Newer Trends in Pancreatic Cancer Treatment: Genetic Alterations and the Role of Immune Therapeutic and Targeted Therapies.

Pancreatic cancer prognosis has remained poor and no significant improvement has been achieved over the past two decades. A number of genetic alterations are found in pancreatic cancer with a complex genome and proteome that needs further research investigation and discovery. There is an urgent need for innovative research findings that would increase the 5-year survival rate in patients with pancreatic ductal carcinoma, which in fact has seen only small increments over the past two decades. Targeting the tumor and modifying the stroma could help improve therapy responses. Genomic medicine is useful in a fraction of patients currently; however, the newer proteomic approaches are potentially more likely to help the majority of patients in the future. Future treatments of pancreatic cancer will likely be based on the development of novel therapies per genomic and proteomic identifications of cellular/immunological processes and molecular pathways as therapeutic targets. Herein, we systematically review the newer trends in pancreatic cancer treatment with emphasis on the genetic alterations and role of immune therapeutics and targeted therapies.

Gemcitabine: A Review of Chemoresistance in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma, an exocrine tumor, is the most common type of cancer of the pancreas and one of the top five most prominent causes of cancer-associated mortality worldwide. The survival rate for pancreatic cancer is sadly less than 8%. The high fatality rate is partly related to late diagnosis and partly to the aggressive nature of malignant cells that disseminate to nearby tissues at an early stage of the disease, making treatment difficult. Available treatment choices consist of both medical and surgical: removal of the tumor, use of various medications like chemotherapeutic drugs and immunotherapeutic agents, radiation therapy, and targeted drug therapy. Since most patients suffer from advanced cancer at the time of diagnosis, chemotherapy becomes the primary therapeutic option in such cases. Drugs like Gemcitabine, Abraxane, FOLFIRINOX, and newer combination therapies are all effective in management, either curatively or palliatively. However, chemoresistance poses a significant challenge. Several factors, both intrinsic and acquired, are involved in drug resistance. Here, we review the mechanism of action of the first-line chemotherapy drugs in pancreatic cancer and various factors associated with cancer chemoresistance.

The role of residue stability in transient protein-protein interactions involved in enzymatic phosphate hydrolysis. A computational study.

Finding why protein-protein interactions (PPIs) are so specific can provide a valuable tool in a variety of fields. Statistical surveys of so-called transient complexes (like those relevant for signal transduction mechanisms) have shown a tendency of polar residues to participate in the interaction region. Following this scheme, residues in the unbound partners have to compete between interacting with water or interacting with other residues of the protein. On the other hand, several works have shown that the notion of active site electrostatic preorganization can be used to interpret the high efficiency in enzyme reactions. This preorganization can be related to the instability of the residues important for catalysis. In some enzymes, in addition, conformational changes upon binding to other proteins lead to an increase in the activity of the enzymatic partner. In this article the linear response approximation version of the semimacroscopic protein dipoles Langevin dipoles (PDLD/S-LRA) model is used to evaluate the stability of several residues in two phosphate hydrolysis enzymes upon complexation with their activating partners. In particular, the residues relevant for PPI and for phosphate hydrolysis in the CDK2/Cyclin A and Ras/GAP complexes are analyzed. We find that the evaluation of the stability of residues in these systems can be used to identify not only active site regions but it can also be used as a guide to locate "hot spots" for PPIs. We also show that conformational changes play a major role in positioning interfacing residues in a proper "energetic" orientation, ready to interact with the residues in the partner protein surface. Thus, we extend the preorganization theory to PPIs, extrapolating the results we obtained from the above-mentioned complexes to a more general case. We conclude that the correlation between stability of a residue in the surface and the likelihood that it participates in the interaction can be a general fact for transient PPIs.