Sitagliptin frequently activated in awide array of human cancers

oral inhibitor of protein kinase C , especially PKC beta , and an inhibitor Ofloxacin of PI3 kinase signaling pathway . PKC is a family of Sitagliptin clinical trial serine/threonine protein kinases which are high affinity intra cellular receptors to phorbol esters, natural products known to induce skin carcinogenesis in mice . PKC beta isone of themost activePKCs involvedin regulating cell proliferation. Activated PKCβ has been found in multiple human tumors including EOC/PPC . Enzastaurin is relatively inactive against other kinases, especially the tyrosine kinase family. PKCβaswell as other PKCs activateAKT which is frequently activated in awide array of human cancers . The activation of PI3 kinase cell signaling pathway promotes tumor cell survival and proliferation .
Enzastaurin blocks the key enzymes of this pathway and has demonstrated the ability to suppress the proliferation of cancer cell lines in vitro including EOC/PPC cell lines: OVCAR 3, OVCAR 4, and OVCAR 8 when tested against the NCI 60 cell line panel . In addition, Sitagliptin structure enzastaurin has anti angiogenic activity and has been shown to suppress vascular endothelial growth factor production by human tumor xenografts . EOC/PPC secrete large amounts of VEGF which stimulates angiogenesis and plays a crucial role in progression of EOC/PPC . A monoclonal antibody to VEGF, bevacizumab, has demonstrated significant activity in ovarian cancer . Thus, anti angiogenic agents hold promise in the treatment of EOC/PPC. Enzastaurin was well tolerated in a phase I trial with Grade I chromaturia , fatigue, and GI side effects being the most common toxicities .
The observed dose limiting toxicity was changed in QTc defined as prolongation of QTc by more than 50 msecs over baseline . The clinical development of enzastaurin, a potent inhibitor of the PKC and PTEN/PI3K signaling pathways, is of great interest in EOC/PPC. A translational research objective Sitagliptin solubility has been embedded in this phase II protocol to evaluate a panel of biomarkers relevant to enzastaurin and disease state. As mentioned earlier, the evidence of deregulation of the PI3K/ PTEN pathway in EOC/PPC has been reported previously and includes gain of function mutations and amplifications of PI 3 kinase ; amplification of AKT2 ; allelic imbalance and loss of heterozygosity in PTEN genes . PTEN is a key tumor suppressor and normally opposes the activation of the protooncogenic PI3K signaling pathway.
Also, there aremultiple nodes of crosstalk between PI3K/PTEN and p53 signaling pathways which may result in cisplatin resistance in EOC/PPC . Given these data, we assessed mutations and copy number changes in PIK3CA, AKT2, PKC, PTEN, andTP53 genes in this study.Wesought to determinewhether these genetic aberrations in the disease tumor might have prognostic value as opposed to the levels or activity of proteins encoded by themwhichmay change in the course of the treatment. We also measured VEGF plasma levels before and after the first cycle of enzastaurin to find out whether the change in VEGF level could serve as a potential marker of early response to the drug. Methods Patients This was a multi center phase II trial of enzastaurin as a singleagent in women with advanced EOC/PPC. To be eligible for the trial, patients must have had histologic documentation of diagnosis .