A Conditionally Activable Small Molecule Pro-Drug Conjugate for Targeted Treatment of Pancreatic Cancer

Approximately 90% of patients suffering from pancreatic ductal adenocarcinoma (PDAC) will die from the disease within five years. Development of novel targeted therapies is essential to improve patient survival. Fibroblast activating protein (FAP) is a type II integral membrane protease that is abundantly and selectively expressed in the stroma of more than 90% of epithelial tumours, including PDAC. In TargPanc, we propose the creation of a highly selective FAP-targeted small molecule chemotherapeutic which would improve drug delivery to pancreatic cancer tumours while also limiting off-target effects and maximizing efficacy. High-affinity FAP ligands have been reported. We plan to conjugate a novel beta-glucuronide-PHB-beta-lapachone prodrug to mono and multivalent- FAP ligands we have designed. This novel FAP-targeted prodrug achieves multi-layer specificity through the beta-glucuronidase dependent release of the warhead (beta-lapachone) in a necrotic tumour microenvironment of optimal pH, as well as the beta-lapachone toxin targeting the overexpressed NAD(P)H dehydrogenase quinone 1 (NQO1) and 5-lipoxygenase (5-LO) enzymes in PDAC cells. We will first synthesize, optimize, and test various derivatives of this small molecule conjugate for optimal stability and drug release. We will then test the conjugate in vitro in PDAC cell lines and in vivo in PDAC-specific KPC genetically engineered mouse models. The cancer cell specificity of this conjugate will also allow this prodrug to effectively treat other solid tumours with poor prognoses. We hypothesize that this smaller, target-specific chemotherapeutic will have greater tumour penetration and improved pharmacokinetic distribution with limited systemic toxicity compared to existing therapies, ultimately extending overall patient survival.