Along the continuum for an IND: An In-Vivo large animal study for opticalimage guided surgery of spontaneous breast cancer.

项目摘要/摘要：乳腺癌是女性最常见的癌症。2021年，Breastancer.org 项目281 550例浸润性乳腺癌和49 290例非浸润性(原位)乳腺癌。 预计还会有43,600人死亡。由于更好的筛查技术，癌症被发现得更早，75%的 患者是保乳手术(BCS)的候选对象，以切除癌症。BCS是一种美化的 优于替代方案(乳房切除术)和长期存活率相当。术后 病理上，现行的“黄金标准”有明显的弊端，包括对患者的要求 如果病理检查发现切除不完全(即，癌症仍在 病人)。此外，目前的病理学方法只评估约1%的体积的1/10 移走了标本。边际欠抽样的后果是局部复发发生在5%-16%的 边缘病理清晰的患者，表明肿瘤的一个或多个区域没有 在病理分析过程中采样，导致肿瘤残留在患者体内。增强的新方法 术中BCS切除的质量正在提高。其中最有希望的是使用 荧光分子探头为癌症点亮并指导切除。然而，所有当前的探测器都需要 大剂量的显像剂在手术前几小时或几天内注射，需要额外的劳动， 使一个相对简单的外科手术变得复杂。此外，浸润性癌细胞在周围组织中 主要肿块可能没有形成血管系统，而我们和其他人的工作表明，它是 使用注射剂可能无法识别这种肿瘤，这些注射剂使用这种血管系统到达 病变组织。利用乳腺癌边缘组织中蛋白水解酶表达的增加，我们介绍了 术中活体局部给药的新概念，可激活的，微剂量的，猝灭的， 荧光分子成像探针用于识别标准手术后可能残留在手术腔内的癌症- 保健性切除。在多年的临床前体外研究的基础上，这个第一阶段的项目是由一个 大型动物外科研究，以在开始前改进和优化手术流程和技术 正式的FDA临床试验。我们将合成研究级探针，在PDX大鼠身上测试其性能， 完成犬的手术优化项目，并向FDA提交IND。这项技术具有 有可能采取一条简短的监管路径，从而有可能减少再切除以及虚假的 病理欠采样导致的负率，从而节省了医疗费用， 提高患者的生活质量。

Project Summary/Abstract: Breast cancer is the most common cancer in women. For 2021, breastcancer.org projects 281,550 new cases of invasive breast cancer and 49,290 new cases of non-invasive (in situ) breast cancer. 43,600 deaths are also projected. Due to better screening techniques cancers are caught earlier and 75% of patients are candidates for breast conserving surgery (BCS) to remove the cancer. BCS is cosmetically preferable to the alternative (mastectomy) and long-term survival rates are equivalent. Postoperative pathology, the current “gold standard” has significant drawbacks, including the requirement for the patient to return for additional surgery if pathology finds an incomplete resection (i.e., cancer remains in the patient). In addition, current pathology methods only assess about 1/10 of 1% of the entire volume of the removed specimen. A consequence of margin undersampling is that local recurrence occurs in 5-16% of patients with pathologically clean margins, suggesting that one or more regions of tumor had not been sampled during pathological analysis resulting in tumor remaining in the patient. New methods to enhance the quality of BCS resection intraoperatively are being developed. One of the most promising is the use of fluorescent molecular probes to “light up” cancer and guide resection. All current probes, however, require large doses of imaging agent to be administered hours or days before surgery, and require extra labwork, complicating a relatively simple surgical procedure. Moreover, infiltrating cancer cells in tissues surrounding the main mass may not have developed a vasculature, and our work and that of others indicates that it is possible such tumors may not be identified using injected agents, which use such vasculature to reach the diseased tissue. Exploiting increased protease expression at the edge of breast cancers we introduce the novel concept of intraoperative in vivo topical administration of an activatable, microdose, quenched, fluorescent molecular imaging probe to identify cancer that may remain in the surgical cavity after standard- of-care resection. Building on years of preclinical ex-vivo studies, this Phase I project is anchored by a large-animal surgical study to refine and optimize the surgical workflow and technique prior to beginning formal FDA clinical trials. We will synthesize research grade probe, test its performance in PDX rats, complete a surgical optimization project in canines, and submit an IND to FDA. This technology has the potential for an abbreviated regulatory path, offering the potential to reduce re-excisions as well as the false negative rate from pathology undersampling, with a consequent savings in healthcare costs and, enhancement in patient life quality.