Esophageal cancer (EC) is a highly aggressive cancer with poor outcomes under current treatment regimens. More recent findings suggest stroma elements, specifically cancer-associated fibroblasts (CAFs), play a role in disease occurrence and progression. Cancer-associated fibroblasts are largely the product of converted fibroblasts, but a variety of other local cell types including epithelial cells, endothelial cells, and mesenchymal cells have also been shown to transform to CAFs under the correct conditions. Cancer-associated fibroblasts primarily function in the communication between the tumor microenvironment and cancer cells via cytokine and chemokine secretions that accentuate immunosuppression and cancer growth. Cancer-associated fibroblasts also pose issues for EC treatment by contributing to resistance of current chemotherapeutics like cisplatin. Targeting this cell type directly proves difficult given the heterogeneity between CAFs subpopulations, but emerging research provides hope that treatment is on the horizon. This review aims to unravel some of the complexities surrounding CAFs’ impact on EC growth and therapy.
Introduction: A major target for esophageal adenocarcinoma (EAC) therapies is the human epidermal growth factor receptor 2 (HER2). Unfortunately, patients treated with lapatinib, a dual EGFR and HER2 inhibitor, frequently develop resistance. Lapatinib fails to improve patient survival in HER2-postive EAC, and the mechanisms contributing to resistance remain largely unknown. Recent studies have demonstrated that HER2 and MET receptor tyrosine kinases are co-overexpressed in a subset EAC. In this study, we therefore studied the role of MET activation in lapatinib resistance mechanisms in experimental EAC. Methods: We first characterized MET and HER2 activation in a panel of human EAC cell lines, and the differential susceptibility of these EAC cell lines to single agent or combination of MET and HER2 inhibitions by foretinib and lapatinib, respectively. We then explored the antitumor efficacy with survival advantage following foretinib and lapatinib monotherapy and in combination in murine subcutaneous xenograft and peritoneal metastatic survival models of human EAC. We also tested MET and HER activation status with sensitivity to their inhibitors in newly generated lapatinib resistant OE19 EAC cells (OE19-LPR). Results: The OE33 EAC cell line with phosphorylation of both MET and HER2, demonstrated reduced sensitivity to foretinib and lapatinib when used as single agents. The co-administration of foretinib and lapatinib effectively inhibited both MET and HER2 phosphorylation, synergistically inhibited cell proliferation and xenograft tumor growth, induced apoptosis, and significantly enhanced overall mouse survival, thus overcoming single agent resistance. In the OE19 EAC cell line with only HER2 phosphorylation and the ESO51 EAC cell line with only MET phosphorylation, profound cell growth inhibition with induction of apoptosis was observed in response to single agent with lack of enhanced growth inhibition when the two agents were combined. Interestingly, OE19-LPR cells showed significant upregulated expression of phosphorylated MET compared to parent OE19 cells, detected by both Activesignal assay and Western blot analysis. In addition, OE19-LPR cells showed significantly reduced sensitivity to lapatinib compared to parent OE19 cells, and the co-administration of foretinib and lapatinib synergistically inhibited cell proliferation in OE19-LPR cells. Conclusion: These data suggest that resistance to HER2 targeted therapies in HER2 and MET overexpressed EAC cells can be due to MET activation. Thus MET and HER2 targeted therapy appears to be a sensible treatment strategy for HER2 positive MET-overexpressing EAC. Citation Format: Md Sazzad Hassan, Fiona Williams, Lucia Petrova, Niranjan Awasthi, Margaret Schwarz, Roderich Schwarz, Urs von Holzen. MET activation mediates lapatinib resistance in experimental esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 289.
β‐catenin signaling, and angiogenesis are associated with colospheroid (CSC), development. CSCs, spheroids derived from colon cancer cells, are responsible for metastasis, drug resistance, and disease recurrence. Whether dysregulating β‐catenin and inhibiting angiogenesis reduce CSC growth is unknown. In this study, the molecular mechanism of CSC growth inhibition was evaluated using a novel combination of melatonin (MLT) and andrographolide (AGP). These drugs have anticarcinogenic, antioxidant, and antimetastatic properties. CSCs were obtained from two metastatic colon cancer cell lines (HT29 and HCT‐15). The viability and stemness were monitored (FDA propidium iodide staining and immunoblot for CD44, CD133, Nanog, Sox2, and Oct4). The drug combination synergistically diminished stemness via increased reactive oxygen species (ROS) levels, reduced mitochondrial membrane potential and ATP level. MLT + AGP induced cell death by inhibiting β‐catenin expression and its downregulatory signals, Cyclin D1, c‐Myc. MLT + AGP treated cells exhibited translocation of phospho‐β‐catenin to the nucleus and dephosphorylated‐β‐catenin. Downregulation of β‐catenin activation and its transcription factors (TCF4 and LEF1) and GTP binding/G‐protein related activity were found in the dual therapy. Angiogenic inhibition is consistent with downregulation of VEGF messenger RNA transcripts (VEGF189), phosphorylated VEGF receptor protein expression, matrigel invasion, and capillary tube inhibition. In vivo, the intravenous injection of MLT + AGP slowed HT29 metastatic colon cancer. Histopathology indicated significant reduction in microvascular density and tumor index. Immunohistochemistry for caspase 7, and β‐catenin found increased apoptosis and downregulation of β‐catenin signals. The mechanism(s) of decreased colospheroids growth were the inhibition of the Wnt/β‐catenin pathway. Our results provide a rationale for using MLT in combination with AGP for the inhibition of CRCs.
Introduction: Esophageal adenocarcinoma (EAC) is one of the fastest growing cancers in the Western world and the overall 5-year survival rate of EAC is below 20 percent. Epidemiological studies have linked obesity with EAC. Insulin-like growth factor (IGF) signaling is an important mediator in obesity-associated EAC. Paclitaxel (PT) has been used in combination with carboplatin as a standard combination therapy for advanced EAC. PT required emulsification with solvents which have resulted in serious adverse effects in patients. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is an albumin-stabilized, cremophor-free and water-soluble nanoparticle formulation of PT. Nab-paclitaxel has recently shown greater efficacy over PT in EAC. In this study, we evaluated the potential of targeting IGF signaling and improvement in nab-paclitaxel response by the addition of BMS-754807 in experimental EAC. Methods: We first evaluated the phosphorylation status of IGF-1R/IR protein by Western blot in a panel of EAC cell lines. BMS-754807 and nab-paclitaxel, alone or in combination were tested for effects on cell growth, cell apoptosis, cell migration and cell cycle analyses of EAC cell lines detected respectively by WST-1 assay, Western blotting, would healing scratch assay and propidium iodide flow cytometry. We then explored the antitumor efficacy of BMS-754807 and nab-paclitaxel monotherapy and in combination in murine subcutaneous xenograft and peritoneal metastatic survival models of human EAC. Results: BMS-754807 dose-dependently inhibited in-vitro cell proliferation of EAC cell lines having phosphorylation of IGF-1R/IR protein. The co-administration of BMS-754807 and nab-paclitaxel effectively enhanced cell growth inhibition, cleavage of caspase-3 and PARP, in-vitro wound healing inhibition and cell cycle arrest at sub G0/G1 phase. BMS-754807 in combination with nab-paclitaxel treatment resulted in significantly higher antitumor efficacy by increasing intratumoral apoptosis and survival benefit compared with BMS-754807 or nab-paclitaxel treatment alone. In subcutaneous xenografts using OE19 cells, average net tumor growth after two weeks in different therapy groups was 558.67 mm3 in control, 208.47 mm3 after BMS-754807 (p=0.043), 104.60 mm3 after nab-paclitaxel (p=0.013), and 14.30 mm3 after BMS-754807 plus nab-paclitaxel (p=0.0005). There was a significant increase in median animal survival after BMS-754807 plus nab-paclitaxel treatment (85 days) compared to control (47 days, p=0.0034), BMS-754807 monotherapy (57 days, p=0.0021) or nab-paclitaxel (68 days, p=0.0339) monotherapy. Conclusion: These results support the potential of BMS-754807 in combination with nab-paclitaxel as an effective option for EAC therapy. Citation Format: Md Sazzad Hassan, Nicholas Cwidak, Chloe Johnson, Saisantosh Ponna, Niranjan Awasthi, Urs von Holzen. BMS-754807, a small-molecule inhibitor of insulin-like growth factor-1 receptor/insulin receptor is cytotoxic to esophageal adenocarcinoma cells and enhances nab-paclitaxel response in experimental esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1066.
Taxanes (paclitaxel and docetaxel) are one of the most useful classes of anticancer drugs. Taxanes are highly hydrophobic; therefore, these drugs must be dissolved in organic solvents (polysorbate or Cremophor EL), which contribute to their toxicities. To reduce this toxicity and to enhance their efficacy, novel formulations have been developed. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is an albumin-stabilized, Cremophor-free, and water-soluble nanoparticle formulation of paclitaxel. Nab-paclitaxel has better solubility and less infusion-associated toxicity compared to solvent-based paclitaxel. Additionally, nab-paclitaxel can be given at higher doses and concentrations compared with solvent-based paclitaxel. Based on its superior clinical efficacy and safety profile, nab-paclitaxel received FDA approval for metastatic breast cancer (2008) and NSCLC (2011). Among gastrointestinal cancers, it is now approved in the USA for treating patients with metastatic adenocarcinoma of the pancreas as first-line therapy in combination with gemcitabine. Furthermore, several clinical trials have suggested the potential efficacy of nab-paclitaxel as a single agent or in combination with other agents for the treatment of metastatic esophageal, gastric, bowel, and biliary tract cancers. Nab-paclitaxel has been demonstrated to have greater overall response rates (ORR) with enhanced progression-free survival (PFS), overall survival (OS) and a superior safety profile with fewer adverse effects in patients with gastrointestinal tract cancers. This review summarizes the advantages associated with nab-paclitaxel-based regimens in terms of improving clinical efficacy and the safety profile in upper gastrointestinal cancer.
Introduction: Esophageal adenocarcinoma (EAC) is one of the most aggressive human cancers with poor prognosis, and the overall 5-year survival rate is less than 20 percent. Prognosis for EAC remains poor even with modern combination therapies due to high resistance to chemotherapy. Therefore, new therapeutic approaches for EAC treatment improvements are urgently needed. Hypoxia or insufficient tissue oxygenation contributes to cancer aggressiveness and poor clinical prognosis. Overexpression of hypoxia-inducible factor 1-alpha (HIF-1 alpha) and immunosuppressive CD73, an ecto-5’-nucleotidase enzyme in cancer can give rise to tumor progression with drug resistance. CD73 has never been proposed as a therapeutic target in EAC and its relationship with hypoxia or HIF-1 alpha has not also been investigated in EAC. In this study, we therefore investigated the therapeutic targeting of HIF-1 alpha and CD73 by acriflavine in experimental EAC. Methods: Hypoxia in EAC cells were induced by 3D culture and hypoxic exposure. NanoCulture® plates and dishes were used for 3D cultures. For hypoxic exposure, cells were placed in a sealed modular incubator chamber flushed with a gas mixture containing 1% O2, 5% CO2 and 94% N2. Hypoxic status was detected by adding hypoxia probe LOX-1 and fluorescent microscopy. Nanoparticle albumin-bound paclitaxel (NPT) was used as chemotherapeutic agent, whereas acriflavine was used as hypoxia-targeting agent. In vitro cell growth was detected by WST-1 and Cell Titer-Glo (CTG) luminescent assays, in vivo tumor growth was detected by measuring subcutaneous xenografts, apoptosis was detected by cleaved caspase 3/PARP expressions and hypoxia-targeting was detected by HIF-1 alpha/CD73 expressions. Results: We observed overexpression of both HIF-1 alpha and CD73 in 3D culture and hypoxic exposure of EAC cells. Interestingly acriflavine treatment drastically inhibited both HIF-1 alpha and CD73 expression in EAC 3D culture and hypoxic exposure. 3D culture was more resistant to antiproliferative effect of chemotherapeutic agent NPT over 2D monolayer culture. Contrary to that, hypoxia-targeting agent acriflavine showed stronger antiproliferative effects in 3D culture than in 2D culture. We also observed hypoxia inside the 3D culture spheroids. In addition, acriflavine showed significant in vivo antitumor efficacy both as monotherapy and in combination with NPT. In subcutaneous xenografts using OE19 EAC cells, acriflavine monotherapy exhibited a significant decrease in relative tumor volume to 55.02% compared to control (p=0.04) and addition of NPT with acriflavine also showed a significant enhancement effect of tumor regression as tumor size decreased to 32.70% compared to control (p=0.002). Conclusion: These results support the potential of acriflavine as HIF-1 alpha and CD73 targeting and its combination with chemotherapy NPT as an effective option for EAC therapy. Citation Format: Md Sazzad Hassan, Aktar Ali, Saisantosh Ponna, Dimitri Scofield, Niranjan Awasthi, Mark Jantz, Urs von Holzen. Therapeutic targeting of HIF-1 alpha induced CD73 expression in experimental esophageal adenocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3960.
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