Abstract 3698: ODSH, a heparin derivative, enhances the efficacy of gemcitabine in a refractory human pancreatic tumor xenograft model

3075 Background: CPI-613 is a novel agent that selectively targets the altered mitochondrial enzymes of tumor cells, causing apoptosis, necrosis, and autophagia. Results assessing clinical efficacy of CPI-613 translated from animal tumor xenograft models to patients with stage IV pancreatic cancer are presented. Methods: Efficacy of CPI-613 was tested in mice with pancreatic tumor xenografts generated by inoculation of BxPC-3 human pancreatic tumor cells. The safety and efficacy of CPI-613 (70-320 mg/m2), when used in combination with gemcitabine (1,000 mg/m2), was assessed in patients with stage IV pancreatic cancer. Results: In the animal pancreatic tumor xenograft model (n=10/grp), CPI-613 (25 mg/kg, IV, 1x weekly for 4 weeks) suppressed tumor growth by ~100%, when compared to vehicle. The positive control, gemcitabine (50 mg/kg, IV, 1x weekly for 4 weeks), suppressed tumor growth by only ~50%. Median overall survival in tumor-bearing mice treated with CPI-613 was ~240 days, which was significantly longer than those with gemcitabine or vehicle treatments (~65 and ~50 days, respectively). In 6 humans with stage IV pancreatic cancer (Table), the CPI-613+gemcitabine combination was well-tolerated. In those without prior chemotherapy before participating in the clinical trial (first three patients in the table), the CPI-613+gemcitabine combination prolonged survival that correlated with the dose of CPI-613. Conclusions: CPI-613 exhibits efficacy against pancreatic cancer in animal models, which is translational to patients with stage IV disease. [Table: see text]

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Structure-guided design fine-tunes pharmacokinetics, tolerability, and antitumor profile of multispecific frizzled antibodies

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1817246116 ◽

2019 ◽

Vol 116 (14) ◽

pp. 6812-6817 ◽

Cited By ~ 9

Author(s):

Swetha Raman ◽

Melissa Beilschmidt ◽

Minh To ◽

Kevin Lin ◽

Francine Lui ◽

...

Keyword(s):

Pancreatic Tumor ◽

Xenograft Model ◽

Tumor Xenograft ◽

Acid Moiety ◽

Plasma Exposure ◽

Stem Cell Maintenance ◽

Exposure In Vivo ◽

Potential Therapeutics

Aberrant activation of Wnt/β-catenin signaling occurs frequently in cancer. However, therapeutic targeting of this pathway is complicated by the role of Wnt in stem cell maintenance and tissue homeostasis. Here, we evaluated antibodies blocking 6 of the 10 human Wnt/Frizzled (FZD) receptors as potential therapeutics. Crystal structures revealed a common binding site for these monoclonal antibodies (mAbs) on FZD, blocking the interaction with the Wnt palmitoleic acid moiety. However, these mAbs displayed gastrointestinal toxicity or poor plasma exposure in vivo. Structure-guided engineering was used to refine the binding of each mAb for FZD receptors, resulting in antibody variants with improved in vivo tolerability and developability. Importantly, the lead variant mAb significantly inhibited tumor growth in the HPAF-II pancreatic tumor xenograft model. Taken together, our data demonstrate that anti-FZD cancer therapeutic antibodies with broad specificity can be fine-tuned to navigate in vivo exposure and tolerability while driving therapeutic efficacy.

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Abstract B32: GRP55 antagonists alter tumor microenvironment and inhibit tumor growth in a pancreatic tumor xenograft model

10.1158/1538-7445.panca16-b32 ◽

2016 ◽

Author(s):

Nagendra S. Singh ◽

Irving W. Wainer

Keyword(s):

Tumor Microenvironment ◽

Tumor Growth ◽

Pancreatic Tumor ◽

Xenograft Model ◽

Tumor Xenograft ◽

Inhibit Tumor Growth

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LINC00958 promotes the proliferation of TSCC via miR-211-5p/CENPK axis and activating the JAK/STAT3 signaling pathway

Cancer Cell International ◽

10.1186/s12935-021-01808-z ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Bo Jia ◽

Junfeng Dao ◽

Jiusong Han ◽

Zhijie Huang ◽

Xiang Sun ◽

...

Keyword(s):

Noncoding Rna ◽

Xenograft Model ◽

Tumor Xenograft ◽

Luciferase Reporter ◽

Cell Cycle Regulators ◽

Normal Tissues ◽

Stat3 Signaling ◽

Long Intergenic Noncoding Rna

Abstract Background Tongue squamous cell carcinoma (TSCC) is one of the most common oral tumors. Recently, long intergenic noncoding RNA 00958 (LINC00958) has been identified as an oncogene in human cancers. Nevertheless, the role of LINC00958 and its downstream mechanisms in TSCC is still unknown. Methods The effect of LINC00958 on TSCC cells proliferation and growth were assessed by CCK-8, colony formation, 5-Ethynyl-2′-deoxyuridline (EdU) assay and flow cytometry assays in vitro and tumor xenograft model in vivo. Bioinformatics analysis was used to predict the target of LINC00958 in TSCC, which was verified by RNA immunoprecipitation and luciferase reporter assays. Results LINC00958 was increased in TSCC tissues, and patients with high LINC00958 expression had a shorter overall survival. LINC00958 knockdown significantly decreased the growth rate of TSCC cells both in vitro and in vivo. In mechanism, LINC00958 acted as a ceRNA by competitively sponging miR-211-5p. In addition, we identified CENPK as a direct target gene of miR-211-5p, which was higher in TSCC tissues than that in adjacent normal tissues. Up-regulated miR-211-5p or down-regulated CENPK could abolish LINC00958-induced proliferation promotion in TSCC cells. Furthermore, The overexpression of CENPK promoted the expression of oncogenic cell cycle regulators and activated the JAK/STAT3 signaling. Conclusions Our findings suggested that LINC00958 is a potential prognostic biomarker in TSCC.

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Gamma-radiated immunosuppressed tumor xenograft mice can be a new ideal model in cancer research

Scientific Reports ◽

10.1038/s41598-020-80428-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Hamid Khodayari ◽

Saeed Khodayari ◽

Solmaz Khalighfard ◽

Arash Tahmasebifar ◽

Mahboubeh Tajaldini ◽

...

Keyword(s):

Gamma Radiation ◽

High Capacity ◽

Xenograft Model ◽

Tumor Xenograft ◽

Whole Body ◽

Cell Injection ◽

Tumor Tissues ◽

Post Radiation ◽

Xenograft Models ◽

Xenograft Mice

AbstractTumor xenograft models can create a high capacity to study human tumors and discover efficient therapeutic approaches. Here, we aimed to develop the gamma-radiated immunosuppressed (GIS) mice as a new kind of tumor xenograft model for biomedical studies. First, 144 mice were divided into the control and treated groups exposed by a medical Cobalt-60 apparatus in 3, 4, and 5 Gy based on the system outputs. Then, 144 BALB/c mice were divided into four groups; healthy, xenograft, radiation, and radiation + xenograft groups. The animals in the xenograft and radiation + xenograft groups have subcutaneously received 3 × 106 MCF-7 cells 24 h post-radiation. On 3, 7, 14, and 21 days after cell injection, the animals were sacrificed. Then, the blood samples and the spleen and tumor tissues were removed for the cellular and molecular analyses. The whole-body gamma radiation had a high immunosuppressive effect on the BALB/c mice from 1 to 21 days post-radiation. The macroscopic and histopathological observations have proved that the created clusters' tumor structure resulted in the xenograft breast tumor. There was a significant increase in tumor size after cell injection until the end of the study. Except for Treg, the spleen level of CD4, CD8, CD19, and Ly6G was significantly decreased in Xen + Rad compared to the Xen alone group on 3 and 7 days. Unlike IL-4 and IL-10, the spleen level of TGF-β, INF-γ, IL-12, and IL-17 was considerably decreased in the Xen + Rad than the Xen alone group on 3 and 7 days. The spleen expressions of the VEGF, Ki67, and Bax/Bcl-2 ratio were dramatically increased in the Xen + Rad group compared to the Xen alone on 3, 7, 14, and 21 days. Our results could confirm a new tumor xenograft model via an efficient immune-suppressive potential of the whole-body gamma radiation in mice.

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The metastasis suppressor, NDRG1, attenuates oncogenic TGF-β and NF-κB signaling to enhance membrane E-cadherin expression in pancreatic cancer cells

Carcinogenesis ◽

10.1093/carcin/bgy178 ◽

2018 ◽

Vol 40 (6) ◽

pp. 805-818 ◽

Cited By ~ 14

Author(s):

Sharleen V Menezes ◽

Leyla Fouani ◽

Michael L H Huang ◽

Bekesho Geleta ◽

Sanaz Maleki ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Membrane ◽

Cancer Cells ◽

Transforming Growth Factor ◽

Xenograft Model ◽

Tumor Xenograft ◽

Metastasis Suppressor ◽

Mesenchymal Transition ◽

Pancreatic Cancer Cells ◽

E Cadherin

AbstractThe metastasis suppressor, N-myc downstream-regulated gene-1 (NDRG1), plays multifaceted roles in inhibiting oncogenic signaling and can suppress the epithelial mesenchymal transition (EMT), a key step in metastasis. In this investigation, NDRG1 inhibited the oncogenic effects of transforming growth factor-β (TGF-β) in PANC-1 pancreatic cancer cells, promoting expression and co-localization of E-cadherin and β-catenin at the cell membrane. A similar effect of NDRG1 at supporting E-cadherin and β-catenin co-localization at the cell membrane was also demonstrated for HT-29 colon and CFPAC-1 pancreatic cancer cells. The increase in E-cadherin in PANC-1 cells in response to NDRG1 was mediated by the reduction of three transcriptional repressors of E-cadherin, namely SNAIL, SLUG and ZEB1. To dissect the mechanisms how NDRG1 inhibits nuclear SNAIL, SLUG and ZEB1, we assessed involvement of the nuclear factor-κB (NF-κB) pathway, as its aberrant activation contributes to the EMT. Interestingly, NDRG1 comprehensively inhibited oncogenic NF-κB signaling at multiple sites in this pathway, suppressing NEMO, Iĸĸα and IĸBα expression, as well as reducing the activating phosphorylation of Iĸĸα/β and IĸBα. NDRG1 also reduced the levels, nuclear co-localization and DNA-binding activity of NF-κB p65. Further, Iĸĸα, which integrates NF-κB and TGF-β signaling to upregulate ZEB1, SNAIL and SLUG, was identified as an NDRG1 target. Considering this, therapies targeting NDRG1 could be a new strategy to inhibit metastasis, and as such, we examined novel anticancer agents, namely di-2-pyridylketone thiosemicarbazones, which upregulate NDRG1. These agents downregulated SNAIL, SLUG and ZEB1 in vitro and in vivo using a PANC-1 tumor xenograft model, demonstrating their marked potential.

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