Development of a Targeted Radiotherapeuitc for Pancreatic Ductal Adenocarcinoma

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.Relevance: In this STTR grant, AdductNE, LLC plans to develop a targeted radionuclide therapeutic (TRT) to improve the clinical outcomes for patients suffering from pancreatic ductal adenocarcinoma (PDAC). The developed TRT utilizes a technology that is expected to deliver substantially higher therapeutic efficacy relative to what can currently be achieved in the clinic.