Development of a Targeted Radiotherapeuitc for Pancreatic Ductal Adenocarcinoma

据估计，仅在2020年，胰腺癌就导致了美国47,050人的死亡，成为美国第四大癌症 癌症相关死亡的主要原因。胰腺导管腺癌(PDAC)占90%以上 在所有胰腺癌诊断中，总的五年存活率只有10%。新的治疗选择 以改善PDAC患者预后不良的状况。外照射治疗是一种主要的治疗方法。 在目前的治疗PDAC中，其临床疗效受到不可避免的剂量限制的限制 对正常组织的毒性及其对转移疾病的靶向能力。低分子-有机硅的发展 体重靶向放射性核素治疗(TRTs)是体外放射治疗的一种有吸引力的替代方案 由于它们降低了非靶标毒性和系统靶向能力。然而，短的停留时间， 肿瘤中的TRT由于清除而大大减少了可传递的辐射剂量，并抑制了临床翻译。这个 内布拉斯加州大学医学中心的加里森实验室开发出一种新的内溶酶体捕捉法 大幅增加肿瘤残留率和受体靶向制剂的辐射剂量传递的方法。 神经降压素受体I亚型(NTSR1)已被证明在PDAC活检组织中过度表达，并已 在临床上得到了验证。使用这种陷阱方法，该项目的长期目标是AdductNE，LLC 目的：开发NTSR1靶向TRT治疗PDAC，以改善临床疗效。 在这个第一阶段的项目中，AdductNE，LLC将优化TRT的结构，以进一步增强肿瘤- 对肾脏(T/K)的辐射剂量比(特定目标1)，并提供其治疗效果和 PDAC模型的安全性(具体目标2)。在具体目标1中，将修改TRT结构以增加NTSR1- 肿瘤残留阳性和肾摄取减少/阻断导致T/K比值升高。离体 将对TRT进行表征，以检查稳定性、蛋白酶抑制、NTSR1亲和力和加合物 队形效能。体内肿瘤靶向和保留效率、肿瘤与非靶点的比率和人体剂量学 估计将在PDAC异种移植模型中确定。对于特定目标2，最大耐受量， TRT的疗效和安全性将得到证实。组织病理学和血液分析/监测 将进行放射毒性测试，以测量肿瘤和正常组织的放射毒性。在第二阶段，AdductNE，LLC将验证 在更先进的PDAC模型中进行TRT，并与当前的化疗方案相结合。这个 还将进行必要的毒性和生产规模研究，以提交 研究用新药(IND)--批准。2018年，胰腺癌治疗的市场价值估计 是19亿美元，但预计到2026年将增长到47亿美元。我们的商业化战略是发展， 在我们迈向首个人体研究的过程中，验证和降低我们的药物风险。AdductNE，LLC将通过 许可或收购，由较大的制药公司帮助支持和指导临床翻译。

In 2020 alone, pancreatic cancer is estimated to have resulted in 47,050 deaths in the U.S. making it the fourth leading cause of cancer-related death. Pancreatic ductal adenocarcinoma (PDAC) makes up greater than 90% of all pancreatic cancer diagnoses and has an overall five-year survival rate of just 10%. New therapeutic options are needed to improve the poor prognosis for patients with PDAC. External beam radiation therapy is a staple in the current treatment of PDAC, but its clinical therapeutic efficacy is limited by unavoidable dose-limiting toxicities to normal tissues and its inability to target metastatic disease. The development of low-molecular- weight targeted radionuclide therapeutics (TRTs) is an attractive alternative to external beam radiation therapy due to their reduced non-target toxicity and systemic targeting capabilities. However, the short residence time of TRTs in tumors due to clearance greatly reduces deliverable radiation doses and inhibits clinical translation. The Garrison laboratory at the University of Nebraska Medical Center has developed a novel endolysosomal trapping approach to substantially increase tumor residualization and radiation dose delivery of receptor-targeted agents. The neurotensin receptor subtype I (NTSR1) has been shown to be overexpressed in PDAC biopsies and has been validated in the clinic. Using this trapping approach, the long-term goal of this project is for AdductNE, LLC to develop an NTSR1-targeted TRT with high therapeutic efficacy for PDAC to improve clinical outcomes. During this Phase I project, AdductNE, LLC will optimize the structure of the TRT to further enhance the tumor- to-kidney (T/K) radiation dose ratios (Specific Aim 1) and provide proof-of-concept of its therapeutic efficacy and safety in PDAC models (Specific Aim 2). In Specific Aim 1, the TRT construct will be altered to increase NTSR1- positive tumor residualization and reduce/block renal uptake resulting in an increase in T/K ratios. In vitro characterization of the TRT will be carried out to examine stability, protease inhibition, NTSR1 affinity and adduct formation efficacy. In vivo tumor targeting and retention efficacy, tumor-to-non-target ratios and human dosimetry estimates will be determined in PDAC xenograft models. For Specific Aim 2, the maximum tolerated dose, therapeutic efficacy and safety of the TRT will be established. Histopathological and blood analysis/monitoring will be carried out to measure radiotoxicity in tumor and normal tissues. In Phase II, AdductNE, LLC will validate the TRT in more advanced PDAC models and in conjunction with current chemotherapeutic regimens. The necessary toxicity and manufacturing scale-up studies will also be performed for the submission of an Investigational New Drug (IND)-approval. In 2018, the market value estimate for pancreatic cancer treatment was $1.9 billion but is expected to grow to $4.7 billion by 2026. Our commercialization strategy is to develop, validate and de-risk our drug as we progress towards first-in-human studies. AdductNE, LLC will partner, through licensure or acquisition, with larger pharmaceutical companies to help support and guide clinical translation.