Diagnosis at this late stage is likely due CC5013 to the absence of specific early signs and symptoms of disease and the lack of reliable screening tests that would allow for therapy at an earlier, potentially curable stage. Less than 20% of patients are diagnosed with disease that is amenable for surgical intervention. Sadly, about half of all patients with this disease die within the first six months of diagnosis resulting in a five year survival rate of less than 5%. The most striking genetic signature of PDAC is muta tions of codon 12 of the c K Ras gene and inactivating mutations of INK4a, which occur in greater than 90% of pancreatic tumors. More Inhibitors,Modulators,Libraries than half of PDAC tumors also exhibit loss of the functional tumor suppressor gene, deleted in pancreatic cancer, locus 4, either due to homozygous deletion or intragenic mutations, and up to 75% of PDAC have a p53 mutation.

As found with other solid tumors, PDAC shows aberrant over expression andor constitutive activation of a num ber of growth factor receptors. In 1997, Burris et al. showed a survival benefit for patients treated with gemcitabine compared with 5 fluorouracil and since that time gemcitabine has been the Inhibitors,Modulators,Libraries most used first line therapy for the management of PDAC. The clinical response rate of Inhibitors,Modulators,Libraries PDAC to gemcitabine is less than 25% and those tumors that show an initial response generally develop resistance during the course of therapy. The rapid develop ment of resistance to gemcitabine may be mediated ei ther by molecular changes of tumor cells or due to selection of a pre existing sub population of tumor cells that are inherently resistant to chemotherapy.

There continue to be clinical trials that use gemcitabine in combination with other chemotherapeutic or biologic targeted agents. Erlotinib, an EGFR kinase inhibitor, in combination with gemcitabine Inhibitors,Modulators,Libraries was approved as therapy for PDAC on the basis of a survival benefit of approxi mately two weeks. However, the enthusiasm for the addition of erlotinib is dampened because of the high cost, minimal increase in survival benefit, prevalence of K Ras mutations in most PDAC, and the potential for additional toxicity. Recent studies show that FOLFIRINOX provides a short term survival benefit over gemcitabine however, this regimen is restricted to patients that have a good functional status.

Thus, new therapeutic targets and approaches are being sought to further im prove the survival of patients with PDAC. Signal Inhibitors,Modulators,Libraries transducer and activation of transcription is a family of transcription Baricitinib FDA factors known to mediate cyto kine and growth factor responses in a wide variety of cells. Among these proteins, STAT3 is often constitutively activated and contributes to tumor progression and resist ance to apoptosis in both solid and hematological malig nancies.