Development of a Targeted Radiotherapeuitc for Pancreatic Ductal Adenocarcinoma

仅在2020年，胰腺癌估计就导致美国47，050人死亡，使其成为第四大癌症。 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，胰腺癌的总五年生存率仅为10%。新的治疗选择 以改善PDAC患者的不良预后。体外放射治疗是 但其临床治疗效果受到不可避免的剂量限制， 对正常组织的毒性和不能靶向转移性疾病。低分子- 重量靶向放射性核素治疗（TRT）是一种有吸引力的替代外束放射治疗 这是因为它们降低了非靶毒性和全身靶向能力。然而，短的停留时间 由于清除，肿瘤中的TRT大大减少了可输送的辐射剂量并抑制了临床转化。的 内布拉斯加大学医学中心的加里森实验室开发了一种新的内溶酶体捕获技术， 这是一种基本上增加肿瘤残留和受体靶向剂的辐射剂量递送的方法。 神经降压素受体亚型I（NTSR 1）已被证明在PDAC活检中过表达， 在临床上得到验证。使用这种捕获方法，该项目的长期目标是为AdductNE，LLC 开发NTSR 1靶向TRT，对PDAC具有高疗效，以改善临床结局。 在这个I期项目中，AdductNE，LLC将优化TRT的结构，以进一步增强肿瘤- 与肾脏（T/K）辐射剂量比（具体目标1），并提供其治疗效果的概念验证， PDAC模型的安全性（具体目标2）。在特定目标1中，TRT构建体将被改变以增加NTSR 1- 阳性肿瘤残留和减少/阻断肾摄取，导致T/K比值增加。体外 将进行TRT的表征以检查稳定性、蛋白酶抑制、NTSR 1亲和力和加合物 形成效能体内肿瘤靶向和保留效力、肿瘤与非靶比和人体剂量测定 将在PDAC异种移植模型中确定估计值。对于特定目标2，最大耐受剂量， 将确定TRT的疗效和安全性。组织学和血液分析/监测 将进行测量肿瘤和正常组织中的放射毒性。在第二阶段，AdductNE，LLC将确认 TRT在更先进的PDAC模型中以及与当前化疗方案联合使用。的 还将进行必要的毒性和生产规模扩大研究，以提交 研究性新药（IND）-批准。2018年，胰腺癌治疗的市场价值估计 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开发， 在我们进行首次人体研究的过程中，验证我们的药物并降低其风险。AdductNE，LLC将通过 许可证或收购，与大型制药公司合作，以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.