Engineered imaging nanoparticles for real-time detection of cancer in the tumor b

描述（由申请人提供）：本申请的总体目标是评价新的成像剂，用于（1）在小鼠原发性结肠癌和肺癌手术期间实时检测肿瘤床中的残留癌症，以消除或显著减少重复手术和局部复发的需要，以及（2）指导患有自然发生癌症的犬患者的切除手术。在一项初步研究中，我们还将测试我们的成像技术，以提高常规结肠镜检查中病变的检出率。手术中未能去除癌细胞是局部肿瘤复发和随后再次手术的主要风险因素。由于切缘阳性而进行二次手术的比例在10-50%之间，具体取决于癌症类型、级别和解剖部位。对于结肠癌筛查，许多小病变未被发现，只有在进展为恶性肿瘤后才被发现。此外，即使对于较大的癌，使用白色光的结肠镜检查也不能识别这22%的时间。因此，一项能够评估肿瘤细胞是否在手术中被充分去除或能够更高效地识别结肠病变的技术将对全球癌症治疗产生重大影响，因为每年有超过200万人接受癌症手术。在SBIR第一阶段的工作中，Lumicell开发了几种成像剂，使用我们的新数学模型来预测它们在不同物种中的性能。其目标是开发高性能，低成本的成像剂，以满足结肠癌筛查和最终皮肤癌手术的需求。这些显像剂是基于我们用于肉瘤和乳腺癌适应症的主要候选药物LUM 015的设计，该药物已获得FDA批准，与我们在杜克大学医学中心的临床合作者一起开始首次人体临床试验。基于对LUM 015的修改，新的成像剂的制造成本降低了约66%，产量提高。在我们的乳腺癌基线小鼠模型中测试后，这些新药物被证明与LUM 015具有相同或更好的性能。低成本的成像剂是进入我们几个新的目标市场所必需的，并将成为其他市场的额外产品。对于II期，我们在目标1和2中提出，与我们在杜克大学和马萨诸塞州总医院的合作者一起，在最先进的肺癌和结肠癌基因工程小鼠模型中评价这些显像剂的性能。在目标3中，我们将使用选定的主要候选药物（基于目标1和目标2的结果）在杜克/兽医专科医院和塔夫茨大学卡明斯兽医学院进行兽医临床试验。将招募患有任何类型癌症的犬患者，以评价主要候选药物在自然发生的癌症中的表现。目标4的重点是达到本提案的终点：提交IND，以支持使用我们的新主要候选人进行结肠癌和肺癌手术以及结肠癌筛查的I期临床试验。

DESCRIPTION (provided by applicant): The overall goal of this application is to evaluate new imaging agents for (1) real-time detection of residual cancer in the tumor bed during surgery in primary colon and lung cancers in mice to eliminate or significantly reduce the need for repeat surgeries and local recurrence, and (2) guiding resection surgeries in canine patients with naturally occurring cancer. In a pilot study, we will also test our imaging technology to improve the detection of lesions during routine colonoscopy examination. Failure to remove cancer cells during surgery is a leading risk factor for local tumor recurrence and subsequent reoperation. Rates of secondary surgeries because of positive margins range between 10-50% depending on cancer type, grade and anatomical site. For colon cancer screening, many small lesions go undetected that are only found after progressing into malignant carcinomas. Furthermore, even for larger carcinomas, colonoscopy using white light will not identify these 22% of the time. Thus, a technology that can assess whether tumor cells have been adequately removed during surgery or can identify colon lesions with higher efficiency will have a major impact on cancer therapy worldwide as more than two million people undergo cancer surgery every year. During the SBIR Phase I work, Lumicell developed several imaging agents by using our novel mathematical model to predict their performance across species. The goal was to develop high-performance, lower cost imaging agents to satisfy the needs for colon cancer screening and eventually skin cancer surgeries. These imaging agents are based upon the design of our lead candidate for sarcoma and breast cancer indications, LUM015, which has been approved by the FDA to start first-in-human clinical trials with our clinical collaborators at Duke University Medical Center. Based upon modifications to LUM015, the new imaging agents cost about 66% less to manufacture with improved yields. After testing them in our baseline mouse model for breast cancer, these new agents proved equal or better performance than LUM015. A lower cost imaging agent is mandatory for entry into several of our new target markets and will be an additional offering for the other markets. For Phase II, we propose in Aims 1 and 2 to evaluate the performance of these imaging agents in state-of-the-art genetically engineered mouse models for lung cancer and colon cancer with our collaborators at Duke University and Massachusetts General Hospital. In Aim 3, we will move forward with the selected lead candidate (based upon results from Aims 1 and 2) into a veterinary clinical trial conducted at Duke/Veterinary Specialty Hospital of the Carolinas and Tufts University Cummings School of Veterinary Medicine. Canine patients suffering from any type of cancer will be recruited to evaluate the performance of the lead candidate in naturally occurring cancers. Aim 4 is focused on reaching the endpoint of this proposal: submit an IND to support a Phase I clinical trial for colon and lung cancer surgeries and colon cancer screening using our new lead candidate.