USpDD

Pancreatic cancer is the 4th cause of death by cancer in western countries. However, only 20% of patients can benefit from the only curative treatment, surgery. Moreover, surgery can be a solution for only 60% of these patients because of lymphatic dissemination of the tumour. Systemic treatments have either a small effect (gemcitabine) or no effect (radiotherapy) on the life outcome of the patients. However, a broad treatment of the tumour and its vicinity could be a solution as pancreatic tumours develop first by lymphatic extension, then peri-nervous, and then vascular peri pancreatic. The goal of the project USpDD is to demonstrate the therapeutic potential of a regional treatment of the pancreatic cancer by combining a physical agent (ultrasound) with pharmacological agents. An original method of selective treatment of tumours consists of applying ultrasound to drug-loaded liposomes. When cavitation occurs, the nano-particles release drugs and cellular permeability is enhanced. This strategy allows limiting the dose of chemotherapy, reducing associated side effects, and increasing drug uptake by tumours. The work is organized in 6 work packages: - WP1: Reproduce and develop an orthotopic model of regional pancreatic tumours in animals - WP2: Check in vitro the sensitivity of the developed model to free or encapsulated drugs - WP3: Design a setup for generating ultrasound, and for detecting and monitoring cavitation during in vitro and in vivo trials - WP4: Encapsulate a fluorescent marker, a contrast agent, or drugs inside sono sensitive liposomes. Characterize these liposomes. - WP5: Study the biodistribution of these liposomes in tumour-bearing animals - WP6: Study the response of the tumour model to drug-loaded liposomes exposed to ultrasound In this project a synergy is envisioned between two complementary teams. The expertise of Inserm U556 on the therapeutic application of ultrasound on localized cancer is recognized worldwide. People at EA1833 performed extensive work in the fields of development of contrast agents and chemotherapies, animal models, and in vivo experimentation. This proof of concept phase is anticipated to last 3 years. The project coordinated by Cyril Lafon (INSERM U556) represents a total cost of 750231€. A grant of 241676€ (i.e. 33% of the cost) is requested from ANR. From the success of the experiments carried out in this project, we will be able to define precisely a form of encapsulated chemotherapy associated with a MRI contrast agent. This agent will allow tumour targeting and favour drug uptake. The procedure will be enhanced by ultrasound. The animal experimentation should demonstrate that the combination of ultrasound with drug-loaded particles slows down the tumour development and enhances the animal survival. This final result will establish the proof of concept.