PACA/PI3K · Characterisation of PI3K isoform roles in pancreatic cancerogenesis

Characterisation of PI3K isoform roles in pancreatic cancerogenesis

Summary description of the project objectives: Pancreatic adenocarcinoma, a cancer with very poor diagnostic. Pancreatic adenocarcinoma is one of the most lethal cancers, with a 5-year death rate of 95 % of diagnosed patients. No efficient chemotherapy is currently available. The vast majority (about 90 percent) of pancreatic tumors have mutations in the K-Ras gene. K-Ras becomes constantly activated by this mutation, signaling the cell to change its morphology, to grow and to ignore cues to stop growing. But, K-Ras does not act alone. Instead, K-Ras activates a complex cascade of other proteins to ultimately lead to cellular changes. One of the key proteins activated when K-Ras is mutated are the PI3Ks. Because efforts to inhibit K-Ras as a means to stop the growth of pancreatic cancer have been unsuccessful, we are opting to target PI3K activity instead. We, therefore, proposed to make the proof-of-concept that hitting PI3Ks prevent pancreatic cancer initiation and to discover which of the PI3K to hit. Description of the work performed since the beginning of the project: Mammals have 4 isoforms of PI3Ks. We have inactivated genetically in mammalian models of initiation of pancreatic cancer the two ubiquitous PI3K p110alpha and p110beta. We then: -assessed the incidence of preneoplasic and cancerous lesions at different stages, -morphologically characterized these lesions, -analyzed signaling pathways, -created primary cultures from these models. We have inactivated both genetically and pharmacologically the two ubiquitous PI3Ks in vitro models of cell transformation by mutated Kras and assessed: -the growth in the absence of matrix, -the proliferation/survival, -the signaling involved, -the cytoarchitectural modifications associated. Description of the main results achieved: We show that inactivating only one of the two isoforms is sufficient to prevent pancreatic cancer initiation both in vivo and in vitro. A paper on the role of one if the ubiquitous PI3K in pancreatic cancer initiation is under writing (Guillermet-Guibert as a last author). Expected final results and their potential impact and use: This project will demonstrate the differences between p110alpha and p110beta in a pancreatic cancer model. If new selective inhibitors are currently available, global PI3K inhibitors are currently in early clinical trials for application on different cancer types such as breast cancer. These compounds inhibiting several isoforms could have potential adverse effects. To develop efficient therapeutic intervention, it is crucial to understand which patients could benefit from a compound targeting one or a group of PI3Ks. This work allows the scientific community to understand the specific role of each isoform in pancreatic cancer and will help the clinicians to direct their clinical trials. This funding allowed the Researcher to: -finalize her first paper as a last author in 4 year time on a new line of research involving long term experiment (comprehensive mouse models of cancer), -go faster than anticipated in her projects, -hire/train persons and secure two 3-year positions for 2 PhDs under her direct supervision- including one PhD on a new line of research (Phosphoproteomics), -collaborate/train other persons of the lab (1 publication accepted in Cell report, 3 publications under submission), -insert herself in european network on pancreatic cancer, -propose a project for the creation of a new team (2 researcher are joining her since 2014).

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