Development of a Targeted Radiotherapeuitc for Pancreatic Ductal Adenocarcinoma

胰腺导管腺癌靶向放射治疗的开发

• 批准号: 10257694
• 负责人: Jered C Garrison
• 金额: $ 40万
• 依托单位: ADDUCTNE, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10257694
• 关键词: Affinity; Animal Model; Biopsy; Blood; Cancer Etiology; Cessation of life; Clinic; Clinical; Clinical Trials; Consultations; Development; Diagnosis; Disease; Dose; Dose-Limiting; External Beam Radiation Therapy; Goals; Grant; Human; In Vitro; Investigational Drugs; Kidney; Label; Laboratories; Licensure; Malignant neoplasm of pancreas; Maximum Tolerated Dose; Measures; Medical center; Molecular Weight; Monitor; Nebraska; Neurotensin Receptors; New Drug Approvals; Normal tissue morphology; Operative Surgical Procedures; Outcome; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patient-Focused Outcomes; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Prognosis; Radiation Dose Unit; Radiation Toxicity; Radiation therapy; Radionuclide therapy; Radiopharmaceuticals; Radiosensitization; Regimen; Residual Tumors; Risk; Safety; Small Business Technology Transfer Research; Structure; Survival Rate; Technology; Therapeutic; Time; Toxic effect; Treatment Efficacy; Treatment Protocols; Tumor Tissue; Tumor Volume; Universities; Xenograft Model; adduct; cancer diagnosis; cancer therapy; chemotherapy; clinical translation; commercial application; commercialization; comparative efficacy; dosimetry; first-in-human; improved; in vivo; manufacturing scale-up; mouse model; novel; novel therapeutics; overexpression; pancreatic ductal adenocarcinoma model; receptor; residence; scale up; targeted agent; targeted radiotherapeutic; tumor; uptake

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.

仅 2020 年，胰腺癌估计就在美国导致 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 占所有胰腺癌诊断的首位，总体五年生存率仅为 10%。新的治疗选择 需要改善 PDAC 患者的不良预后。外照射放射治疗是主要手段 目前治疗PDAC，但不可避免的剂量限制限制了其临床疗效 对正常组织的毒性及其无法靶向转移性疾病。低分子材料的开发 体重靶向放射性核素治疗 (TRT) 是外束放射治疗的一种有吸引力的替代方案 由于其降低的非目标毒性和系统靶向能力。但停留时间短 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。这 内布拉斯加大学医学中心的加里森实验室开发了一种新型的内溶酶体捕获 显着增加肿瘤残留和受体靶向药物的辐射剂量递送的方法。 神经降压素受体亚型 I (NTSR1) 已被证明在 PDAC 活检中过度表达，并且 并在临床中得到验​​证。使用这种捕获方法，该项目的长期目标是 AdductNE, LLC 开发针对 PDAC 具有高效治疗效果的 NTSR1 靶向 TRT，以改善临床结果。 在这一一期项目中，AdductNE, LLC 将优化 TRT 的结构，以进一步增强肿瘤- 到肾脏 (T/K) 的辐射剂量比（具体目标 1）并提供其治疗功效的概念验证和 PDAC 模型的安全性（具体目标 2）。在具体目标 1 中，TRT 结构将被改变以增加 NTSR1- 阳性肿瘤残留并减少/阻断肾脏摄取，导致 T/K 比率增加。体外 将进行 TRT 的表征，以检查稳定性、蛋白酶抑制、NTSR1 亲和力和加合物 形成功效。体内肿瘤靶向和保留功效、肿瘤与非靶标比率和人体剂量测定 估计值将在 PDAC 异种移植模型中确定。对于具体目标 2，最大耐受剂量， TRT 的治疗效果和安全性将得到确定。组织病理学和血液分析/监测 将进行测量肿瘤和正常组织的放射毒性。在第二阶段，AdductNE, LLC 将验证 更先进的 PDAC 模型中的 TRT 以及与当前化疗方案的结合。这 还将进行必要的毒性和生产放大研究，以提交一份 研究性新药 (IND) 批准。 2018年胰腺癌治疗市场价值预估 为 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、 随着我们在首次人体研究方面取得进展，验证我们的药物并降低风险。 AdductNE, LLC 将通过 与大型制药公司一起获得许可或收购，以帮助支持和指导临床转化。