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

沿着 IND 的连续体：光学图像引导自发性乳腺癌手术的体内大型动物研究。

• 批准号: 10701065
• 负责人: Brian Straight
• 金额: $ 80.12万
• 依托单位: AKROTOME IMAGING, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-08 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10701065
• 关键词: Abbreviations; Address; Adjuvant Therapy; Allergic Reaction; Animals; Breast-Conserving Surgery; Canis familiaris; Cessation of life; Clinical; Clinical Trials; Collaborations; Cosmetics; Cytology; Data; Detection; Development; Disadvantaged; Disease; Distant; Documentation; Dose; Drug Kinetics; Ensure; Excision; FDA approved; Frozen Sections; Goals; Health Care Costs; High Pressure Liquid Chromatography; Home; Hospitals; Hour; Human; Image; In Situ; Infiltration; Infusion procedures; Light; Malignant Neoplasms; Mammaplasty; Market Research; Maryland; Mastectomy; Methods; Molecular Probes; Morbidity - disease rate; Operating Rooms; Operative Surgical Procedures; Pathologic; Pathology; Pathway interactions; Patients; Peptide Hydrolases; Performance; Phase; Postoperative Period; Procedures; Process; Quality of life; Rattus; Recurrence; Recurrent disease; Repeat Surgery; Research; Research Design; Residual Cancers; Risk; Sampling; Savings; Sensitivity and Specificity; Signal Transduction; Specimen; Structure; Surface; Surgical Pathology; Survival Rate; Techniques; Technology; Testing; Time; Tissues; Topical application; Toxicology; Translations; Tumor Tissue; Validation; Visit; Wait Time; Woman; Work; Xenograft procedure; breast lumpectomy; cancer cell; cancer surgery; clinical translation; design; experience; fluorescence imaging; imaging agent; imaging probe; imaging study; imaging system; in vivo; malignant breast neoplasm; manufacturing scale-up; meetings; molecular imaging; mortality; mortality risk; mouse model; novel; optical imaging; phase 2 study; pre-Investigational New Drug meeting; pre-clinical; preclinical imaging; screening; standard of care; success; tumor

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.

项目摘要/摘要：乳腺癌是 2021 年女性最常见的癌症。 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。 由于更好的筛查技术，预计将有 43,600 人死亡，其中 75% 的人可以更早地发现癌症。 患者适合接受保乳手术（BCS）以去除癌症，以达到美观目的。 优于替代方案（乳房切除术），并且术后长期生存率相当。 病理学方面，目前的“金标准”有很大的缺陷，包括对患者的要求 如果发现切除不完全（即癌症仍然存在于肿瘤中），请返回进行额外的手术病理检查 此外，目前的病理学方法只能评估整个体积的 1% 的 1/10。 边缘采样不足的结果是 5-16% 的样本发生局部复发。 病理学边缘干净的患者，表明肿瘤的一个或多个区域未被切除 在病理分析过程中取样导致肿瘤残留在患者体内的新方法。 术中BCS切除术的质量正在开发中，其中最有前途的是使用。 然而，目前所有的探针都需要荧光分子探针来“照亮”癌症并指导切除。 在手术前数小时或数天施用大剂量显像剂，并且需要额外的实验室工作， 此外，使相对简单的外科手术变得复杂化。 主要群体可能还没有发展出脉管系统，我们和其他人的工作表明它是 可能无法使用注射剂来识别此类肿瘤，注射剂使用此类脉管系统到达 利用乳腺癌边缘蛋白酶表达增加，我们引入了 术中体内局部给药的新概念，可激活、微剂量、猝灭、 荧光分子成像探针可识别标准手术后可能残留在手术腔内的癌症 以多年的临床前离体研究为基础，该第一阶段项目的基础是 大型动物外科研究，以在开始之前完善和优化手术流程和技术 我们将合成研究级探针，在PDX大鼠中测试其性能， 完成犬类手术优化项目，并向 FDA 提交 IND。 简化监管路径的潜力，提供减少再次切除和错误切除的潜力 病理欠采样带来的负率，从而节省医疗费用， 提高患者的生活质量。