Browsing by Subject "gastric cancer"

Now showing 1 - 4 of 4
  • Thumbnail Image
    Item
  • Thumbnail Image
    Item
    Hereditary diffuse gastric cancer therapeutic roadmap: current and novel approaches in a nutshell
    (Sage, 2020-01) El Rami, Fadi E.; Barsoumian, Hampartsoum B.; Khneizer, Gebran W.; Medicine, School of Medicine
    Hereditary diffuse gastric cancer (HDGC) is a rare malignancy characterized by autosomal dominant inheritance of pathological variants of the CDH1 gene encoding E-cadherin, which is involved in cell–cell adhesion, maintenance of epithelial architecture, tumor suppression, and regulation of intracellular signaling pathways. Late-stage recognition of HDGC is typically associated with a poor clinical outcome due to its metastatic potential and risk of lobular breast cancer (LBC) development. The American College of Gastroenterology issued guidelines to evaluate HDGC, test for CDH1 genetic variants, and recommend prophylactic gastrectomy for carriers of CDH1 mutations. If surgery is not pursued, endoscopy is a surveillance alternative, although it carries a limited ability to detect malignant foci. As part of clinical research efforts, novel endoscopy advances are currently studied, and a center of excellence for HDGC was created for a comprehensive multidisciplinary team approach. Within this review, we cover current conventional treatment modalities such as gastrectomy and chemotherapy, as the mainstay treatments, in addition to Pembrolizumab, an immune checkpoint inhibitor, as the last therapeutic resort. We also shed light on novel and promising approaches with emphasis on immunotherapy to treat HDGC. We further break down the therapeutic paradigms to utilize molecular tools, antibodies against checkpoint inhibitors, TGF-β and tyrosine kinase inhibitors, cell-based adoptive therapies, and oncolytic viral therapies. We aim to expand the understanding on how to modulate the tumor microenvironment to tip the balance towards an anti-tumor phenotype, prevent metastasis of the primary disease, and potentially alter the therapeutic landscape for HDGC.
  • Thumbnail Image
    Item
    Prevention of Gallstone Formation After Gastrectomy
    (AMA, 2020-06) Pitt, Henry A.; Nakeeb, Attila; Surgery, School of Medicine
  • Thumbnail Image
    Item
    Targeted Inhibition of the HGF/c-Met Pathway by Merestinib Augments the Effects of Albumin-Bound Paclitaxel in Gastric Cancer
    (2022-07-28) Kaurich, Quinn; Huang, Jennifer; Awasthi, Niranjan
    BACKGROUND AND HYPOTHESIS: Combination chemotherapy regimens are commonly used to treat gastric adenocarcinoma (GAC), but the median survival time remains less than one year. Nab-paclitaxel has demonstrated high antitumor activity in previous GAC studies. Many growth factors and their receptors are overexpressed in GAC and have been implicated in its pathophysiology. We hypothesize that merestinib, a small-molecule inhibitor targeting c-Met, Axl, and DDR1/2 pathways, will have significant antitumor effects and will enhance the response to nab-paclitaxel in GAC preclinical models. PROJECT METHODS: In vitro proliferation and protein expression were assessed using WST-1 and immunoblot assays. Subcutaneous xenografts of MKN-45 and SNU-1 cell lines were implanted in mice to study tumor growth inhibition. Immunohistochemistry was performed to examine intratumor proliferation and microvessel density. RESULTS: In vitro assays showed that nab-paclitaxel and merestinib decreased cell proliferation in all three cell lines, with an additive effect in combination. Reduction in cell proliferation at low doses of nab-paclitaxel (10 nM), merestinib (100 nM), and their combination was 87%, 82%, and 94% (MKN-45 cell line, high phospho-c-Met expression), 59%, 50%, and 82% (SNU-1 cell line, low phospho-c-Met expression), and 53%, 19%, and 66% in gastric fibroblasts. Immunoblot analysis of merestinib treated MKN-45 cells revealed increased expression of apoptotic proteins and decreased expression of phospho-c-Met, phospho-EGFR, phospho-IGF-1R, phospho-ERK, and phospho-AKT. In gastric fibroblasts, merestinib decreased phospho-ERK and increased apoptotic protein expression. Phospho-c-Met and phospho-EGFR were not detected in SNU-1 immunoblots; however, phospho-ERK, phospho-VEGFR, and apoptotic protein expression increased after treatment. In MKN-45 xenografts, net tumor growth in control, nab¬-paclitaxel, merestinib, and combination groups was 503 mm3, 115 mm3, 91 mm3, and -9.7 mm3. Immunohistochemistry analysis of tumor cell proliferation and microvessel density corroborated tumor growth study results. CONCLUSION: The data suggest that merestinib in combination with nab-paclitaxel carry a promising potential for improving clinical GAC therapy.