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Pancreatic Neoplasms: HELP
Articles by Alexander H. Kroemer
Based on 4 articles published since 2010
(Why 4 articles?)
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Between 2010 and 2020, A. Kroemer wrote the following 4 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Article Gastrin vaccine improves response to immune checkpoint antibody in murine pancreatic cancer by altering the tumor microenvironment. 2019

Osborne, Nicholas / Sundseth, Rebecca / Burks, Julian / Cao, Hong / Liu, Xunxian / Kroemer, Alexander H / Sutton, Lynda / Cato, Allen / Smith, Jill P. ·Cato Research, Durham, NC, USA. · Department of Medicine, Georgetown University, 4000 Reservoir Rd, NW, Building D, Room 338, Washington, DC, 20007, USA. · The MedStar Georgetown Transplant Institute, Georgetown University, Washington, DC, USA. · Cancer Advances, Inc., Durham, NC, USA. · Department of Medicine, Georgetown University, 4000 Reservoir Rd, NW, Building D, Room 338, Washington, DC, 20007, USA. jps261@georgetown.edu. ·Cancer Immunol Immunother · Pubmed #31549214.

ABSTRACT: Pancreatic cancer has been termed a 'recalcitrant cancer' due to its relative resistance to chemotherapy and immunotherapy. This resistance is thought to be due in part to the dense fibrotic tumor microenvironment and lack of tumor infiltrating CD8 + T cells. The gastrointestinal peptide, gastrin, has been shown to stimulate growth of pancreatic cancer by both a paracrine and autocrine mechanism. Interruption of gastrin at the CCK receptor may reduce tumor-associated fibrosis and alter tumor immune cells. Polyclonal Ab Stimulator (PAS) is a vaccine that targets gastrin and has been shown to prolong survival of patients with pancreatic cancer. Here, we report that PAS vaccination monotherapy elicits both a humoral and cellular immune response when used in immune competent mice-bearing pancreatic tumors and that PAS monotherapy produced a marked T-cell activation and influx of CD8 + lymphocytes into pancreatic tumors. Isolated peripheral lymphocytes elicited cytokine release upon re-stimulation with gastrin in vitro demonstrating specificity of immune activation for the target peptide. Combination therapy with PAS and PD-1 Ab activated CD4 -/CD8 - TEMRA cells important in T-cell-mediated tumor death and memory. Tumors of mice treated with PAS (250 μg) or PAS (100 and 250 μg) in combination with a PD-1 Ab were significantly smaller compared to tumors from PBS or PD-1 Ab-treated mice. When PAS was given in combination with PD-1 Ab, tumors had less fibrosis, fewer inhibitory Treg lymphocytes, and fewer tumor-associated macrophages. These findings reveal a novel approach to improve treatment strategies for pancreatic cancer.

2 Article Inhibition of mTORC2 component RICTOR impairs tumor growth in pancreatic cancer models. 2017

Schmidt, Katharina M / Hellerbrand, Claus / Ruemmele, Petra / Michalski, Christoph W / Kong, Bo / Kroemer, Alexander / Hackl, Christina / Schlitt, Hans J / Geissler, Edward K / Lang, Sven A. ·Department of Surgery, University Hospital Regensburg, Regensburg, Germany. · Department of Internal Medicine I, University Hospital Regensburg, Germany. · Department of Pathology, Hospital of Erlangen, Erlangen, Germany. · Department of Surgery, University of Heidelberg, Germany. · Department of Surgery, Technische Universität München (TUM), Munich, Germany. · Department of Surgery, Universität Freiburg, Freiburg, Germany. ·Oncotarget · Pubmed #28445935.

ABSTRACT: Mammalian Target of Rapamycin complex 2 (mTORC2) and its regulatory component Rapamycin-insensitive companion of mTOR (RICTOR) are increasingly recognized as important players in human cancer development and progression. However, the role of RICTOR in human pancreatic ductal adenocarcinoma (PDAC) is unclear so far. Here, we sought to analyze the effects of RICTOR inhibition in human pancreatic cancer cell lines in vitro and in vivo. Furthermore, RICTOR expression was determined in human PDAC samples. Results demonstrate that depletion of RICTOR with siRNA (transient knock-down) or shRNA (stable knock-down) has an inhibitory effect on tumor growth in vitro. Moreover, RICTOR inhibition led to impaired phosphorylation/activity of AGC kinases (AKT, SGK1). Interestingly, hypoxia-induced expression of hypoxia-induced factor-1α (HIF-1α) was diminished and secretion of vascular-endothelial growth factor-A (VEGF-A) was impaired upon targeting RICTOR. Stable RICTOR knock-down led to significant inhibition of tumor growth in subcutaneous and orthotopic tumor models which was accompanied by significant reduction of tumor cell proliferation. Finally, immunohistochemical analyses of 85 human PDAC samples revealed significantly poorer survival in patients with higher RICTOR expression. In conclusion, these findings provide first evidence for mTORC2/RICTOR as an attractive novel target for treatment of human PDAC.

3 Article HDAC1 and HDAC2 integrate the expression of p53 mutants in pancreatic cancer. 2017

Stojanovic, N / Hassan, Z / Wirth, M / Wenzel, P / Beyer, M / Schäfer, C / Brand, P / Kroemer, A / Stauber, R H / Schmid, R M / Arlt, A / Sellmer, A / Mahboobi, S / Rad, R / Reichert, M / Saur, D / Krämer, O H / Schneider, G. ·II. Medizinische Klinik, Technische Universität München, München, Germany. · Department of Toxicology, University of Mainz Medical Center, Mainz, Germany. · Institute of Biochemistry and Biophysics/Center for Molecular Biomedicine (CMB), Friedrich-Schiller-University Jena, Jena, Germany. · Molecular and Cellular Oncology/ENT, University Medical Center Mainz, Mainz, Germany. · Laboratory of Molecular Gastroenterology and Hepatology, 1st Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany. · Institute of Pharmacy, Department of Pharmaceutical Chemistry I, Faculty of Chemistry and Pharmacy, University of Regensburg, Regensburg, Germany. · German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany. · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. ·Oncogene · Pubmed #27721407.

ABSTRACT: Mutation of p53 is a frequent genetic lesion in pancreatic cancer being an unmet clinical challenge. Mutants of p53 have lost the tumour-suppressive functions of wild type p53. In addition, p53 mutants exert tumour-promoting functions, qualifying them as important therapeutic targets. Here, we show that the class I histone deacetylases HDAC1 and HDAC2 contribute to maintain the expression of p53 mutants in human and genetically defined murine pancreatic cancer cells. Our data reveal that the inhibition of these HDACs with small molecule HDAC inhibitors (HDACi), as well as the specific genetic elimination of HDAC1 and HDAC2, reduce the expression of mutant p53 mRNA and protein levels. We further show that HDAC1, HDAC2 and MYC directly bind to the TP53 gene and that MYC recruitment drops upon HDAC inhibitor treatment. Therefore, our results illustrate a previously unrecognized class I HDAC-dependent control of the TP53 gene and provide evidence for a contribution of MYC. A combined approach targeting HDAC1/HDAC2 and MYC may present a novel and molecularly defined strategy to target mutant p53 in pancreatic cancer.

4 Article STAT5b as molecular target in pancreatic cancer--inhibition of tumor growth, angiogenesis, and metastases. 2012

Moser, Christian / Ruemmele, Petra / Gehmert, Sebastian / Schenk, Hedwig / Kreutz, Marina P / Mycielska, Maria E / Hackl, Christina / Kroemer, Alexander / Schnitzbauer, Andreas A / Stoeltzing, Oliver / Schlitt, Hans J / Geissler, Edward K / Lang, Sven A. ·Department of Surgery, University of Regensburg Medical Center, Regensburg, Germany. ·Neoplasia · Pubmed #23097626.

ABSTRACT: The prognosis of patients suffering from pancreatic cancer is still poor and novel therapeutic options are urgently needed. Recently, the transcription factor signal transducer and activator of transcription 5b (STAT5b) was associated with tumor progression in human solid cancer. Hence, we assessed whether STAT5b might serve as an anticancer target in ductal pancreatic adenocarcinoma (DPAC). We found that nuclear expression of STAT5b can be detected in approximately 50% of DPAC. Blockade of STAT5b by stable shRNA-mediated knockdown showed no effects on tumor cell growth in vitro. However, inhibition of tumor cell motility was found even in response to stimulation with epidermal growth factor or interleukin-6. These findings were paralleled by a reduction of prometastatic and proangiogenic factors in vitro. Subsequent in vivo experiments revealed a strong growth inhibition on STAT5b blockade in subcutaneous and orthotopic models. These findings were paralleled by impaired tumor angiogenesis in vivo. In contrast to the subcutaneous model, the orthotopic model revealed a strong reduction of tumor cell proliferation that emphasizes the meaning of assessing targets in an appropriate microenvironment. Taken together, our results suggest that STAT5b might be a potential novel target for human DPAC.