A novel strategy to see and treat breast cancer: translation to intra-operative breast margin assessment

观察和治疗乳腺癌的新策略：转化为术中乳房边缘评估

基本信息

批准号：
9387262
负责人：
Nirmala Ramanujam
金额：
$ 19.24万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9387262
关键词：
Adoption Algorithms Anxiety Back Beds Biological Assay Biopsy Biopsy Specimen Breast Breast Cancer Cell Breast Cancer Model Breast-Conserving Surgery Cell Density Clinic Clinical Clinical Research Control Groups Diagnostic Dose Duct (organ) structure Ductal ERBB2 gene Ensure Excision Flow Cytometry Fluorescence Food and Drug Administration Drug Approval Future Guidelines Health Health Expenditures Healthcare Systems Heat-Shock Proteins 90 Image Imagery Intervention Investigational Drugs Label Literature Lobular Local Therapy Malignant - descriptor Malignant Neoplasms Mammaplasty Mammary Gland Parenchyma Mammography Methodology Methods Modeling Modernization Noise Noninfiltrating Intraductal Carcinoma Oncogenes Operative Surgical Procedures Outcome Pathology Patient Selection Patient-Focused Outcomes Patients Performance Population Pre-Clinical Model Primary Neoplasm Proteins Protocols documentation Radiation Radiation therapy Reporting Research Residual Tumors Resolution Role Safety Sampling Screening for cancer Second Primary Cancers Sensitivity and Specificity Series Signal Transduction Site Specificity Specimen Technology Testing Therapeutic Therapeutic Agents Time Tissues Topical application Translating Translations Ultrasonography Visit Western Blotting base breast cancer diagnosis cancer invasiveness cancer radiation therapy cost design disorder risk experience fluorophore high resolution imaging imaging system improved in vivo inhibitor/antagonist innovation lens malignant breast neoplasm neoplastic cell novel strategies overexpression portability pre-clinical prognostic protein biomarkers risk minimization small molecule tool tumor tumor growth uptake

项目摘要

Abstract With the widespread adoption of mammograms for early cancer detection, modern research has principally pivoted towards a focus on how to reduce over treatment of patients, particularly those with early stage breast cancer. Unfortunately, there remains a distinct lack of tools to reduce overtreatment, while ensuring the best possible outcome for patients. One such example is Breast Conserving Surgery (BCS) followed by radiation therapy. There is a wide-range of re-excision rates reported in the literature, but most groups report that 20-40% of patients undergo at least one re-excision. Taking additional shavings during BCS, new guidelines dictating relationships between margin status after BCS and re-excision, and radiation therapy all strive to maximize removal of residual tumor cells with as few surgeries as possible in patients with a new breast cancer diagnosis. However, secondary cancers from radiation therapy, the potential for cancer dissemination as a result of re-excision surgeries, and the burgeoning costs of repeat visits and interventions to an already depleted health care system necessitate new and innovative solutions to improve health outcomes, patient experience and reduce health expenditures. We propose a new paradigm for the effective visualization and treatment of residual disease at the time of the initial BCS while minimizing risks of re-excision surgeries and radiation and the cost of repeat visits and interventions. In our model, the primary tumor or the tumor cavity will be rapidly assayed for the presence of residual disease. The tumor cells will be selectively visualized using a fluorescently labeled agent that when topically applied targets a ubiquitous signaling node common to the all subtypes of breast cancer, including DCIS. The tumor cells will be localized by easily navigating back and forth between wide-field (to maximize sensitivity) and high-resolution imaging (to maximize specificity). The agent will be designed to have a dual role of selectively targeting tumor cells, at a low dose and demonstrating therapeutic potency at a high dose. This will allow for the same agent to eradicate residual tumor cells when applied topically to the tumor bed for those patients with residual disease. Heat shock protein 90 (Hsp90) stabilizes a number of proteins required for tumor growth. The overexpression of Hsp90 in breast cancer, the presence of ectopic Hsp90 only on breast tumor cells and the therapeutic potency of small molecule Hsp90 inhibitors provides the rationale for pursuing Hsp90 as the agent of choice. The first aim will focus on creating an effective platform for Hsp90 imaging to detect margin positivity and guide local therapy with proof-of-concept demonstration in pre-clinical models. The second aim will specifically focus on translating Hs-27 to the clinic, by first optimizing the protocol for imaging hps90 on pre-clinical issue specimens and then evaluating biopsies from patients undergoing diagnostic biopsy or mammoplasty. Given the overexpression of Hsp90 in breast cancer, the presence of ectopic Hsp90 only on breast cancer and the therapeutic potency of Hsp90 inhibitors, our technology platform will not only benefit margin assessment and treatment, but also diagnostic biopsy, prognostication and patient selection for Hsp90 inhibitor therapy.

抽象的随着乳房X光检查广泛应用于早期癌症检测，现代研究主要重点关注如何减少患者的过度治疗，特别是早期乳腺癌患者癌症。不幸的是，仍然明显缺乏减少过度治疗的工具，同时确保最好的治疗患者可能的结果。其中一个例子是保乳手术 (BCS)，然后进行放射治疗治疗。文献中报道的再切除率范围很广，但大多数研究组报告说，20-40% 患者至少接受一次再次切除。新指南规定在 BCS 期间额外刨花 BCS 后边缘状态与再次切除之间的关系以及放射治疗都致力于最大限度地切除在新诊断乳腺癌的患者中，通过尽可能少的手术来清除残留的肿瘤细胞。然而，放射治疗引起的继发性癌症、再次切除手术导致癌症扩散的可能性、重复就诊和对本已枯竭的医疗保健系统进行干预的费用不断增加，因此有必要旨在改善健康结果、患者体验并减少医疗支出的创新解决方案。我们提出了一种新的范例，用于有效可视化和治疗残留疾病初始 BCS，同时最大限度地降低再次切除手术和辐射的风险以及重复就诊的成本和干预措施。在我们的模型中，将快速检测原发肿瘤或肿瘤腔是否存在残留疾病。局部使用荧光标记剂时，肿瘤细胞将被选择性地可视化靶向所有乳腺癌亚型（包括导管原位癌）所共有的普遍存在的信号节点。肿瘤细胞将通过在宽视场（以最大化灵敏度）和高分辨率之间轻松来回导航来定位成像（以最大化特异性）。该药物将被设计成具有选择性靶向肿瘤细胞的双重作用，在低剂量下表现出治疗效力，在高剂量下表现出治疗效力。这将允许同一个代理根除对于有残留疾病的患者，局部应用于肿瘤床时残留的肿瘤细胞。热休克蛋白质 90 (Hsp90) 可以稳定肿瘤生长所需的多种蛋白质。 Hsp90在乳腺中的过度表达癌症、仅在乳腺肿瘤细胞上存在异位 Hsp90 以及小分子的治疗效力 Hsp90 抑制剂为追求 Hsp90 作为首选药物提供了理由。第一个目标将集中于创建一个有效的 Hsp90 成像平台，用于检测切缘阳性并通过概念验证指导局部治疗临床前模型的演示。第二个目标将特别侧重于将 Hs-27 转化为临床，首先优化临床前问题标本上 hps90 成像的方案，然后评估患者的活检结果正在进行诊断性活检或乳房成形术。鉴于 Hsp90 在乳腺癌中过度表达，异位 Hsp90 仅对乳腺癌的研究以及 Hsp90 抑制剂的治疗效力，我们的技术平台将不仅包括效益边际评估和治疗，还包括诊断性活检、预测和患者选择用于 Hsp90 抑制剂治疗。