Browsing by Author "Hassan, Md Sazzad"

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    Cytokine Interaction With Cancer-Associated Fibroblasts in Esophageal Cancer
    (Sage, 2022) Hassan, Md Sazzad; Cwidak, Nicholas; Awasthi, Niranjan; von Holzen, Urs; Surgery, School of Medicine
    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.
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    Cytokine Interaction With Cancer-Associated Fibroblasts in Esophageal Cancer
    (Sage, 2022) Hassan, Md Sazzad; Cwidak, Nicholas; Awasthi, Niranjan; von Holzen, Urs; Surgery, School of Medicine
    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.
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    Inhibition of Insulin-like Growth Factor 1 Receptor/Insulin Receptor Signaling by Small-Molecule Inhibitor BMS-754807 Leads to Improved Survival in Experimental Esophageal Adenocarcinoma
    (MDPI, 2024-09-17) Hassan, Md Sazzad; Johnson, Chloe; Ponna, Saisantosh; Scofield, Dimitri; Awasthi, Niranjan; von Holzen, Urs; Surgery, School of Medicine
    The insulin-like growth factor-1 (IGF-1) and insulin axes are upregulated in obesity and obesity-associated esophageal adenocarcinoma (EAC). Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a contemporary nanotechnology-based paclitaxel (PT) bound to human albumin, ensuring its solubility in water rather than a toxic solvent. Here, we examined the benefits of inhibiting insulin-like growth factor-1 receptor/insulin receptor (IGF-1/IR) signaling and the enhancement of nab-paclitaxel effects by inclusion of the small-molecule inhibitor BMS-754807 using both in vitro and in vivo models of EAC. Using multiple EAC cell lines, BMS-754807 and nab-paclitaxel were evaluated as mono and combination therapies for in vitro effects on cell proliferation, cell death, and cell movement. We then analyzed the in vivo anticancer potency with survival improvement with BMS-754807 and nab-paclitaxel mono and combination therapies. BMS-754807 monotherapy suppressed in vitro cell proliferation and wound healing while increasing apoptosis. BMS-754807, when combined with nab-paclitaxel, enhanced those effects on the inhibition of cell proliferation, increment in cell apoptosis, and inhibition of wound healing. BMS-754807 with nab-paclitaxel produced substantially greater antitumor effects by increasing in vivo apoptosis, leading to increased mice survival compared to those of BMS-754807 or nab-paclitaxel monotherapy. Our outcomes support the use of BMS-754807, alone and in combination with nab-paclitaxel, as an efficient and innovative treatment choice for EAC.
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    Melatonin and Andrographolide synergize to inhibit the colospheroid phenotype by targeting Wnt/beta-catenin signaling
    (Wiley, 2022) Sokolov, Daniil; Sharda, Neha; Giri, Banabihari; Hassan, Md Sazzad; Singh, Damandeep; Tarasiewicz, Agnieszka; Lohr, Charity; von Holzen, Urs; Kristian, Tibor; Waddell, Jaylyn; Reiter, Russel J.; Ahmed, Hafiz; Banerjee, Aditi; Surgery, School of Medicine
    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 reduces 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 anti-carcinogenic, antioxidant, and anti-metastatic properties. CSCs were obtained from two metastatic colon cancer cell lines (HT29 and HCT-15). The viability and stemness were monitored (FDA PI staining and immunoblot for CD44, CD133, Nanog, Sox2 and Oct4). The drug combination synergistically diminished stemness via increased 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 de-phosphorylated-β-catenin. Downregulation of β-catenin activation and its transcription factors (TCF4, LEF1) and GTP binding/G-protein related activity were found in the dual therapy. Angiogenic inhibition is consistent with downregulation of VEGF mRNA 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 rationale for using MLT in combination with AGP for inhibition of CRCs.
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    Nab-Paclitaxel in the Treatment of Gastrointestinal Cancers—Improvements in Clinical Efficacy and Safety
    (MDPI, 2023-07-15) Hassan, Md Sazzad; Awasthi, Niranjan; Ponna, Saisantosh; von Holzen, Urs; Surgery, School of Medicine
    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.
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    A novel intraperitoneal metastatic xenograft mouse model for survival outcome assessment of esophageal adenocarcinoma
    (Plos, 2017-02-22) Hassan, Md Sazzad; Awasthi, Niranjan; Li, Jun; Schwarz, Margaret A.; Schwarz, Roderich E.; von Holzen, Urs; Department of Surgery, IU School of Medicine
    Esophageal adenocarcinoma (EAC) has become the dominant type of esophageal cancer in United States. The 5-year survival rate of EAC is below 20% and most patients present with locally advanced or widespread metastatic disease, where current treatment is largely ineffective. Therefore, new therapeutic approaches are urgently needed. Improvement of EAC patient outcome requires well-characterized animal models in which to evaluate novel therapeutics. In this study we aimed to establish a peritoneal dissemination xenograft mouse model of EAC that would support survival outcome analyses. To find the best candidate cell line from 7 human EAC cell lines of different origin named ESO26, OE33, ESO51, SK-GT-2, OE19, OACM5.1C and Flo-1 were injected intraperitoneally/subcutaneously into SCID mice. The peritoneal/xenograft tumor formation and mouse survival were compared among different groups. All cell lines injected subcutaneously formed tumors within 3 months at variable rates. All cell lines except OACM5.1C formed intraperitoneal tumors within 3 months at variable rates. Median animal survival with peritoneal dissemination was 108 days for ESO26 cells (5X106), 65 days for OE33 cells (5X106), 88 days for ESO51 cells (5X106), 76 days for SK-GT-2 cells (5X106), 55 days for OE19 cells (5X106), 45 days for OE19 cells (10X106) and 82 days for Flo-1 cells (5X106). Interestingly, only in the OE19 model all mice (7/7 for 5X106 and 5/5 for10X106) developed bloody ascites with liver metastasis after intraperitoneal injection. The median survival time of these animals was the shortest (45 days for 10X106 cells). In addition, median survival was significantly increased after paclitaxel treatment compared with the control group (57 days versus 45 days, p = 0.0034) along with a significant decrease of the relative subcutaneous tumor volume (p = 0.00011). Thus peritoneal dissemination mouse xenograft model for survival outcome assessment after intraperitoneal injection of OE19 cells will be very useful for the evaluation of cancer therapeutics.
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    Superior Therapeutic Efficacy of Nanoparticle Albumin Bound Paclitaxel Over Cremophor-Bound Paclitaxel in Experimental Esophageal Adenocarcinoma
    (Elsevier, 2018-04) Hassan, Md Sazzad; Awasthi, Niranjan; Li, Jun; Williams, Fiona; Schwarz, Margaret A.; Schwarz, Roderich E.; von Holzen, Urs; Surgery, School of Medicine
    Esophageal adenocarcinoma (EAC) is the fastest growing cancer in the western world and the overall 5 year survival rate of EAC is below 20%. Most patients with EAC present with locally advanced or widespread metastatic disease, where current treatment is largely ineffective. Therefore, new therapeutic approaches are urgently needed. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a novel albumin-stabilized, cremophor-free and water soluble nanoparticle formulation of paclitaxel, and the potential role of nab-paclitaxel has not been tested yet in experimental EAC. Here we tested the antiproliferative and antitumor efficacy with survival advantage of nab-paclitaxel as monotherapy and in combinations in in-vitro, and in murine subcutaneous xenograft and peritoneal metastatic survival models of human EAC. Nab-paclitaxel significantly inhibited in-vitro cell proliferation with higher in-vivo antitumour efficacy and survival benefit compared to paclitaxel or carboplatin treatments both in mono- and combination therapies. Nab-paclitaxel treatment increased expression of mitotic-spindle associated phospho-stathmin, decreased expression of proliferative markers and enhanced apoptosis. This study demonstrates that nab-paclitaxel had stronger antiproliferative and antitumor activity in experimental EAC than the current standard chemotherapeutic agents which supports the rationale for its clinical use in EAC.
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    Targeted therapy in esophageal cancer
    (AME, 2021-06) Hassan, Md Sazzad; Makuru, Victoria; von Holzen, Urs; Surgery, School of Medicine
    Esophageal cancer consists of two distinct histological types, esophageal squamous cell-carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Esophageal carcinoma is a grave malignancy with regards to prognosis and mortality. ESCC remains the dominant histological type of esophageal cancer worldwide, with about 90 percent of all cases worldwide. However, EAC is now much more common in the United States and the Western World, and represents one of the fastest growing cancers there. Despite significant progress in multimodality treatment options, the overall prognosis remains poor, and 5-year survival rates for all-comers are still below 20 percent. Although esophageal cancer initially responds well to systemic therapy, most patients recur and eventually die from their disease. Therefore, new treatment options are urgently needed. The combination of traditional systemic therapy with new biologicals and/or targeted agents is one of these new treatment options. Some of these agents are already approved, while others are currently undergoing clinical trials. These targeted therapies have emerged as an important tool for the treatment of many different cancer types, including esophageal cancer. Herein, we review the recent literature and ongoing clinical trials in esophageal cancer targeted therapies, and discuss the different targeted pathways. Currently, most esophageal cancer patients are still treated with a combination of chemotherapies like taxanes (paclitaxel, docetaxel), platinums (carboplatin, cisplatin), anthracyclines (doxorubicin, epirubicin) or pyrimidine analogs (5-fluorouracil). Future treatment strategies should be based on the molecular features of each patient’s individual tumor, and should include biologicals/targeted agents tailored to these specific findings.
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    Targeting KRAS for the potential treatment of pancreatic ductal adenocarcinoma: Recent advancements provide hope (Review)
    (Spandidos Publications, 2023) Zhang, Joshua; Darman, Lily; Hassan, Md Sazzad; Von Holzen, Urs; Awasthi, Niranjan; Surgery, School of Medicine
    Kirsten rat sarcoma viral oncogene homolog (KRAS) is one of the most frequently mutated oncogenes in solid tumors. More than 90% of pancreatic ductal adenocarcinoma (PDAC) are driven by mutations in the KRAS gene, suggesting the importance of targeting this oncogene in PDAC. Initial efforts to target KRAS have been unsuccessful due to its small size, high affinity for guanosine triphosphate/guanosine diphosphate, and lack of distinct drug‑binding pockets. Therefore, much of the focus has been directed at inhibiting the activation of major signaling pathways downstream of KRAS, most notably the PI3K/AKT and RAF/MAPK pathways, using tyrosine kinase inhibitors and monoclonal antibodies. While preclinical studies showed promising results, clinical data using the inhibitors alone and in combination with other standard therapies have shown limited practicality, largely due to the lack of efficacy and dose‑limiting toxicities. Recent therapeutic approaches for KRAS‑driven tumors focus on mutation‑specific drugs such as selective KRASG12C inhibitors and son of sevenless 1 pan‑KRAS inhibitors. While KRASG12C inhibitors showed great promise against patients with non‑small cell lung cancer (NSCLC) harboring KRASG12C mutations, they were not efficacious in PDAC largely because the major KRAS mutant isoforms in PDAC are G12D, G12V, and G12R. As a result, KRASG12D and pan‑KRAS inhibitors are currently under investigation as potential therapeutic options for PDAC. The present review summarized the importance of KRAS oncogenic signaling, challenges in its targeting, and preclinical and clinical targeted agents including recent direct KRAS inhibitors for blocking KRAS signaling in PDAC.