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Browsing by Author "Awasthi, Niranjan"
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Item Augmentation of Nab-Paclitaxel Chemotherapy Response by Mechanistically Diverse Antiangiogenic Agents in Preclinical Gastric Cancer Models(American Association for Cancer Research, 2018-11) Awasthi, Niranjan; Schwarz, Margaret A.; Zhang, Changhua; Schwarz, Roderich E.; Surgery, School of MedicineGastric adenocarcinoma (GAC) remains the third most common cause of cancer-related deaths worldwide. Systemic chemotherapy is commonly recommended as a fundamental treatment for metastatic GAC; however, standard treatment has not been established yet. Angiogenesis plays a crucial role in the progression and metastasis of GAC. We evaluated therapeutic benefits of mechanistically diverse antiangiogenic agents in combination with nab-paclitaxel, a next-generation taxane, in preclinical models of GAC. Murine survival studies were performed in peritoneal dissemination models, whereas tumor growth studies were performed in subcutaneous GAC cell-derived or patient-derived xenografts. The mechanistic evaluation involved IHC and Immunoblot analysis in tumor samples. Nab-paclitaxel increased animal survival that was further improved by the addition of antiangiogenic agents ramucirumab (or its murine version DC101), cabozantinib and nintedanib. Nab-paclitaxel combination with nintedanib was most effective in improving animal survival, always greater than 300% over control. In cell-derived subcutaneous xenografts, nab-paclitaxel reduced tumor growth while all three antiangiogenic agents enhanced this effect, with nintedanib demonstrating the greatest inhibition. Furthermore, in GAC patient-derived xenografts the combination of nab-paclitaxel and nintedanib reduced tumor growth over single agents alone. Tumor tissue analysis revealed that ramucirumab and cabozantinib only reduced tumor vasculature, whereas nintedanib in addition significantly reduced tumor cell proliferation and increased apoptosis. Effects of nab-paclitaxel, a promising chemotherapeutic agent for GAC, can be enhanced by new-generation antiangiogenic agents, especially nintedanib. The data suggest that nab-paclitaxel combinations with multitargeted antiangiogenic agents carry promising potential for improving clinical GAC therapy.Item Augmentation of response to nab-paclitaxel by inhibition of insulin-like growth factor (IGF) signaling in preclinical pancreatic cancer models(Impact Journals, 2016-07-26) Awasthi, Niranjan; Scire, Emily; Monahan, Sheena; Grojean, Meghan; Zhang, Eric; Schwarz, Margaret A.; Schwarz, Roderich E.; Department of Surgery, IU School of MedicineNab-paclitaxel has recently shown greater efficacy in pancreatic ductal adenocarcinoma (PDAC). Insulin like growth factor (IGF) signaling proteins are frequently overexpressed in PDAC and correlate with aggressive tumor phenotype and poor prognosis. We evaluated the improvement in nab-paclitaxel response by addition of BMS-754807, a small molecule inhibitor of IGF-1R/IR signaling, in preclinical PDAC models. In subcutaneous xenografts using AsPC-1 cells, average net tumor growth in different therapy groups was 248.3 mm3 in controls, 42.4 mm3 after nab-paclitaxel (p = 0.002), 93.3 mm3 after BMS-754807 (p = 0.01) and 1.9 mm3 after nab-paclitaxel plus BMS-754807 (p = 0.0002). In subcutaneous xenografts using Panc-1 cells, average net tumor growth in different therapy groups was: 294.3 mm3 in controls, 23.1 mm3 after nab-paclitaxel (p = 0.002), 118.2 mm3 after BMS-754807 (p = 0.02) and -87.4 mm3 (tumor regression) after nab-paclitaxel plus BMS-754807 (p = 0.0001). In peritoneal dissemination model using AsPC-1 cells, median animal survival was increased compared to controls (21 days) after therapy with nab-paclitaxel (40 days, a 90% increase, p = 0.002), BMS-754807 (27 days, a 29% increase, p = 0.01) and nab-paclitaxel plus BMS-754807 (47 days, a 124% increase, p = 0.005), respectively. Decrease in proliferation and increase in apoptosis by nab-paclitaxel and BMS-754807 therapy correlated with their in vivo antitumor activity. In vitro analysis revealed that the addition of IC25 dose of BMS-754807 decreased the nab-paclitaxel IC50 of PDAC cell lines. BMS-754807 therapy decreased phospho-IGF-1R/IR and phospho-AKT expression, and increased cleavage of caspase-3 and PARP-1. These results support the potential of BMS-754807 in combination with nab-paclitaxel as an effective targeting option for pancreatic cancer therapy.Item Augmenting Experimental Gastric Cancer Activity of Irinotecan through Liposomal Formulation and Antiangiogenic Combination Therapy(American Association for Cancer Research, 2022) Awasthi, Niranjan; Schwarz, Margaret A.; Zhang, Changhua; Klinz, Stephan G.; Meyer-Losic, Florence; Beaufils, Benjamin; Thiagalingam, Arunthathi; Schwarz, Roderich E.; Surgery, School of MedicineGastric adenocarcinoma (GAC) is the third most common cause of cancer-related deaths worldwide. Combination chemotherapy remains the standard treatment for advanced GAC. Liposomal irinotecan (nal-IRI) has improved pharmacokinetics (PK) and drug biodistribution compared with irinotecan (IRI, CPT-11). Angiogenesis plays a crucial role in the progression and metastasis of GAC. We evaluated the antitumor efficacy of nal-IRI in combination with novel antiangiogenic agents in GAC mouse models. Animal survival studies were performed in peritoneal dissemination xenografts. Tumor growth and PK studies were performed in subcutaneous xenografts. Compared with controls, extension in animal survival by nal-IRI and IRI was >156% and >94%, respectively. The addition of nintedanib or DC101 extended nal-IRI response by 13% and 15%, and IRI response by 37% and 31% (MKN-45 xenografts); nal-IRI response by 11% and 3%, and IRI response by 16% and 40% (KATO-III xenografts). Retardation of tumor growth was greater with nal-IRI (92%) than IRI (71%). Nintedanib and DC101 addition tend to augment nal-IRI or IRI response in this model. The addition of antiangiogenic agents enhanced tumor cell proliferation inhibition effects of nal-IRI or IRI. The tumor vasculature was decreased by nintedanib (65%) and DC101 (58%), while nal-IRI and IRI alone showed no effect. PK characterization in GAC xenografts demonstrated that compared with IRI, nal-IRI treatment groups had higher retention, circulation time, and tumor levels of CPT-11 and its active metabolite SN-38. These findings indicate that nal-IRI, alone and in combination with antiangiogenic agents, has the potential for improving clinical GAC therapy.Item A C-X-C Chemokine Receptor Type 2–Dominated Cross-talk between Tumor Cells and Macrophages Drives Gastric Cancer Metastasis(AACR, 2019-06) Zhou, Zhijun; Xia, Guanggai; Xiang, Zhen; Liu, Mingyang; Wei, Zhewei; Yan, Jie; Chen, Wei; Zhu, Jintao; Awasthi, Niranjan; Sun, Xiaotian; Fung, Kar-Ming; He, Yulong; Li, Min; Zhang, Changhua; Surgery, School of MedicinePurpose: C-X-C chemokine receptor type 2 (CXCR2) is a key regulator that drives immune suppression and inflammation in tumor microenvironment. CXCR2-targeted therapy has shown promising results in several solid tumors. However, the underlying mechanism of CXCR2-mediated cross-talk between gastric cancer cells and macrophages still remains unclear. Experimental Design: The expression of CXCR2 and its ligands in 155 human gastric cancer tissues was analyzed via immunohistochemistry, and the correlations with clinical characteristics were evaluated. A coculture system was established, and functional assays, including ELISA, transwell, cell viability assay, and qPCR, were performed to determine the role of the CXCR2 signaling axis in promoting gastric cancer growth and metastasis. A xenograft gastric cancer model and a lymph node metastasis model were established to study the function of CXCR2 in vivo. Results: CXCR2 expression is associated with the prognosis of patients with gastric cancer (P = 0.002). Of all the CXCR2 ligands, CXCL1 and CXCL5 can significantly promote migration of gastric cancer cells. Macrophages are the major sources of CXCL1 and CXCL5 in the gastric cancer microenvironment, and promote migration of gastric cancer cells through activating a CXCR2/STAT3 feed-forward loop. Gastric cancer cells secrete TNF-α to induce release of CXCL1 and CXCL5 from macrophages. Inhibiting CXCR2 pathway of gastric cancer cells can suppress migration and metastasis of gastric cancer in vitro and in vivo. Conclusions: Our study suggested a previously uncharacterized mechanism through which gastric cancer cells interact with macrophages to promote tumor growth and metastasis, suggesting that CXCR2 may serve as a promising therapeutic target to treat gastric cancer.Item Cytokine Interaction With Cancer-Associated Fibroblasts in Esophageal Cancer(Sage, 2022) Hassan, Md Sazzad; Cwidak, Nicholas; Awasthi, Niranjan; von Holzen, Urs; Surgery, School of MedicineEsophageal 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.Item Cytokine Interaction With Cancer-Associated Fibroblasts in Esophageal Cancer(Sage, 2022) Hassan, Md Sazzad; Cwidak, Nicholas; Awasthi, Niranjan; von Holzen, Urs; Surgery, School of MedicineEsophageal 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.Item Dr. Niranjan Awasthi: nanoparticle formulation of cytotoxic chemotherapy in combination with antiangiogenic agents: Potential for improving treatment outcome in gastric cancer(AME, 2020) Awasthi, Niranjan; Zhang, Anita; Surgery, School of MedicineItem Enhancing gastric cancer conventional chemotherapy effects by triple angiokinase inhibitor nintedanib in preclinical models(Frontiers Media, 2023-05-10) Awasthi, Niranjan; Schwarz, Margaret A.; Kaurich, Quinn; Zhang, Changhua; Hilberg, Frank; Schwarz, Roderich E.; Surgery, School of MedicineBackground: Gastric adenocarcinoma (GAC) is the fourth leading cause of cancer death worldwide. Systemic chemotherapy is a preferred treatment option for advanced and recurrent GAC, but response rates and survival prolongation remain limited. Tumor angiogenesis plays a critical role in GAC growth, invasion and metastasis. We investigated the antitumor efficacy of nintedanib, a potent triple angiokinase inhibitor for VEGFR-1/2/3, PDGFR-α/β and FGFR-1/2/3, alone or in combination with chemotherapy, in preclinical models of GAC. Methods: Animal survival studies were performed in peritoneal dissemination xenografts in NOD/SCID mice using human GAC cell lines MKN-45 and KATO-III. Tumor growth inhibition studies were performed in subcutaneous xenografts in NOD/SCID mice using human GAC cell lines MKN-45 and SNU-5. The mechanistic evaluation involved Immunohistochemistry analyses in tumor tissues obtained from subcutaneous xenografts. In vitro cell viability assays were performed using a colorimetric WST-1 reagent. Results: In MKN-45 GAC cell-derived peritoneal dissemination xenografts, animal survival was improved by nintedanib (33%), docetaxel (100%) and irinotecan (181%), while oxaliplatin, 5-FU and epirubicin had no effect. The addition of nintedanib to docetaxel (157%) or irinotecan (214%) led to a further extension in animal survival. In KATO-III GAC cell-derived xenografts carrying FGFR2 gene amplification, nintedanib extended survival by 209%. Again, the addition of nintedanib further enhanced the animal survival benefits of docetaxel (273%) and irinotecan (332%). In MKN-45 subcutaneous xenografts, nintedanib, epirubicin, docetaxel and irinotecan reduced tumor growth (range: 68-87%), while 5-FU and oxaliplatin had a smaller effect (40%). Nintedanib addition to all chemotherapeutics demonstrated a further reduction in tumor growth. Subcutaneous tumor analysis revealed that nintedanib attenuated tumor cell proliferation, reduced tumor vasculature and increased tumor cell death. Conclusion: Nintedanib showed notable antitumor efficacy and significantly improved taxane or irinotecan chemotherapy responses. These findings indicate that nintedanib, alone and in combination with a taxane or irinotecan, has the potential for improving clinical GAC therapy.Item 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 MedicineThe 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.Item Inhibition of the MEK/ERK pathway augments nab-paclitaxel-based chemotherapy effects in preclinical models of pancreatic cancer(Impact Journals, 2017-12-25) Awasthi, Niranjan; Monahan, Sheena; Stefaniak, Alexis; Schwarz, Margaret A.; Schwarz, Roderich E.; Surgery, School of MedicineNab-paclitaxel (NPT) combination with gemcitabine (Gem) represents the standard chemotherapy for pancreatic ductal adenocarcinoma (PDAC). Genetic alterations of the RAS/RAF/MEK/ERK (MAPK) signaling pathway yielding constitutive activation of the ERK cascade have been implicated as drivers of PDAC. Inhibition of downstream targets in the RAS-MAPK cascade such as MEK remains a promising therapeutic strategy. The efficacy of trametinib (Tra), a small molecule inhibitor of MEK1/2 kinase activity, in combination with nab-paclitaxel-based chemotherapy was evaluated in preclinical models of PDAC. The addition of trametinib to chemotherapy regimens showed a trend for an additive effect on tumor growth inhibition in subcutaneous AsPC-1 and Panc-1 PDAC xenografts. In a peritoneal dissemination model, median animal survival compared to controls (20 days) was increased after therapy with NPT (33 days, a 65% increase), Tra (31 days, a 55% increase), NPT+Tra (37 days, a 85% increase), NPT+Gem (39 days, a 95% increase) and NPT+Gem+Tra (49 days, a 145% increase). Effects of therapy on intratumoral proliferation and apoptosis corresponded with tumor growth inhibition. Trametinib effects were specifically accompanied by a decrease in phospho-ERK and an increase in cleaved caspase-3 and cleaved PARP-1 proteins. These findings suggest that the effects of nab-paclitaxel-based chemotherapy can be enhanced through specific inhibition of MEK1/2 kinase activity, and supports the clinical application of trametinib in combination with standard nab-paclitaxel-based chemotherapy in PDAC patients.
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