Characterizing the Evolution of Pre-malignant Tissues at High Risk for Malignancy

描述（由申请人提供）： 我们最近在DCIS活检中发现了生物标志物，可以在实际发生前几年预测基底样肿瘤的形成，具有很高的准确性。候选生物标志物在从诊断为DCIS的女性人群队列中获得的活检标本上进行了验证，仅接受乳房肿瘤切除术治疗并随访20年[2]。这些标志物鉴定了高度侵袭性的癌前亚型，在本申请中我们称之为“基底样”导管原位癌（B-L DCIS），因为它具有对基底样侵袭性肿瘤特异性的标志物。在本申请中，我们假设通过鉴定这种非常侵袭性的基底样癌前亚型（B-L DCIS）的其他功能、细胞和分子特征，我们将能够（a）完善其进展为侵袭性肿瘤的风险分类，以及（B）开发临床上有用的探针，用于非侵入性成像，以跟踪这些体内高风险病变。在这些研究的准备过程中，我们发现了许多基底样浸润性肿瘤特异性的过程和潜在的表面表位，并与B-L DCIS和PRIMED细胞共享。重要的是，我们相信，B-L DCIS的非侵入性成像的发展和体内询问癌前细胞的能力可以使我们深入了解肿瘤发生和发展的关键生物学和风险因素，非侵入性检测人类乳腺癌中侵袭性癌前病变的新方法，以及监测其演变为侵袭性疾病的能力。我们组建了一个由基础和临床科学家组成的综合团队，以（具体目标1）确定候选预后标志物和功能，并（具体目标2-4）开发具有未来侵袭性肿瘤形成高风险的基底样癌前病变的非侵入性成像。我们将：具体目标1：识别B-L DCIS中发现的人乳腺上皮细胞和基质细胞的独特表面表位，并表征预测恶性进展的功能改变。具体目标2：使用光学成像在体外和体内验证细胞表面靶标的功效和特异性。具体目标3：开发用于检测乳腺组织中B-L DCIS的临床显像剂。具体目标4：开发和应用功能成像来识别与未来侵袭性肿瘤形成相关的基底样癌前病变（B-L DCIS）。这些研究将产生细胞过程和分子生物标志物的鉴定，这些生物标志物在未来的侵袭性肿瘤事件发生前几年预测它们。间质信号和上皮细胞反应之间的合作，在最早阶段的癌前病变将得到阐明。这些标志物的应用将允许诊断为DCIS的妇女的风险分层和预防药物的潜在目标。开发选定的标记物作为非侵入性成像的工具，将为研究早期侵袭性癌前病变和导致其进展的风险因素开辟一条前所未有的途径。

DESCRIPTION (provided by applicant): We have recently identified biomarkers in DCIS biopsies that predict formation of basal-like tumors, with high accuracy, years before it actually occurs. The biomarker candidates were validated on biopsy specimens obtained from a population-based cohort of women diagnosed with DCIS, treated by lumpectomy alone and followed for twenty years [2]. These markers identify a highly aggressive pre-malignant subtype that we call "basal-like" ductal carcinoma in situ (B-L DCIS) in this application since it shares markers specific to basal-like invasive tumors. In this application, we hypothesize that by identifying additional functional, cellular, and molecular characteristics of this very aggressive basal-like pre-malignant subtype (B-L DCIS) we will be able to (a) refine their classification for risk of progression to invasive tumors and (b) develop clinically useful probes for non-invasive imaging to track these high-risk lesions in vivo. In preparation for these studies we have discovered a number of processes and potential surface epitopes specific to basal-like invasive tumors and shared with B-L DCIS and PRIMED cells. Importantly, we believe that the development of non-invasive imaging of B-L DCIS and the ability to interrogate pre-malignant cells in vivo may give us insights into the biology and risk factors critical to tumor initiation and progression, a new approach to non-invasively detect aggressive pre-malignancy in human breast cancer and the ability to monitor its' evolution as it progresses to invasive disease. We have assembled an integrated team of basic and clinical scientists to (Specific Aim 1) identify candidate prognostic markers and functions, and (Specific Aims 2-4) develop non-invasive imaging of basal-like pre-malignant lesions with high risk for future invasive tumor formation. We will: Specific Aim 1: Identify distinctive surface epitopes for human mammary epithelial and stromal cells found in B-L DCIS and characterize functional alterations that predict progression to malignancy. Specific Aim 2: Validate the efficacy and specificity of cell surface targets in vitro and in vivo using optical imaging. Specific Aim 3: Develop clinical imaging agents for detection of B-L DCIS in breast tissue. Specific Aim 4: Develop and apply functional imaging to identify basal-like pre-malignancies (B-L DCIS) that are associated with future formation of invasive tumors. These studies will generate the identification of cellular processes and molecular biomarkers that predict future invasive tumors events years before they occur. Collaboration between stromal signals and epithelial responses at the earliest stages of pre-malignancy will be elucidated. Application of these markers will allow for risk stratification of women diagnosed with DCIS and potential targets for preventive agents. Development of selected markers as tools for non-invasive imaging will open an unprecedented avenue to study early aggressive pre-malignancies and risk factors that contribute to their progression.