Abstract
For patients with metastatic pancreatic cancer that are not eligible for surgery, signal-targeted therapies have so far failed to significantly improve survival. These therapeutic options have been tested in phase II/III clinical trials mostly in combination with the reference treatment gemcitabine. Innovative therapies aim to annihilate oncogenic dependency, or to normalize the tumoural stroma to allow immune cells to function and/or re-vascularisation to occur. Large scale transcriptomic and genomic analysis revealed that pancreatic cancers display great heterogeneity but failed to clearly delineate specific oncogene dependency, besides oncogenic Kras. Beyond these approaches, proteomics appears to be an appropriate approach to classify signal dependency and to identify specific alterations at the targetable level. However, due to difficulties in sampling, proteomic data for this pathology are scarce. In this review, we will discuss the current state of clinical trials for targeted therapies against pancreatic cancer. We will then highlight the most recent proteomic data for pancreatic tumours and their metastasis, which could help to identify major oncogenic signalling dependencies, as well as provide future leads to explain why pancreatic tumours are intrinsically resistant to signal-targeted therapies. We will finally discuss how studies on phosphatidylinositol-3-kinase (PI3K) signalling, as the paradigmatic pro-tumoural signal downstream of oncogenic Kras in pancreatic cancer, would benefit from exploratory proteomics to increase the efficiency of targeted therapies.
Highlights
To date, surgical resection provides the best chance of a cure for patients with pancreatic cancer.this curative approach is only proposed in 15 to 20% of cases
The first major advance in the palliative treatment of patients with pancreatic cancer occurred in 2011 using FOLFIRINOX, a combination chemotherapy combining 5-fluorouracil, folinic acid, irinotecan and oxaliplatin
Overall survival (OS) and progression-free survival (PFS) improved slightly in PDAC patients treated with an EGFR inhibitor in combination with gemcitabine, there was no significant difference in the objective response as compared to placebo plus gemcitabine [61,62]
Summary
Surgical resection provides the best chance of a cure for patients with pancreatic cancer. The first major advance in the palliative treatment of patients with pancreatic cancer occurred in 2011 using FOLFIRINOX, a combination chemotherapy combining 5-fluorouracil, folinic acid, irinotecan and oxaliplatin. It has become the standard treatment for metastatic PDAC in patients in good general condition. III), and metastatic PDACs (grade IV) (www.asco.org/guidelineswiki) Their recommendations for therapeutic interventions, including FOLFORINOX, irradiation and/or gemcitabine in combination with nab-paclitaxel, are based on relevant articles published between 2004 and 2015. It remains necessary and urgent to discover new targets and associated therapeutics, as well as improve irradiation protocols and current therapeutic strategies, by determining the mechanisms of intrinsic pancreatic resistance to anti-tumour agents including targeted therapies. Proteomics Is a Technological Tool Which Can Help to Improve the Clinical Management of Pancreatic
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