Background: Pancreatic Ductal Adenocarcinoma (PDAC) often presents with mutations in KRAS (>80%) and inactivating and/or potentially gain-of-function mutations in the tumor suppressor TP53 (60-70%). The latter contributes to reprogramming PDAC towards more malignant phenotypes. However, so far p53-targeted therapies have met limited clinical success, mainly due to off-target effects and difficulties in delivering them at pharmacologically relevant doses within tumor cells.
Hypothesis: Current obstacles to p53 targeted therapy in PDAC could be overcome by delivering structure-specific p53 modulators using controllable nanovectors, including small MUTp53 reactivating peptides and WTp53-enhancing long non-coding (lnc)RNAs.
Aims: Primary aim is proof-of-concept (PoC) of preclinical efficacy for delivery of lead compounds using controllable liposomal carriers to PDAC organoids and mouse xenografts. Secondary aims are (1) understanding mechanisms including effects on tumor microenvironment; (2) identifying biomarkers of response.
Methods: Novel peptides and human lncRNAs that target either MUTp53 or WTp53 will be delivered to PDAC in a microfluidic system that mimics a pancreatic environment through X-ray lipid nanoparticles. PoC will be established in human PDAC xenografts in mice.
Expected results and impact: This multidisciplinary project involves chemists, structural, molecular and cell biologists as well as clinicians. Innovation resides in the novelty and originality of the compounds tested and in their delivery into PDAC using nanovectors controllable through X-rays. Combining these technologies will break the deadlock for reactivating p53 and thus provide a blueprint for early phase trials aimed at sensitizing PDAC to combined therapeutic modalities, fulfilling the objectives of Aim2 of Transcan-3: identification and validation of novel therapeutical targets for hard-to-treat cancers.