FRESCO-2: a global Phase III study investigating the efficacy and safety of fruquintinib in metastatic colorectal cancer

Desenvolupament clínic; Fruquintinib; Càncer colorrectal metastàtic refractariDesarrollo clinico; Fruquintinib; Cáncer colorrectal metastásico refractarioClinical development; Fruquintinib; Refractory metastatic colorectal cancerFruquintinib, a novel, highly selective, small-molecule tyrosine kinase inhibitor of VEGF receptors (VEGFRs)-1, -2 and -3, is approved in China for the treatment of metastatic colorectal cancer. FRESCO-2, a global, randomized, double-blind, placebo-controlled, Phase III study, is investigating the efficacy and safety of fruquintinib in patients with refractory metastatic colorectal cancer. Key inclusion criteria include: progression on or intolerance to TAS-102 and/or regorafenib; and prior treatment with approved chemotherapy, anti-VEGF therapy, and, if RAS wild-type, anti-EGFR therapy. Approximately 687 patients will be randomized 2:1 to fruquintinib plus best supportive care or placebo plus best supportive care. Primary and key secondary end points are overall survival and progression-free survival, respectively. FRESCO-2 is enrolling in the USA, Europe, Australia and Japan

ramucirumab in advanced hepatocellular carcinoma and elevated alpha fetoprotein following sorafenib outcomes by prior transarterial chemoembolisation from two randomised double blind placebo controlled phase 3 studies reach 2 and reach

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Targeting apoptosis in solid tumors: the role of bortezomib from preclinical to clinical evidence.

The ubiquitin-proteasome pathway is the main proteolytic system present in the nucleus and cytoplasm of all eukaryotic cells. Apoptosis activation induced by ubiquitin-proteasome pathway inhibition makes the proteasome a new target of anticancer therapy. Bortezomib is the first proteasome inhibitor to be approved by the US FDA; in 2003 as a third line and in 2005 as a second line therapy for the treatment of multiple myeloma only. This review focuses on the use of bortezomib, not only in its therapeutic role but also, more specifically, in its biologic role and discusses the most recent applications of the drug in solid tumors, both at a preclinical and clinical level

Chronic NMDA administration to rats increases brain pro-apoptotic factors while decreasing anti-Apoptotic factors and causes cell death

<p>Abstract</p> <p>Background</p> <p>Chronic <it>N</it>-Methyl-d-aspartate (NMDA) administration to rats is reported to increase arachidonic acid signaling and upregulate neuroinflammatory markers in rat brain. These changes may damage brain cells. In this study, we determined if chronic NMDA administration (25 mg/kg i.p., 21 days) to rats would alter expression of pro- and anti-apoptotic factors in frontal cortex, compared with vehicle control.</p> <p>Results</p> <p>Using real time RT-PCR and Western blotting, chronic NMDA administration was shown to decrease mRNA and protein levels of anti-apoptotic markers Bcl-2 and BDNF, and of their transcription factor phospho-CREB in the cortex. Expression of pro-apoptotic Bax, Bad, and 14-3-3ζ was increased, as well as Fluoro-Jade B (FJB) staining, a marker of neuronal loss.</p> <p>Conclusion</p> <p>This alteration in the balance between pro- and anti-apoptotic factors by chronic NMDA receptor activation in this animal model may contribute to neuronal loss, and further suggests that the model can be used to examine multiple processes involved in excitotoxicity.</p

Angiotensin II Modulation of NMDA Receptor Function: Characterization of Mechanisms Attenuating Excitotoxicity in Neurons

138 p.Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2000.In the last study, we investigated the involvement of Bcl-2 in the suppression of NMDA-mediated neurotoxicity by Ang II. The viability of differentiated N1E and NG108 neuronal cell lines was reduced following exposure to NMDA in a dose-dependent manner. Excitotoxicity in N1E cells was inhibited by the noncompetitive NMDA receptor antagonist, MK-801. Further, NMDA receptor-mediated cell death was attenuated by Ang II in NG108 cells. A concentration-dependent decrease in intracellular Bcl-2 protein levels was observed following treatment with NMDA, and this reduction was inhibited by MK801. Addition of Ang II suppressed the NMDA receptor-mediated reduction in Bcl-2. The Ang II effect on NMDA-mediated changes in Bcl-2 expression was blocked by PD 123319, but was not significantly altered by losartan. Taken together, these results suggest that the decrease in Bcl-2 expression induced by NMDA is attenuated by AT2 activation. (Abstract shortened by UMI.).U of I OnlyRestricted to the U of I community idenfinitely during batch ingest of legacy ETD