Fluorescence-guided resection of breast tumors using a topically-applied molecular probe

使用局部应用分子探针进行荧光引导乳腺肿瘤切除术

• 批准号: 10322725
• 负责人: James Peter Basilion
• 金额: $ 52.34万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10322725
• 关键词: Academic Medical Centers; Agreement; Animals; Breast; Breast-Conserving Surgery; Cancerous; Carcinoma; Cessation of life; Clinical; Clinical Trials; Cosmetics; Cyclic GMP; Cytology; Data; Detection; Development; Diffusion; Disease; Distant; Dose; Drug Kinetics; European; Evaluation; Excision; FDA approved; Fluorescence; Fluorescent Probes; Formalin; Frozen Sections; Goals; Health Care Costs; Home; Hour; Human; Image; Imaging Device; Malignant Neoplasms; Mammaplasty; Mammary Neoplasms; Mastectomy; Maximum Tolerated Dose; Methods; Microscopic; Molecular Probes; Morbidity - disease rate; Noninfiltrating Intraductal Carcinoma; Operative Surgical Procedures; Paraffin Embedding; Pathologic; Pathology; Patients; Peptide Hydrolases; Performance; Phase; Postoperative Period; Procedures; Process; Prognostic Factor; Quality of life; Radiation therapy; Recurrence; Repeat Surgery; Residual Cancers; Risk; Risk Factors; Safety; Sampling; Savings; Signal Transduction; Specimen; Surface; Surgeon; Survival Rate; Techniques; Technology; Testing; Time; Tissue Sample; Tissues; Topical application; Touch sensation; Toxicology; Translating; Translational Research; Translations; Tumor Tissue; Vascularization; Woman; acute toxicity; base; breast lumpectomy; cancer cell; clinical application; clinical imaging; clinical translation; experience; first-in-human; healthy volunteer; image guided; imager; imaging agent; imaging probe; imaging study; in vivo; industry partner; malignant breast neoplasm; manufacturing facility; molecular imaging; mortality risk; next generation; novel; novel strategies; optical imaging; pharmacokinetics and pharmacodynamics; photonics; preclinical imaging; preclinical study; prevent; sample fixation; screening; standard of care; success; tumor

Project Summary/Abstract: Breast cancer is the most common cancer in women, with an estimated 246,660 cases (and 40,450 deaths) in the US during 2015. 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 [1]. The success of BCS is assessed post-operatively by pathology. The status of the microscopic margins of excision of the lumpectomy specimen is still the most important prognostic and risk factor for local recurrence [2,3]. A positive margin indicates that invasive carcinoma or ductal carcinoma in situ is touching a tissue edge of a lumpectomy specimen. Among patients treated by BCS and radiation therapy, positive margins are associated with a 2-fold increase in the risk of local recurrence when compared with negative margins [4]. A finding of positive margins is estimated to occur between 8% to 86% of the time, requiring patients to return for further treatment often associated with poorer cosmetic results and increases in local and distant recurrence of the disease. 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. In addition, there is still no universal agreement among breast surgeons on what constitutes an adequate negative margin for patients undergoing BCS [5]. Together these data demonstrate the unmet clinical need for technologies that rapidly and globally identify cancerous tissues in the surgical cavity and can be used to guide their surgical resections during the procedure. Molecular imaging guided resections of tumors during surgeries are now being developed. However, most approaches employ IV administration of optical imaging agents, which require hours or days to highlight tumor tissues. Moreover, infiltrating cancer cells in tissues surrounding the main mass may not have developed a vasculature and likely would not be identified using injected agents. Finally, illuminating the entire cancer mass may create a high background signal from tumor that is not “at the margin” of the lumpectomy. Exploiting increased protease expression at the edge of breast cancers we introduce the novel concept of in vivo topical administration of quenched fluorescent molecular imaging probes to identify cancer that may remain in the surgical cavity after standard-of-care resection. This builds on years of preclinical studies and seeks to characterize, perform toxicology, and finally a Phase 1A & B clinical trial to demonstrate the utility of this novel approach. It has 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：乳腺癌是女性最常见的癌症，估计有246,660人患有乳腺癌。 2015年美国的病例(和40,450例死亡)。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 在美观上优于替代方案(乳房切除术)，长期存活率相当[1]。这个 BCS的成功与否通过术后病理进行评估。食管瘤切除的显微切缘现状 肿瘤切除标本仍然是局部复发的最重要的预后和危险因素[2，3]。一个 阳性边缘表示浸润性癌或导管原位癌正在接触组织边缘 肿块切除标本。在接受BCS和放射治疗的患者中，阳性切缘与 与负边缘相比，局部复发的风险增加了2倍[4]。对…的发现 据估计，8%到86%的时间会出现正向利润率，这需要患者返回医院进一步治疗。 治疗通常与较差的美容效果和增加局部和远处复发有关。 疾病。目前的病理学方法只能评估取出的标本总体积的1%的约十分之一。 边缘抽样不足的后果是局部复发发生在5%-16%的病理上 边缘干净，表明在病理分析过程中没有对一个或多个肿瘤区域进行采样 导致肿瘤残留在患者体内。此外，乳房之间仍然没有普遍的共识 外科医生为接受BCS的患者提供足够的负值范围[5]。把这些放在一起 数据表明，对快速和全球识别癌症组织的技术的临床需求尚未得到满足 在手术过程中，可以用来指导他们的手术切除。分子成像 在手术过程中引导肿瘤切除现在正在开发中。然而，大多数方法使用IV 使用光学显像剂，这需要数小时或数天来突出肿瘤组织。此外， 主要肿块周围组织中浸润性癌细胞可能没有形成血管系统，很可能 不会被注射药剂识别出来。最后，照亮整个癌症肿块可能会产生一种兴奋 肿瘤的背景信号不在肿块切除的边缘。利用增强型蛋白酶 乳腺癌边缘的表达我们引入了体内局部给药的新概念 猝灭的荧光分子成像探针用于识别手术后可能残留在手术腔内的癌症 标准护理切除。这建立在多年的临床前研究的基础上，并寻求表征、执行 毒理学，最后是一项1A&B期临床试验，以证明这一新方法的实用性。它有一个 减少再次切除的可能性以及病理采样不足的假阴性率， 因此节省了医疗成本，并提高了患者的生活质量。