New preclinical models

With a 5-year survival rate of less than 5%, pancreatic ductal adenocarcinoma (PDAC) is the most lethal and chemoresistant among the major tumors. Experimental therapeutic agents have thus far showed limited effects.

This may be explained by their selection in traditional preclinical models, such as xenografts from established cell lines, which undergo substantial changes that deviate from their originator tumors, including loss of distinct stem cell populations, or genetically engineered mouse models, which depend on a few genetic lesions that might not reflect the genetic diversity of human PDAC.

Recent studies support the testing of drug sensitivity in “avatar” mice, created by subcutaneous implant of tumor pieces. However, subcutaneous tumors do not recapitulate critical features of PDAC growth, such as spatial interactions and ability of metastasizing. Therefore, the application of imaging techniques for orthotopic tumors represents another crucial step for the development of successful models.

The working hypothesis of our AIRC-Start-Up project is that PDAC therapies can be implemented by the establishment of a novel platform of orthotopic preclinical models, bearing the genetic profiles and stemness properties of PDAC, and that could be monitored longitudinally, with new effective imaging techniques. Therefore we propose to use our unique primary PDAC cell cultures and tissues library in order to establish a robust imaging platform for in vivo screening of selected innovative drugs, as well as to further delineate the biology and genetic characteristics of PDAC.

Our main articles related to this project

1. Maftouh M, Belo AI, Avan A, Funel N, Peters GJ, Giovannetti E, Van Die I.
   Galectin-4 expression is associated with reduced lymph node metastasis and modulation of Wnt/β-catenin signalling in pancreatic adenocarcinoma. Oncotarget. 2014 Jul 30;5(14):5335-49.
   Link: www.ncbi.nlm.nih.gov/pubmed/24977327
   Free pdf: click here
2. Giovannetti E, Wang Q, Avan A, Funel N, Lagerweij T, Lee JH, Caretti V, van der Velde A, Boggi U, Wang Y, Vasile E, Peters GJ, Wurdinger T, Giaccone G.
   Role of CYB5A in pancreatic cancer prognosis and autophagy modulation. J Natl Cancer Inst. 2014 Jan;106(1):djt346.
   Link: www.ncbi.nlm.nih.gov/pubmed/24301457
3. Avan A, Caretti V, Funel N, Galvani E, Maftouh M, Honeywell RJ, Lagerweij T, Van Tellingen O, Campani D, Fuchs D, Verheul HM, Schuurhuis GJ, Boggi U, Peters GJ, Würdinger T, Giovannetti E.
   Crizotinib inhibits metabolic inactivation of gemcitabine in c-Met-driven pancreatic carcinoma. Cancer Res. 2013 Nov 15;73(22):6745-56.
   Link: www.ncbi.nlm.nih.gov/pubmed/24085787
4. Funel N, Giovannetti E, Del Chiaro M, Mey V, Pollina LE, Nannizzi S, Boggi U, Ricciardi S, Del Tacca M, Bevilacqua G, Mosca F, Danesi R, Campani D.
   Laser microdissection and primary cell cultures improve pharmacogenetic analysis in pancreatic adenocarcinoma. Lab Invest. 2008 Jul;88(7):773-84.
   Link: www.ncbi.nlm.nih.gov/pubmed/18490900

For our ongoing studies on the role of hypoxia drug resistance and new models to test targeted anti-LDH agents we recently obtained, in collaboration with Prof. Minutolo (www.unimap.unipi.it), a “Clinical Research and Innovation – scouting” grant from the University of Pisa.