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，breastcancer.org 预计将有281 550例新的浸润性乳腺癌病例和49 290例新的非浸润性（原位）乳腺癌病例。 预计也有43，600人死亡。由于更好的筛查技术，癌症被更早发现，75%的 患者是乳房保留手术（BCS）的候选者以移除癌症。BCS是一种化妆品 优于替代方案（乳房切除术），长期生存率相当。术后 病理学，目前的“金标准”有显着的缺点，包括对病人的要求， 如果病理学发现不完全切除（即，癌症仍然存在于 患者）。此外，目前的病理学方法仅评估肿瘤的整个体积的1%的约1/10。 取出标本。边缘采样不足的结果是局部复发发生在5-16%的患者中， 病理学上边缘干净的患者，表明一个或多个肿瘤区域未被切除。 在病理分析期间取样，导致肿瘤残留在患者体内。新的方法来提高 术中BCS切除的质量正在提高。其中最有前途的是使用 荧光分子探针来“照亮”癌症并指导切除。然而，所有现有探针都需要 在手术前数小时或数天给予大剂量的显像剂，并且需要额外的实验室工作， 使相对简单的外科手术复杂化。此外，周围组织中的浸润癌细胞 主肿块可能没有发展出脉管系统，我们和其他人的工作表明，它是 使用注射的药剂可能无法识别这种肿瘤，注射的药剂使用这种脉管系统到达肿瘤。 病变组织利用乳腺癌边缘蛋白酶表达的增加，我们引入了 本发明涉及一种新的概念，即术中体内局部施用可活化的、微剂量的、淬灭的、 荧光分子成像探针，以确定标准手术后可能残留在手术腔中的癌症， 护理切除术。在多年临床前离体研究的基础上，该I期项目以 大型动物手术研究，以在开始之前完善和优化手术工作流程和技术 正式的FDA临床试验我们将合成研究级探针，在PDX大鼠中测试其性能， 完成犬的手术优化项目，并向FDA提交IND。这项技术有 缩短监管路径的潜力，提供减少再次切除以及虚假的 病理学采样不足导致的阴性率，从而节省了医疗保健成本， 提高患者生活质量。

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.