Targeting the Transforming Growth Factor-beta Signaling Pathway in the Treatment of Gynecologic Cancer.

The transforming growth factor-beta (TGF-ß) signaling pathway has been reported to be dysregulated in the pathogenesis of several malignancies, including gynecologic cancers. This provides proof of concept of its potential value as a therapeutic target and prognostic biomarker in cervical cancer. Here we provide an overview of the biological role and clinical impact of TGF-ß inhibitors either as a single agent or as a combinatorial therapy in gynecological cancers, concentrating on phase I to phase II/III clinical trials. Aberrant TGF-ß signaling may lead to carcinogenesis. Inhibition of TGF-ß represents an interesting area of focus for the treatment of gynecological cancer. Several TGF-ß inhibitors are potential anticancer agents and are undergoing clinical trials in cancer, including galunisertib, dalantercept, and vigil. There is a growing body of data showing the potential therapeutic impact of targeting the TGF-ß pathway in different cancer types, although further studies are still warranted to explore the value of this strategy and finding the most appropriate patients who could most benefit from therapy.

The Therapeutic Potential of MEK1/2 Inhibitors in the Treatment of Gynecological Cancers: Rational Strategies and Recent Progress.

The mitogen-activated protein kinase (MAPK) pathway is among the key factors in numerous cellular processes involved in tumorigenesis, suggesting it as a potential therapeutic target in gynecological cancer. MAPKs connect gene expression pathways and external stimulations. They include a network consisting of Ras, Raf or MAP3K, MEK or MAP2K, ERK or MAPK. Among these, MEK is an attractive molecular target of novel cancer therapeutics as it joints upstream activators and their corresponding downstream targets. MEK inhibitors were among the first inhibitors of the MAPK pathway entering into clinical trials. Several drugs have recently been developed as MEK inhibitors. MEK1/2 inhibitors demonstrate promising efficacy and anticancer activity to treat this malignancy and captured much attention in the past decade. Here, we summarize the role of MAPK/MEK/ERK pathway in the pathogenesis of gynecological cancer, with particular emphasis on MEK inhibitors in clinical settings, including PD-0325901, Selumetinib, Cobimetinib, Refametinib, Trametinib, Pimasertib, MEK162 and WX-554 in gynecologic cancers.

AMP-kinase inhibitor dorsomorphin reduces the proliferation and migration behavior of colorectal cancer cells by targeting the AKT/mTOR pathway.

Colorectal cancer (CRC) is among the leading causes of cancer-related mortality, despite extensive efforts in the identification of new treatment options. Hence, there is a need for the development of novel agents with therapeutic potential in treatment of CRC. Dorsomorphin has demonstrated antiproliferative activity against different malignancies. Here we have investigated the pharmaceutical potential of dorsomorphin in two-dimensional and three-dimensional cell-culture models of CRC. The antiproliferative, antimigratory, apoptotic activity and effect of this agent on cell cycle was evaluated by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, wound healing assay, and flow cytometry, respectively, while the expression of genes involved in Wnt/Pi3K pathways was assessed at mRNA and/or proteins by reverse transcription polymerase chain reaction (RT-PCR) or western blot. Dorsomorphin inhibited CRC cell growth by modulating the cyclinD1, surviving and p-Akt. This agent was able to reduce the migratory behaviors of CRC cells, compared to control cells, through perturbation of E-cadherin. Also our data showed that dorsomorphin enhanced the percentage of the cells in sub-G1 and induced apoptosis in both late/early stages, as detected by annexin V. Also the regulatory effect of dorsomorphin on oxidant/antioxidant balance was assessed by cellular reactive oxygen species (ROS) generation. In particular, these data showed that dorsomorphin markedly increased the ROS production in CRC cells. Our finding demonstrated that dorsomorphin antagonizes cell growth and migration, through perturbation of Akt/mTOR/Wnt pathways in CRC, supporting further studies on the therapeutic potential of this novel anticancer agent in treatment of CRC.

Targeting the C-MET/HGF Signaling Pathway in Pancreatic Ductal Adenocarcinoma.

The c-mesenchymal-epithelial transition factor (c-MET) is involved in the tumorigenesis of various cancers. HGF/Met inhibitors are now attracting considerable interest due to their anti-tumor activity in multiple malignancies such as pancreatic cancer. It is likely that within the next few years, HGF/Met inhibitors will become a crucial component for cancer management. In this review, we summarize the role of HGF/Met pathway in the pathogenesis of pancreatic cancer, with particular emphasize on HGF/Met inhibitors in the clinical setting, including Cabozantinib (XL184, BMS-907351), Crizotinib (PF-02341066), MK-2461, Merestinib (LY2801653), Tivantinib (ARQ197), SU11274, Onartuzumab (MetMab), Emibetuzumab (LY2875358), Ficlatuzumab (AV- 299), Rilotumumab (AMG 102), and NK4 in pancreatic cancer.