Final Report Summary - STARGET-IN-PANR (Determination of specific components from “stromal PDAC signature” involved in PDAC Associated Neural Remodeling (PANR) and their use as clinical tool-box.)
Pancreatic ductal carcinoma (PDAC) is predicted to become the second leading cause of cancer death by 2020, without clear epidemiological explanation of the increased incidence. With an overall 3-year survival rate of only ~6%, PDAC figures as the solid cancer with the worst prognosis. While PDAC-related fundamental research might have provided substantial novel insights, translational research aimed at improving the clinical tool-box to fight this disease has met with rather limited success, overall survival improving by “only” 4 months in the last decade. The poor outcome for PDAC patients is mainly due to: (1) a late diagnosis, with only 15% of patients eligible for surgery; (2) the lack of unbiased biomarkers, preventing the screening of at risk patient populations; (3) the resistance of the disease to current mono or combined therapies, without any second line choices other than palliative treatments; and (4) the by necessity restrictive use of the best chemotherapies available, most patients failing to meet the global health criteria required to withstand those toxicity. In trying to understand “the” reason for such negative outlook, one has to consider that the fundamental and clinical research conducted during the last 30 years has focused on characterizing and understanding the properties of the PDAC cancer cells, neglecting the specific cellular context of those tumors. Indeed, as mentioned by pathologists since decades, PDAC is a solid tumor with a most prominent desmoplastic reaction (also called intra-tumoral microenvironment or stroma compartment). Regarding this statement, our ERC project aimed at the improvement of the clinical tool-box available for clinicians facing this disease through the determination of a specific stromal impact on PDAC Associated Neural remodeling or “PANR”.
In order to improve the management of PDAC patients, we had to better understand the various physiologic modifications present within PDAC. One of the major changes consists in “PANR” and the significant enhanced innervation of PDAC compared to healthy pancreas, a phenomenon correlated with pain, recurrence, metastasis onset and global survival. Our project intended to determine 1/ how the stroma compartment influence this PANR, 2/ how we can determine the level of PANR and so stratify PDAC patients, 3/ if specific molecule from stroma can be relevant biomarkers for PANR and 4/ if other stroma-related molecules can constitute putative therapeutic targets in order to better manage PDAC patients and improve global survival and life quality. Data obtained through this project improved considerably our knowledge on the relation stroma/PANR and how we could use this relationship in a clinical point-of-view. We determined so far 3 molecules (all patented) and 5 others under validation. Among the validated one, we demonstrated that stroma compartment influences drastically the PANR and so patients’ survival but, more importantly, that we can use the stroma (through the presence of those 3 molecules) to predict the fate of patients. In other terms, we brought to the clinic new tools permitting to stratify PDAC patients. This point is a crucial progress for a disease with a dramatic heterogeneity and for which the clustering of PDAC sub-classes is the only way to determine the “efficiency” of a treatment through the establishment of better conducted clinical trials leading to a more personalized medicine.
Besides the main objectives of the project, we also succeeded to enrich the possibility of the scientific community by creating new technical tools to assess PANR in vitro and in vivo. Our project permitted to unravel novel diagnostic, prognostic, and therapeutic options making the use of such components involved in PANR a new tool-box against this deadly malignancy with the final goal to optimize patient survival and life quality.
In order to improve the management of PDAC patients, we had to better understand the various physiologic modifications present within PDAC. One of the major changes consists in “PANR” and the significant enhanced innervation of PDAC compared to healthy pancreas, a phenomenon correlated with pain, recurrence, metastasis onset and global survival. Our project intended to determine 1/ how the stroma compartment influence this PANR, 2/ how we can determine the level of PANR and so stratify PDAC patients, 3/ if specific molecule from stroma can be relevant biomarkers for PANR and 4/ if other stroma-related molecules can constitute putative therapeutic targets in order to better manage PDAC patients and improve global survival and life quality. Data obtained through this project improved considerably our knowledge on the relation stroma/PANR and how we could use this relationship in a clinical point-of-view. We determined so far 3 molecules (all patented) and 5 others under validation. Among the validated one, we demonstrated that stroma compartment influences drastically the PANR and so patients’ survival but, more importantly, that we can use the stroma (through the presence of those 3 molecules) to predict the fate of patients. In other terms, we brought to the clinic new tools permitting to stratify PDAC patients. This point is a crucial progress for a disease with a dramatic heterogeneity and for which the clustering of PDAC sub-classes is the only way to determine the “efficiency” of a treatment through the establishment of better conducted clinical trials leading to a more personalized medicine.
Besides the main objectives of the project, we also succeeded to enrich the possibility of the scientific community by creating new technical tools to assess PANR in vitro and in vivo. Our project permitted to unravel novel diagnostic, prognostic, and therapeutic options making the use of such components involved in PANR a new tool-box against this deadly malignancy with the final goal to optimize patient survival and life quality.