Discovery and Clinical Validation of Cancer Biomarkers Using Printed Glycan Array

描述（由申请人提供）：本研究致力于开发和临床验证用于早期检测癌症和癌症风险的基于血清的诊断测试。我们开发了一种打印的聚糖阵列（PGA），可检测癌症患者和高危患者血清中的一组强大的癌症特异性抗聚糖自身抗体。恶性转化期间蛋白质和脂质的异常糖基化导致细胞表面和血清组分上出现称为肿瘤相关碳水化合物抗原或TACA的特异性聚糖结构。TACA的组合总是存在于恶性转化过程中，我们已经证明，针对这些TACA的多种血清自身抗体可以同时检测使用PGA的乳腺癌的所有阶段的患者，包括个体与癌前病变。使用专门的统计和机器学习方法，我们已经确定了一组自身抗体，可以将转移性乳腺癌患者与健康个体区分开来。尽管是初步的，但这些结果使我们得出结论，PGA与我们专用的数据处理方法一起可用作发现糖生物标志物的工具，用于开发用于早期检测癌症和癌症风险的临床血清筛查测试，以及用于评估恶性肿瘤状态。我们的实验室已经建立了推进研究的三个关键组成部分：（1）定制聚糖阵列的内部打印，（2）PGA专用的数学数据处理工具和（3）肿瘤相关聚糖发现工具。继续的研究将使用打印的聚糖阵列作为主要的生物标志物发现技术。此外，我们的研究团队，包括糖生物学家，肿瘤学家，数学家，临床免疫学家和化学家的综合专业知识将在具有以下特定目的的大型人群研究中使用PGA：1.识别和验证乳腺癌疾病特定阶段的抗聚糖自身抗体特征，包括：乳腺癌风险增加、浸润前（DCIS）和早期乳腺癌、乳腺癌进展。2.将研究扩展至至少三种其他主要恶性肿瘤（包括卵巢癌、黑色素瘤和非小细胞肺癌（NSCLC））的抗聚糖自身抗体特征的鉴定和验证。3.鉴定、分离和/或合成血清和细胞材料中的新型肿瘤相关聚糖，并对其进行初步检测，作为癌症诊断抗原。

DESCRIPTION (provided by applicant): This research is dedicated to the development and clinical validation of a serum-based diagnostic test for early detection of cancer and cancer risk. We have developed a printed glycan array (PGA) that detects a robust panel of cancer-specific anti-glycan autoantibodies in sera from cancer patients and at-risk patients. Aberrant glycosylation of proteins and lipids during malignant transformation results in the appearance of specific glycan structures known as Tumor Associated Carbohydrate Antigens, or TACAs, on cell surfaces and serum components. Combinations of TACAs are always present during malignant transformation and we have already demonstrated that multiple serum autoantibodies against these TACAs can be simultaneously detected using a PGA for patients with all stages of breast cancer including individuals with premalignant diseases. Using dedicated statistical and machine learning methods, we have identified sets of autoantibodies allowing differentiation of patients with metastatic breast cancer from healthy individuals. Although preliminary, these results allow us to conclude that PGAs together with our dedicated data processing methods can be used as a tool for the discovery of glyco-biomarkers, for the development of clinical serum-based screening tests for early detection of cancer and cancer risk, and for the evaluation of malignancy status. The three key components for advancing research have been established in our labratory: (1) in-house printing of custom glycan arrays, (2) PGA-dedicated mathematical data processing tools and (3) tumor-associated glycan discovery tools. The continued research will use the printed glycan array as a major biomarker-discovery technique. Further, the combined expertise of our team of investigators including glycobiologists, oncologists, mathematicians, clinical immunologists and chemists will use PGAs in large population-based studies with the following Specific Aims: 1. To identify and validate anti-glycan autoantibody signatures of the specific stages of breast cancer disease, including: increased breast cancer risk, pre-invasive (DCIS) and early breast cancer, breast cancer progression. 2. To expand the study to the identification and validation of anti-glycan autoantibody signatures for at least three other major malignancies, including ovarian, melanoma and Non-Small Cell Lung Cancer (NSCLC). 3. To identify, isolate and/or synthesize, and perform preliminary testing of novel tumor-associated glycans in serum and cellular materials as cancer-diagnostic antigens.