Pro-oxidant Therapy for Pancreatic Cancer
Project Summary
By 2040, approximately 46,000 individuals each year in the U.S. are predicted to die from pancreatic ductal adenocarcinoma (PDAC) which highlights an urgent need to develop new therapeutic modalities. Gemcitabine plus Abraxane or FOLFIRINOX-type regimens are the standard of care chemotherapies for pancreatic cancer patients; however, cumulative toxicities associated with these therapies and a general lack of promising combination therapies make the statistics for pancreatic cancer survival stagnant. PDAC, like several other malignancies, displays a uniquely elevated production of reactive oxygen species (ROS) which leaves cells vulnerable to programmed cell death by exploiting and increasing this elevated amount of ROS. The potential product developed in this proposal is based on our novel, patented (US 10,781,183 B2 and WO 2020/181207A1) class of quinazolinediones (QD) compounds. These compounds induce even higher ROS levels in PDAC which leads to cancer cell death. Extensive in vitro and in vivo data on our lead compounds QD501 and QD502 (along with earlier generations) show promising pharmacological characteristics and potent anti-cancer activity. Our highly promising new-generation QD compounds, QD501 and QD502 demonstrate outstanding sensitivity (nanomolar potency), are metabolically stable, water-soluble, show desirable acute PK properties, and are orally active. Additionally, these compounds show efficacy and specificity in killing pancreatic cancer cells, while not impacting body weight or other organ functions in preclinical PDAC mouse models. The aims of this FastTrack SBIR are to first, determine the feasibility of using clinically relevant PK-guided doses of either QD501 or QD502 in treating PDAC in multiple mouse models of pancreatic cancer disease. If milestones of appropriate PK (stability > 3hrs in vivo) and efficacy (therapeutic index > 10, decrease in tumor > 80%) are met in Phase I, we will proceed to Phase II which aims to scale the synthesis of the lead compound (QD501 or QD502)(synthesize 190g of pure product) and test its toxicology for 14 days in larger animals (male and female rats and dogs) (milestone=body weight loss < 5%, and maintained organ function). Toxicology and efficacy studies in this proposal will provide the foundation for an IND application to test if QD drugs can improve survival rates for patients with advanced PDAC.
Project Narrative
PDAC metastasizes microscopically during early temporal phases of disease incidence, limiting the effectiveness of local therapies such as surgery and radiation. The drug therapy being developed in this proposal will test the feasibility, efficacy, and toxicity of novel “QD-based ROS inducers” in preclinical pancreatic cancer models. We hope to provide a treatment for pancreatic cancer that is effective, non-toxic, and will help increase both time and quality of life for patients.
A new understanding of disease.
Our mission is to develop & deliver oncology, cardiovascular, and other therapies for patients with high unmet medical needs.