Abstract 3134: Crizotinib inhibits tumor growth and metabolic inactivation of gemcitabine in new patient derived orthotopic pancreatic tumors with c-Met overexpression: A step toward personalized treatment in pancreatic cancer

Pancreatic cancer is resistant to chemotherapy in part due to the dense desmoplastic fibrosis surrounding the tumor, the immunosuppressive cells in the tumor microenvironment (TME), and the early rate of metastases. In this study, we examined the effects of a CCK receptor antagonist, proglumide, alone and in combination with gemcitabine in murine models of pancreatic cancer. Tumor growth rate, metastases, and survival were assessed in mice bearing syngeneic murine or human pancreatic tumors treated with PBS (control), gemcitabine, proglumide, or the combination of gemcitabine and proglumide. Excised tumors were evaluated histologically for fibrosis, immune cells, molecular markers, and uptake of chemotherapy by mass spectroscopy. Peripheral blood was analyzed with a microRNAs biomarker panel associated with fibrosis and oncogenesis. Differentially expressed genes between tumors of mice treated with gemcitabine monotherapy and combination therapy were compared by RNAseq. When given in combination the two compounds exhibited inhibitory effects by decreasing tumor growth rate by 70%, metastases, and prolonging survival. Proglumide monotherapy altered the TME by decreasing fibrosis, increasing intratumoral CD8+ T-cells, and decreasing arginase-positive cells, thus rendering the tumor sensitive to chemotherapy. Proglumide altered the expression of genes involved in fibrosis, epithelial–mesenchymal transition, and invasion. CCK-receptor antagonism with proglumide renders pancreatic cancer susceptible to chemotherapy.

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A Study Comparing the Effects of Targeted Intra-Arterial and Systemic Chemotherapy in an Orthotopic Mouse Model of Pancreatic Cancer

Scientific Reports ◽

10.1038/s41598-019-52490-1 ◽

2019 ◽

Vol 9 (1) ◽

Author(s):

Melika Rezaee ◽

Jing Wang ◽

Mehdi Razavi ◽

Gang Ren ◽

Fengyan Zheng ◽

...

Keyword(s):

Pancreatic Cancer ◽

Mouse Model ◽

Tumor Growth ◽

Systemic Chemotherapy ◽

Pancreatic Tumors ◽

Therapeutic Effects ◽

Orthotopic Mouse Model ◽

Systemic Injection ◽

Arterial Blood ◽

Poor Outcomes

Abstract Systemic chemotherapy is the first line treatment for patients with unresectable pancreatic cancer, however, insufficient drug delivery to the pancreas is a major problem resulting in poor outcomes. We evaluated the therapeutic effects of targeted intra-arterial (IA) delivery of gemcitabine directly into the pancreas in an orthotopic mouse model of pancreatic cancer. Nude mice with orthotopic pancreatic tumors were randomly assigned into 3 groups receiving gemcitabine: systemic intravenous (IV) injection (low: 0.3 mg/kg and high: 100 mg/kg) and direct IA injection (0.3 mg/kg). Treatments were administered weekly for 2 weeks. IA treatment resulted in a significantly greater reduction in tumor growth compared to low IV treatment. To achieve a comparable reduction in tumor growth as seen with IA treatment, gemcitabine had to be given IV at over 300x the dose (high IV treatment) which was associated with some toxicity. After 2 weeks, tumor samples from animals treated with IA gemcitabine had significantly lower residual cancer cells, higher cellular necrosis and evidence of increased apoptosis when compared to animals treated with low IV gemcitabine. Our study shows targeted IA injection of gemcitabine directly into the pancreas, via its arterial blood supply, has a superior therapeutic effect in reducing tumor growth compared to the same concentration administered by conventional systemic injection.

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WDR5-H3K4me3 epigenetic axis regulates OPN expression to compensate PD-L1 function to promote pancreatic cancer immune escape

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-002624 ◽

2021 ◽

Vol 9 (7) ◽

pp. e002624

Author(s):

Chunwan Lu ◽

Zhuoqi Liu ◽

John D Klement ◽

Dafeng Yang ◽

Alyssa D Merting ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Growth ◽

Tumor Cells ◽

Protein Level ◽

Pancreatic Tumor ◽

Immune Escape ◽

Epigenetic Mechanism ◽

Human Pancreatic Cancer ◽

Pancreatic Tumors ◽

Genome Wide

BackgroundDespite PD-L1 (Programmed death receptor ligand-1) expression on tumor cells and cytotoxic T lymphocytes tumor infiltration in the tumor microenvironment, human pancreatic cancer stands out as one of the human cancers that does not respond to immune checkpoint inhibitor (ICI) immunotherapy. Epigenome dysregulation has emerged as a major mechanism in T cell exhaustion and non-response to ICI immunotherapy, we, therefore, aimed at testing the hypothesis that an epigenetic mechanism compensates PD-L1 function to render pancreatic cancer non-response to ICI immunotherapy.MethodsTwo orthotopic pancreatic tumor mouse models were used for chromatin immunoprecipitation-Seq and RNA-Seq to identify genome-wide dysregulation of H3K4me3 and gene expression. Human pancreatic tumor and serum were analyzed for osteopontin (OPN) protein level and for correlation with patient prognosis. OPN and PD-L1 cellular location were determined in the tumors using flow cytometry. The function of WDR5-H3K4me3 axis in OPN expression were determined by Western blotting. The function of H3K4me3-OPN axis in pancreatic cancer immune escape and response to ICI immunotherapy was determined in an orthotopic pancreatic tumor mouse model.ResultsMouse pancreatic tumors have a genome-wide increase in H3K4me3 deposition as compared with normal pancreas. OPN and its receptor CD44 were identified being upregulated in pancreatic tumors by their promoter H3K4me3 deposition. OPN protein is increased in both tumor cells and tumor-infiltrating immune cells in human pancreatic carcinoma and is inversely correlated with pancreatic cancer patient survival. OPN is primarily expressed in tumor cells and monocytic myeloid-derived suppressor cells (M-MDSCs), whereas PD-L1 is expressed in tumor cells, M-MDSCs, polymorphonuclear MDSCs and tumor-associated macrophages. WDR5 is essential for H3K4me3-specific histone methyltransferase activity that regulates OPN expression in tumor cells and MDSCs. Inhibition of WDR5 significantly decreased OPN protein level. Inhibition of WDR5 or knocking out of OPN suppressed orthotopic mouse pancreatic tumor growth. Inhibition of WDR5 also significantly increased efficacy of anti-PD-1 immunotherapy in suppression of mouse pancreatic tumor growth in vivo.ConclusionsOPN compensates PD-L1 function to promote pancreatic cancer immune escape. Pharmacological inhibition of the WDR5-H3K4me3 epigenetic axis is effective in suppressing pancreatic tumor immune escape and in improving efficacy of anti-PD-1 immunotherapy in pancreatic cancer.

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The antitumoral activity of TLR7 ligands is corrupted by the microenvironment of pancreatic tumors

10.1101/2020.03.05.978767 ◽

2020 ◽

Author(s):

Marie Rouanet ◽

Hubert Lulka ◽

Pierre Garcin ◽

Martin Sramek ◽

Delphine Pagan ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Growth ◽

Pancreatic Tumors ◽

Antitumoral Activity ◽

Toll Like Receptor ◽

Immunodeficient Mice ◽

Pancreatic Cancer Cells ◽

Promote Tumor Growth

AbstractToll like receptors are key players in the innate immune system. Recent studies have suggested that they may impact the growth of pancreatic cancer, a disease with no cure. Among them, Toll like receptor-7 shows promise for therapy but may also promote tumor growth. Thus, we aimed to better understand the mechanism of action of Toll like receptor-7 ligands in pancreatic cancer, to open the door for clinical applications. In vitro, Toll like receptor-7 ligands strongly inhibit the proliferation and induce cell death by apoptosis of pancreatic cancer cells. In vivo, while Toll like receptor-7 agonists significantly delay the growth of aggressive tumors engrafted in immunodeficient mice, they instead surprisingly promote tumor growth and accelerate animal death in immunocompetent models. Molecular investigations revealed that Toll like receptor-7 agonists strongly increase the number of tumor-promoting macrophages to drive pancreatic tumorigenesis in immunocompetent mice. This is in stark contrast with Toll like receptor-7 ligands’ great potential to inhibit pancreatic cancer cell proliferation in vitro and tumor growth in vivo in immunosuppressed models. Collectively, our findings shine a light on the duality of action of Toll like receptor-7 agonists in experimental cancer models, and calls into question their use for pancreatic cancer therapy.

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MIB1 Upregulates IQGAP1 and Promotes Pancreatic Cancer Progression by inducing ST7 Degradation

10.21203/rs.3.rs-76668/v1 ◽

2020 ◽

Author(s):

Tao Liu ◽

Bin Zhang ◽

xin jin ◽

Xiang Cheng

Keyword(s):

Pancreatic Cancer ◽

Tumor Growth ◽

Cancer Cells ◽

Western Blotting ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Pancreatic Tumors ◽

Pancreatic Cancer Cells ◽

The Relationship

Abstract BackgroundPancreatic cancer is a highly heterogeneous and has a poor prognosis. Elucidating the molecular mechanisms underlying pancreatic cancer progression is essential for improving patient survival. Although the E3 ubiquitin ligase mind bomb 1 (MIB1) is involved in cancer cell proliferation and is often overexpressed in pancreatic cancer, the role of MIB1 in pancreatic cancer progression remains unclear.Methods The relationship of MIB1 with the clinicopathological features of pancreatic tumors was bioinformatically investigated in different datasets. The protein levels of MIB1 and ST7 were assessed by Western blotting and immunohistochemistry. The role of MIB1 and ST7 in pancreatic cancer growth was assessed by MTS assays, colony formation assays, and experiments in mouse xenograft models. The interaction between MIB1 and ST7 was investigated by co-immunoprecipitation. The relationship between MIB1, ST7, and IQGAP1 levels was explored by Western blotting and quantitative real-time PCR.ResultsMIB1 expression was elevated in pancreatic cancer tissues, and its expression levels were associated with unfavorable prognosis. MIB1 overexpression enhanced pancreatic cancer proliferation and invasion in vitro and in vivo. We identified ST7 as a novel MIB1 target for proteasomal degradation. Further, we found that ST7 suppressed tumor growth by downregulating IQGAP1 in pancreatic cancer cells.ConclusionsThese data suggest that MIB1 promotes pancreatic cancer progression by inducing ST7 degradation. ST7 suppresses tumor growth by downregulating IQGAP1 in pancreatic cancer cells. Therefore, the MIB1/ST7/IQGAP1 axis is essential for pancreatic cancer progression, and MIB1 inhibition may improve the survival of pancreatic cancer patients.

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Hepatocyte Growth Factor and Macrophage-stimulating Protein “Hinge” Analogs to Treat Pancreatic Cancer

Current Cancer Drug Targets ◽

10.2174/1568009619666190326130008 ◽

2019 ◽

Vol 19 (10) ◽

pp. 782-795

Author(s):

John W. Wright ◽

Kevin J. Church ◽

Joseph W. Harding

Keyword(s):

Pancreatic Cancer ◽

Signal Transduction ◽

Growth Factor ◽

Hepatocyte Growth Factor ◽

Tumor Growth ◽

Receptor Activation ◽

Signal Transduction Pathways ◽

Met Receptor ◽

Macrophage Stimulating Protein ◽

Hepatocyte Growth

Pancreatic cancer (PC) ranks twelfth in frequency of diagnosis but is the fourth leading cause of cancer related deaths with a 5 year survival rate of less than 7 percent. This poor prognosis occurs because the early stages of PC are often asymptomatic. Over-expression of several growth factors, most notably vascular endothelial growth factor (VEGF), has been implicated in PC resulting in dysfunctional signal transduction pathways and the facilitation of tumor growth, invasion and metastasis. Hepatocyte growth factor (HGF) acts via the Met receptor and has also received research attention with ongoing efforts to develop treatments to block the Met receptor and its signal transduction pathways. Macrophage-stimulating protein (MSP), and its receptor Ron, is also recognized as important in the etiology of PC but is less well studied. Although the angiotensin II (AngII)/AT1 receptor system is best known for mediating blood pressure and body water/electrolyte balance, it also facilitates tumor vascularization and growth by stimulating the expression of VEGF. A metabolite of AngII, angiotensin IV (AngIV) has sequence homology with the “hinge regions” of HGF and MSP, key structures in the growth factor dimerization processes necessary for Met and Ron receptor activation. We have developed AngIV-based analogs designed to block dimerization of HGF and MSP and thus receptor activation. Norleual has shown promise as tested utilizing PC cell cultures. Results indicate that cell migration, invasion, and pro-survival functions were suppressed by this analog and tumor growth was significantly inhibited in an orthotopic PC mouse model.

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Role of Endoscopic Ultrasonography and Endoscopic Retrograde Cholangiopancreatography in the Diagnosis of Pancreatic Cancer

Diagnostics ◽

10.3390/diagnostics11020238 ◽

2021 ◽

Vol 11 (2) ◽

pp. 238

Author(s):

Yasutaka Ishii ◽

Masahiro Serikawa ◽

Tomofumi Tsuboi ◽

Ryota Kawamura ◽

Ken Tsushima ◽

...

Keyword(s):

Pancreatic Cancer ◽

Endoscopic Retrograde Cholangiopancreatography ◽

Endoscopic Ultrasonography ◽

Treatment Decision ◽

Needle Aspiration ◽

Pancreatic Tumors ◽

Decision Strategy ◽

Endoscopic Retrograde ◽

Small Pancreatic Cancer ◽

Eus Elastography

Pancreatic cancer has the poorest prognosis among all cancers, and early diagnosis is essential for improving the prognosis. Along with radiologic modalities, such as computed tomography (CT) and magnetic resonance imaging (MRI), endoscopic modalities play an important role in the diagnosis of pancreatic cancer. This review evaluates the roles of two of those modalities, endoscopic ultrasonography (EUS) and endoscopic retrograde cholangiopancreatography (ERCP), in the diagnosis of pancreatic cancer. EUS can detect pancreatic cancer with higher sensitivity and has excellent sensitivity for the diagnosis of small pancreatic cancer that cannot be detected by other imaging modalities. EUS may be useful for the surveillance of pancreatic cancer in high-risk individuals. Contrast-enhanced EUS and EUS elastography are also useful for differentiating solid pancreatic tumors. In addition, EUS-guided fine needle aspiration shows excellent sensitivity and specificity, even for small pancreatic cancer, and is an essential examination method for the definitive pathological diagnosis and treatment decision strategy. On the other hand, ERCP is invasive and performed less frequently for the purpose of diagnosing pancreatic cancer. However, ERCP is essential in cases that require evaluation of pancreatic duct stricture that may be early pancreatic cancer or those that require differentiation from focal autoimmune pancreatitis.

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The Cellular and Biological Impact of Extracellular Vesicles in Pancreatic Cancer

Cancers ◽

10.3390/cancers13123040 ◽

2021 ◽

Vol 13 (12) ◽

pp. 3040

Author(s):

Zainab Hussain ◽

Jeremy Nigri ◽

Richard Tomasini

Keyword(s):

Pancreatic Cancer ◽

Tumor Cells ◽

Extracellular Vesicles ◽

Cell Communication ◽

Pancreatic Tumors ◽

Mediated Communication ◽

Biological Impact ◽

Physiological Relevance ◽

Cellular Components ◽

Tumoral Cells

Deciphering the interactions between tumor and stromal cells is a growing field of research to improve pancreatic cancer-associated therapies and patients’ care. Indeed, while accounting for 50 to 90% of the tumor mass, many pieces of evidence reported that beyond their structural role, the non-tumoral cells composing the intra-tumoral microenvironment influence tumor cells’ proliferation, metabolism, cell death and resistance to therapies, among others. Simultaneously, tumor cells can influence non-tumoral neighboring or distant cells in order to shape a tumor-supportive and immunosuppressive environment as well as influencing the formation of metastatic niches. Among intercellular modes of communication, extracellular vesicles can simultaneously transfer the largest variety of signals and were recently reported as key effectors of cell–cell communication in pancreatic cancer, from its development to its evolution as well as its ability to resist available treatments. This review focuses on extracellular vesicles-mediated communication between different cellular components of pancreatic tumors, from the modulation of cellular activities and abilities to their biological and physiological relevance. Taking into consideration the intra-tumoral microenvironment and its extracellular-mediated crosstalk as main drivers of pancreatic cancer development should open up new therapeutic windows.

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