative measurement of this multi-analyte signature to a robust clinical diagnostic platform (ABI TaqMan(r) automated, quantitative RT-PCR cards); 2) validate the predictive power of this classifier in an independent cohort of 500 high-risk ALL cases relative to the newly defined prognostic molecular abnormalities (involving IKAROS, JAK, CRLF2), and known risk factors (such as minimal residual disease) to develop a new molecular algorithm for risk classification and therapeutic targeting; 3) prospectively test the predictive power of the new molecular signatures and risk algorithms in the next generation of COG clinical trials opening in 2011 which will accrue >3000 children with high-risk ALL; and 4) determine the predictive utility of these classifiers, molecular signatures, and risk algorithms in adolescent and young adult ALL patient cohorts as well as older adults with ALL accrued to clinical trials conducted by the adult NCI Cooperative Groups.