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

• 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
• 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

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 随着对早期癌症检测的乳房X线照片的广泛采用，现代研究主要是 关注如何减少患者的过度治疗，尤其是早期乳房的患者的治疗 癌症。不幸的是，仍然缺乏减少过度治疗的工具，同时确保最好 患者可能的结果。这样的例子是乳房保存手术（BCS），然后是辐射 治疗。文献中报告了大量的重新审计率，但大多数小组报告说20-40％ 患者至少重新进行了一次。在BCS期间取下额外的剃须，新的指南决定 BCS和重新拆卸后的边距状态与放射疗法之间的关系均致力于最大化去除 新乳腺癌诊断患者的残留肿瘤细胞具有尽可能少的手术。然而， 放射疗法的次要癌症，这是由于重新测试手术而导致的癌症传播的潜力， 重复访问和对已经耗尽的医疗保健系统的干预措施的迅速成本也需要 新的和创新的解决方案，以改善健康成果，患者经验并减少健康支出。 我们提出了一个新的范式，以有效地可视化和治疗残留疾病 最初的BC在最大程度地降低重新拆卸手术和辐射的风险以及重复访问的成本和 干预措施。在我们的模型中，将迅速测定原发性肿瘤或肿瘤腔的残留 疾病。肿瘤细胞将使用荧光标记的剂选择性地观察到，当局部应用时 靶向乳腺癌所有亚型（包括DCIS）共有的无处不在的信号传导节点。肿瘤细胞 将通过轻松在宽场之间来回航行（以最大化灵敏度）和高分辨率来定位 成像（以最大化特异性）。该试剂将被设计为具有选择性靶向肿瘤细胞的双重作用， 在低剂量下表现出高剂量的治疗效力。这将允许同一代理消除 残留肿瘤细胞局部应用于那些残留疾病患者的肿瘤床。热量冲击 蛋白90（HSP90）稳定了许多肿瘤生长所需的蛋白质。 HSP90在乳房中的过表达 癌症，仅在乳腺肿瘤细胞上存在异位HSP90和小分子的治疗效力 HSP90抑制剂为追求HSP90作为首选代理提供了理由。第一个目标将重点用于创建 HSP90成像的有效平台，以检测边缘阳性并指导概念验证的局部治疗 在临床前模型中的演示。第二个目标将专门针对将HS-27转换为诊所，首先 优化在临床前问题标本上成像HPS90的方案，然后评估患者的活检 进行诊断活检或哺乳动物成形术。鉴于HSP90在乳腺癌中的过表达，存在 仅针对乳腺癌的异位HSP90和HSP90抑制剂的治疗效力，我们的技术平台将 不仅有益于保证金评估和治疗，而且还受益于诊断活检，预后和患者选择 用于HSP90抑制剂疗法。