Metastatic pancreatic cancer: Is there a light at the end of the tunnel?

Due to extremely poor prognosis,pancreatic cancer(PDAC)represents the fourth leading cause of cancerrelated death in Western countries.For more than a decade,gemcitabine(Gem)has been the mainstay of first-line PDAC treatment.Many efforts aimed at improving single-agent Gem efficacy by either combining it with a second cytotoxic/molecularly targeted agent or pharmacokinetic modulation provided disappointing results.Recently,the field of systemic therapy of advanced PDAC is finally moving forward.Polychemotherapy has shown promise over single-agent Gem:regimens like PEFG-PEXG-PDXG and GTX provide significant potential advantages in terms of survival and/or disease control,although sometimes at the cost of poor tolerability.The PRODIGE 4/ACCORD 11 was the first phaseⅢtrial to provide unequivocal benefit using the polychemotherapy regimen FOLFIRINOX;however the less favorable safety profile and the characteristics of the enrolled population,restrict the use of FOLFIRINOX to young and fit PDAC patients.The nanoparticle albumin-bound paclitaxel(nab-Paclitaxel)formulation was developed to overcome resistance due to the desmoplastic stroma surrounding pancreatic cancer cells.Regardless of whether or not this is its main mechanisms of action,the combination of nabPaclitaxel plus Gem showed a statistically and clinically significant survival advantage over single agent Gem and significantly improved all the secondary endpoints.Furthermore,recent findings on maintenance therapy are opening up potential new avenues in the treatment of advanced PDAC,particularly in a new era in which highly effective first-line regimens allow patients to experience prolonged disease control.Here,we provide an overview of recent advances in the systemic treatment of advanced PDAC,mostly focusing on recent findings that have set new standards in metastatic disease.Potential avenues for further development in the metastatic setting and current efforts to integratenew effective chemotherapy regimens in earlier stages of disease(neoadjuvant,adjuvant,and multimodal approaches in both resectable and unresectable patients)are also briefly discussed.

To metabolomics and beyond:a technological portfolio to investigate cancer metabolism

Tumour cells have exquisite flexibility in reprogramming their metabolism in order to support tumour initiation, progression,metastasis and resistance to therapies. These reprogrammed activities include a complete rewiring of the bioenergetic, biosyntheticand redox status to sustain the increased energetic demand of the cells. Over the last decades, the cancer metabolism field hasseen an explosion of new biochemical technologies giving more tools than ever before to navigate this complexity. Within a cell ora tissue, the metabolites constitute the direct signature of the molecular phenotype and thus their profiling has concrete clinicalapplications in oncology. Metabolomics and fluxomics, are key technological approaches that mainly revolutionized the fieldenabling researchers to have both a qualitative and mechanistic model of the biochemical activities in cancer. Furthermore, theupgrade from bulk to single-cell analysis technologies provided unprecedented opportunity to investigate cancer biology at cellularresolution allowing an in depth quantitative analysis of complex and heterogenous diseases. More recently, the advent offunctional genomic screening allowed the identification of molecular pathways, cellular processes, biomarkers and noveltherapeutic targets that in concert with other technologies allow patient stratification and identification of new treatmentregimens. This review is intended to be a guide for researchers to cancer metabolism, highlighting current and emergingtechnologies, emphasizing advantages, disadvantages and applications with the potential of leading the development ofinnovative anti-cancer therapies.