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

摘要 随着乳房X光检查在早期癌症检测中的广泛采用，现代研究主要 重点关注如何减少对患者的过度治疗，特别是那些早期乳腺癌患者 癌不幸的是，仍然明显缺乏减少过度治疗的工具，同时确保最好的治疗。 患者的可能结果。一个这样的例子是保乳手术（BCS）， 疗法文献中报道了广泛的再次切除率，但大多数研究组报告20-40%的 患者经历至少一次再切除。在BCS期间采取额外的刨花，新的指导方针规定 BCS后边缘状态与再次切除以及放射治疗之间的关系都致力于最大限度地切除 在新诊断的乳腺癌患者中，尽可能少地进行手术，以减少残留肿瘤细胞。然而，在这方面， 放射治疗引起的继发性癌症，再切除手术导致癌症扩散的可能性， 重复访问和干预已经枯竭的医疗保健系统的费用不断增加， 新的和创新的解决方案，以改善健康结果，病人的经验和减少卫生支出。 我们提出了一个新的范例，有效的可视化和治疗的残留疾病的时候， 初始BCS，同时最大限度地减少再次切除手术和放射的风险以及重复访问的费用， 干预措施。在我们的模型中，将快速测定原发性肿瘤或肿瘤腔中残留的肿瘤抑制剂的存在。 疾病肿瘤细胞将使用荧光标记剂选择性地可视化，当局部应用时， 靶向所有乳腺癌亚型（包括DCIS）共有的普遍存在的信号节点。肿瘤细胞 通过在宽视场（以最大限度地提高灵敏度）和高分辨率之间轻松来回导航， 成像（最大化特异性）。该试剂将被设计成具有选择性靶向肿瘤细胞的双重作用， 并在高剂量下显示出治疗效力。这将允许相同的代理根除 对于那些有残留疾病的患者，当局部应用于肿瘤床时，可以减少残留的肿瘤细胞。热休克 蛋白90（Hsp 90）稳定肿瘤生长所需的许多蛋白质。乳腺癌组织中Hsp 90的过度表达 肿瘤、异位Hsp 90仅在乳腺肿瘤细胞上的存在以及小分子Hsp 90的治疗效力 热休克蛋白90抑制剂提供了追求热休克蛋白90作为选择的代理的理由。第一个目标将集中在创造 Hsp 90成像的有效平台，用于检测边缘阳性并通过概念验证指导局部治疗 在临床前模型中进行演示。第二个目标将特别侧重于将Hs-27转化为临床， 优化用于在临床前问题样本上成像HPS 90的方案，然后评估来自患者的活检 接受诊断性活检或乳房成形术。考虑到乳腺癌中Hsp 90的过度表达， 异位Hsp 90仅对乳腺癌的作用以及Hsp 90抑制剂的治疗效力，我们的技术平台将 不仅有利于切缘的评估和治疗，而且有利于诊断性活检、定位和病人的选择 热休克蛋白90抑制剂治疗

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.