Metastasis, the dissemination and growth of neoplastic cells in an organ distinct from that in which they originated, is the most common cause of death in cancer patients. This is particularly true for pancreatic cancers, where most patients are diagnosed with metastatic disease and few show a sustained response to chemotherapy or radiation therapy. Whether the dismal prognosis of patients with pancreatic cancer compared to patients with other types of cancer is a result of late diagnosis or early dissemination of disease to distant organs is not known. Here we rely on data generated by sequencing the genomes of seven pancreatic cancer metastases to evaluate the clonal relationships among primary and metastatic cancers. We find that clonal populations that give rise to distant metastases are represented within the primary carcinoma, but these clones are genetically evolved from the original parental, non-metastatic clone. Thus, genetic heterogeneity of metastases reflects that within the primary carcinoma. A quantitative analysis of the timing of the genetic evolution of pancreatic cancer was performed, indicating at least a decade between the occurrence of the initiating mutation and the birth of the parental, non-metastatic founder cell. At least five more years are required for the acquisition of metastatic ability and patients die an average of two years thereafter. These data provide novel insights into the genetic features underlying pancreatic cancer progression and define a broad time window of opportunity for early detection to prevent deaths from metastatic disease.

SF-010-4 Distant metastasis occurs late during the genetic evolution of pancreatic cancer

LB-194 Lung cancer is the most prevalent form of cancer worldwide and accounts for the most cancer deaths. MicroRNAs (miRNAs) are small, non-protein coding RNAs that have recently emerged as important regulators of gene expression and direct proper cellular growth, differentiation and cell death - all mechanisms that go awry in cancer. The let-7 miRNA is postulated to function as a tumor suppressor gene in a variety of human tissues, particularly in the lung, by negatively regulating the post-transcriptional expression of multiple oncogenes including RAS, MYC, and HMGA2, as well as other cell cycle progression genes. Here we have used both in vitro and in vivo approaches to show that let-7 directly represses cancer growth in  the lung. We show that let-7 inhibits the growth of multiple human lung cancer cell lines in culture, as well as the growth of lung cancer cell xenografts in immunodeficient mice. Using the established Lox-Stop-Lox K-ras mouse lung cancer model, we find that intranasal let-7 administration can reduce tumor formation in vivo in the lungs of animals expressing a G12D activating mutation for the K-ras oncogene. These findings support the notion that let-7 functions as a tumor suppressor in the lung and indicates that this miRNA could be used as a therapeutic agent to treat lung cancer.

The let-7 microrna reduces tumor growth in mouse models of lung cancer

Pancreatic ductal adenocarcinoma (PDAC), which constitutes 90% of pancreatic cancers, is the fourth leading cause of cancer-related deaths in the world. Due to the broad heterogeneity of genetic mutations and dense stromal environment, PDAC belongs to one of the most chemoresistant cancers. Most of the available treatments are palliative, with the objective of relieving disease-related symptoms and prolonging survival. Currently, available therapeutic options are surgery, radiation, chemotherapy, immunotherapy, and use of targeted drugs. However, thus far, therapies targeting cancer-associated molecular pathways have not given satisfactory results; this is due in part to the rapid upregulation of compensatory alternative pathways as well as dense desmoplastic reaction. In this review, we summarize currently available therapies and clinical trials, directed towards a plethora of pathways and components dysregulated during PDAC carcinogenesis. Emerging trends towards targeted therapies as the most promising approach will also be discussed.

Pancreatic Ductal Adenocarcinoma: Current and Evolving Therapies.

MicroRNAs (miRNAs), a highly conserved class of tissue specific, small non-protein coding RNAs maintain cell homeostasis by negative gene regulation. Proper controlling of miRNA expression is required for a balanced physiological environment, as these small molecules influence almost every genetic pathway from cell cycle checkpoint, cell proliferation to apoptosis, with a wide range of target genes. Deregulation in miRNAs expression correlates with various cancers by acting as tumor suppressors and oncogenes. Although promising therapies exist to control tumor development and progression, there is a lack of efficient diagnostic and therapeutic approaches for delineating various types of cancer. The molecularly different tumors can be differentiated by specific miRNA profiling as their phenotypic signatures, which can hence be exploited to surmount the diagnostic and therapeutic challenges. Present review discusses the involvement of miRNAs in oncogenesis with the analysis of patented research available on miRNAs.

Exploring miRNA based approaches in cancer diagnostics and therapeutics.

Previous studies identified microRNAs (miRNAs) and messenger RNAs with significantly different expression between normal pancreas and pancreatic cancer (PDAC) tissues. Due to technological limitations of microarrays and real-time PCR systems these studies focused on a fixed set of targets. Expression of other RNA classes such as long intergenic non-coding RNAs or sno-derived RNAs has rarely been examined in pancreatic cancer. Here, we analysed the coding and non-coding transcriptome of six PDAC and five control tissues using next-generation sequencing. Besides the confirmation of several deregulated mRNAs and miRNAs, miRNAs without previous implication in PDAC were detected: miR-802, miR-2114 or miR-561. SnoRNA-derived RNAs (e.g. sno-HBII-296B) and piR-017061, a piwi-interacting RNA, were found to be differentially expressed between PDAC and control tissues. In silico target analysis of miR-802 revealed potential binding sites in the 3′ UTR of TCF4, encoding a transcription factor that controls Wnt signalling genes. Overexpression of miR-802 in MiaPaCa pancreatic cancer cells reduced TCF4 protein levels. Using Massive Analysis of cDNA Ends (MACE) we identified differential expression of 43 lincRNAs, long intergenic non-coding RNAs, e.g. LINC00261 and LINC00152 as well as several natural antisense transcripts like HNF1A-AS1 and AFAP1-AS1. Differential expression was confirmed by qPCR on the mRNA/miRNA/lincRNA level and by immunohistochemistry on the protein level. Here, we report a novel lncRNA, sncRNA and mRNA signature of PDAC. In silico prediction of ncRNA targets allowed for assigning potential functions to differentially regulated RNAs.

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Erratum to: Next-generation sequencing reveals novel differentially regulated mRNAs, lncRNAs, miRNAs, sdRNAs and a piRNA in pancreatic cancer.

Targeting miR-21 for the Therapy of Pancreatic Cancer

The present invention relates to methods and pharmaceutical compositions for use in the treatment of pancreatic cancer in a subject in need thereof. The inventors showed that targeting cytidine deaminase sensitizes cancer cells to chemotherapy (gemcitabine dFdC) both in vitro and in vivo in experimental models of PDA, with very high efficacy. To their surprise, CDA targeting in the absence of chemotherapy strongly alters cell proliferation and tumor progression. In particular, the present invention relates to a method for treating pancreatic cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a cytidine deaminase inhibitor in combination with an anti-pancreatic cancer treatment selected from the group consisting of CHK1 inhibitor, WEE1 inhibitor, ART inhibitor, DHODH inhibitor or gene therapy.

Cytidine deaminase inhibitors for the treatment of pancreatic cancer

Current Understanding of microRNAs as Therapeutic Targets in Cancer

Pancreatic cancer is the fourth leading cause of death by cancer worldwide. There is currently no curative treatment excepting surgery for 15 % of patients. Consequently, it is necessary to identify new therapeutic targets such as microRNAs to help manage this disease. Interestingly, these short non-coding RNAs can negatively control the expression of hundreds of genes, and thus are key regulators of tumor progression and dissemination. In addition, they are implicated in cancer cell resistance to treatment. Taken together, microRNAs can represent a new class of molecular targets. MicroRNAs can be combined with different carriers (either non viral or viral) to increase their stability and specificity. Successful examples of microRNA targeting in vivo for the therapy of experimental models of pancreatic cancer have recently emerged. Nevertheless, clinical trials based on microRNA targeting for cancer are still lacking while their interest as biomarkers is emerging. Importantly, improved delivery and specificity to reduce off-target effects must be controlled to accelerate the use of microRNA as new therapeutic targets in oncology.

Modulating MicroRNA Expression for the Therapy of Pancreatic Cancer

A Myb34.5 virus for use in a method of treating pancreatic cancer preferably associated to at least one chemotherapeutic compound, products containing a Myb34.5 virus and at least one chemotherapeutic compound, as a combined preparation for simultaneous, separate or sequential use in therapy of pancreatic ductal adenocarcinoma and pharmaceutical compositions.

Marion Gayral

Papers

Targeting miR-21 for the Therapy of Pancreatic Cancer

Cytidine deaminase inhibitors for the treatment of pancreatic cancer

Current Understanding of microRNAs as Therapeutic Targets in Cancer

Modulating MicroRNA Expression for the Therapy of Pancreatic Cancer

Compounds and associations for treating pancreatic cancer