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Zhou K, Liu Y, Tang C, Zhu H. Pancreatic Cancer: Pathogenesis and Clinical Studies. MedComm (Beijing) 2025; 6:e70162. [PMID: 40182139 PMCID: PMC11965705 DOI: 10.1002/mco2.70162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 03/08/2025] [Accepted: 03/12/2025] [Indexed: 04/05/2025] Open
Abstract
Pancreatic cancer (PC) is a highly lethal malignancy, with pancreatic ductal adenocarcinoma (PDAC) being the most common and aggressive subtype, characterized by late diagnosis, aggressive progression, and resistance to conventional therapies. Despite advances in understanding its pathogenesis, including the identification of common genetic mutations (e.g., KRAS, TP53, CDKN2A, SMAD4) and dysregulated signaling pathways (e.g., KRAS-MAPK, PI3K-AKT, and TGF-β pathways), effective therapeutic strategies remain limited. Current treatment modalities including chemotherapy, targeted therapy, immunotherapy, radiotherapy, and emerging therapies such as antibody-drug conjugates (ADCs), chimeric antigen receptor T (CAR-T) cells, oncolytic viruses (OVs), cancer vaccines, and bispecific antibodies (BsAbs), face significant challenges. This review comprehensively summarizes these treatment approaches, emphasizing their mechanisms, limitations, and potential solutions, to overcome these bottlenecks. By integrating recent advancements and outlining critical challenges, this review aims to provide insights into future directions and guide the development of more effective treatment strategies for PC, with a specific focus on PDAC. Our work underscores the urgency of addressing the unmet needs in PDAC therapy and highlights promising areas for innovation in this field.
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Affiliation(s)
- Kexun Zhou
- Department of Medical OncologyCancer CenterWest China HospitalSichuan UniversityChengduChina
| | - Yingping Liu
- Department of RadiotherapyCancer HospitalChinese Academy of Medical SciencesBeijingChina
| | - Chuanyun Tang
- The First Clinical Medical College of Nanchang UniversityNanchang UniversityNanchangChina
| | - Hong Zhu
- Department of Medical OncologyCancer CenterWest China HospitalSichuan UniversityChengduChina
- Division of Abdominal Tumor Multimodality TreatmentCancer CenterWest China HospitalSichuan UniversityChengduChina
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2
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Yan W, Menjivar RE, Bonilla ME, Steele NG, Kemp SB, Du W, Donahue KL, Brown K, Carpenter ES, Avritt FR, Irizarry-Negron VM, Yang S, Burns WR, Zhang Y, di Magliano MP, Bednar F. Notch Signaling Regulates Immunosuppressive Tumor-Associated Macrophage Function in Pancreatic Cancer. Cancer Immunol Res 2024; 12:91-106. [PMID: 37931247 PMCID: PMC10842043 DOI: 10.1158/2326-6066.cir-23-0037] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 07/08/2023] [Accepted: 10/31/2023] [Indexed: 11/08/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDA) continues to have a dismal prognosis. The poor survival of patients with PDA has been attributed to a high rate of early metastasis and low efficacy of current therapies, which partly result from its complex immunosuppressive tumor microenvironment. Previous studies from our group and others have shown that tumor-associated macrophages (TAM) are instrumental in maintaining immunosuppression in PDA. Here, we explored the role of Notch signaling, a key regulator of immune response, within the PDA microenvironment. We identified Notch pathway components in multiple immune cell types within human and mouse pancreatic cancer. TAMs, the most abundant immune cell population in the tumor microenvironment, expressed high levels of Notch receptors, with cognate ligands such as JAG1 expressed on tumor epithelial cells, endothelial cells, and fibroblasts. TAMs with activated Notch signaling expressed higher levels of immunosuppressive mediators, suggesting that Notch signaling plays a role in macrophage polarization within the PDA microenvironment. Genetic inhibition of Notch in myeloid cells led to reduced tumor size and decreased macrophage infiltration in an orthotopic PDA model. Combination of pharmacologic Notch inhibition with PD-1 blockade resulted in increased cytotoxic T-cell infiltration, tumor cell apoptosis, and smaller tumor size. Our work implicates macrophage Notch signaling in the establishment of immunosuppression and indicates that targeting the Notch pathway may improve the efficacy of immune-based therapies in patients with PDA.
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Affiliation(s)
- Wei Yan
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
| | - Rosa E. Menjivar
- Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Monica E. Bonilla
- Cancer Biology Program, University of Michigan, Ann Arbor, MI 48109, USA
| | - Nina G. Steele
- Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Samantha B. Kemp
- Molecular and Cellular Pathology Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA
| | - Wenting Du
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
| | - Katelyn L. Donahue
- Cancer Biology Program, University of Michigan, Ann Arbor, MI 48109, USA
| | - Kristee Brown
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
| | - Eileen S. Carpenter
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor MI 48109, USA
| | - Faith R. Avritt
- College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, MI 48109, USA
| | | | - Sion Yang
- College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, MI 48109, USA
| | - William R. Burns
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
| | - Yaqing Zhang
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
| | - Marina Pasca di Magliano
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
- Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
| | - Filip Bednar
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
- Cancer Biology Program, University of Michigan, Ann Arbor, MI 48109, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
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3
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Zhai S, Lin J, Ji Y, Zhang R, Zhang Z, Cao Y, Liu Y, Tang X, Liu J, Liu P, Lin J, Li F, Li H, Shi Y, Fu D, Deng X, Shen B. A microprotein N1DARP encoded by LINC00261 promotes Notch1 intracellular domain (N1ICD) degradation via disrupting USP10-N1ICD interaction to inhibit chemoresistance in Notch1-hyperactivated pancreatic cancer. Cell Discov 2023; 9:95. [PMID: 37714834 PMCID: PMC10504324 DOI: 10.1038/s41421-023-00592-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 07/28/2023] [Indexed: 09/17/2023] Open
Abstract
The extensively activated Notch signaling pathway in pancreatic cancer cells is important in carcinogenesis, chemoresistance, and recurrence. Targeting this pathway is a promising therapeutic strategy for pancreatic cancer; however, few successful approaches have been reported, and currently used molecular inhibitors of this pathway exhibit limited clinical benefits. In this study, we identified a previously uncharacterized microprotein, Notch1 degradation-associated regulatory polypeptide (N1DARP), encoded by LINC00261. N1DARP knockout accelerated tumor progression and enhanced stem cell properties in pancreatic cancer organoids and LSL-Kras, LSL-Trp53, and Pdx1-Cre (KPC) mice. Mechanistically, N1DARP suppressed canonical and non-canonical Notch1 pathways by competitively disrupting the interaction between N1ICD and ubiquitin-specific peptidase 10 (USP10), thereby promoting K11- and K48-linked polyubiquitination of N1ICD. To evaluate the therapeutic potential of N1DARP, we designed a cell-penetrating stapled peptide, SAH-mAH2-5, with a helical structure similar to that of N1DARP that confers remarkable physicochemical stability. SAH-mAH2-5 interacted with and promoted the proteasome-mediated degradation of N1ICD. SAH-mAH2-5 injection provided substantial therapeutic benefits with limited off-target and systemic adverse effects in Notch1-activated pancreatic cancer models. Taken together, these findings confirm that N1DARP acts as a tumor suppressor and chemosensitizer by regulating USP10-Notch1 oncogenic signaling, and suggest a promising therapeutic strategy targeting the N1DARP-N1ICD interaction in Notch1-activated pancreatic cancer.
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Affiliation(s)
- Shuyu Zhai
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Jiewei Lin
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yuchen Ji
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Ronghao Zhang
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Zehui Zhang
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Yizhi Cao
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Yang Liu
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Xiaomei Tang
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Jia Liu
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Pengyi Liu
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Jiayu Lin
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Fanlu Li
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Hongzhe Li
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Yusheng Shi
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China.
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China.
| | - Da Fu
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China.
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China.
| | - Xiaxing Deng
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China.
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China.
| | - Baiyong Shen
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China.
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China.
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4
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Agrawal R, Natarajan KN. Oncogenic signaling pathways in pancreatic ductal adenocarcinoma. Adv Cancer Res 2023; 159:251-283. [PMID: 37268398 DOI: 10.1016/bs.acr.2023.02.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common (∼90% cases) pancreatic neoplasm and one of the most lethal cancer among all malignances. PDAC harbor aberrant oncogenic signaling that may result from the multiple genetic and epigenetic alterations such as the mutation in driver genes (KRAS, CDKN2A, p53), genomic amplification of regulatory genes (MYC, IGF2BP2, ROIK3), deregulation of chromatin-modifying proteins (HDAC, WDR5) among others. A key event is the formation of Pancreatic Intraepithelial Neoplasia (PanIN) that often results from the activating mutation in KRAS. Mutated KRAS can direct a variety of signaling pathways and modulate downstream targets including MYC, which play an important role in cancer progression. In this review, we discuss recent literature shedding light on the origins of PDAC from the perspective of major oncogenic signaling pathways. We highlight how MYC directly and indirectly, with cooperation with KRAS, affect epigenetic reprogramming and metastasis. Additionally, we summarize the recent findings from single cell genomic approaches that highlight heterogeneity in PDAC and tumor microenvironment, and provide molecular avenues for PDAC treatment in the future.
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Affiliation(s)
- Rahul Agrawal
- DTU Bioengineering, Technical University of Denmark, Kongens Lyngby, Denmark
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5
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Correlation between hypoxia and HGF/c-MET expression in the management of pancreatic cancer. Biochim Biophys Acta Rev Cancer 2023; 1878:188869. [PMID: 36842767 DOI: 10.1016/j.bbcan.2023.188869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 01/16/2023] [Accepted: 02/07/2023] [Indexed: 02/28/2023]
Abstract
Pancreatic cancer (PC) is very deadly and difficult to treat. The presence of hypoxia has been shown to increase the probability of cancer developing and spreading. Pancreatic ductal adenocarcinoma (PDAC/PC) has traditionally viewed a highly lethal form of cancer due to its high occurrence of early metastases. Desmoplasia/stroma is often thick and collagenous, with pancreatic stellate cells as the primary source (PSCs). Cancer cells and other stromal cells interact with PSCs, promoting disease development. The hepatocyte growth factor (HGF)/c-MET pathway have been proposed as a growth factor mechanism mediating this interaction. Human growth factor (HGF) is secreted by pancreatic stellate cells (PSCs), and its receptor, c-MET, is generated by pancreatic cancer cells and endothelial cells. Hypoxia is frequent in malignant tumors, particularly pancreatic (PC). Hypoxia results from limitless tumor development and promotes survival, progression, and invasion. Hypoxic is becoming a critical driver and therapeutic target of pancreatic cancer as its hypoxia microenvironment is defined. Recent breakthroughs in cancer biology show that hypoxia promotes tumor proliferation, aggressiveness, and therapeutic resistance. Hypoxia-inducible factors (HIFs) stabilize hypoxia signaling. Hypoxia cMet is a key component of pancreatic tumor microenvironments, which also have a fibrotic response, that hypoxia, promotes and modulates. c-Met is a tyrosine-protein kinase. As describe it simply, the MET gene in humans' codes for a protein called hepatocyte growth factor receptor (HGFR). Most cancerous tumors and pancreatic cancer in particular, suffer from a lack of oxygen (PC). Due to unrestrained tumor development, hypoxia develops, actively contributing to tumor survival, progression, and invasion. As the processes by which hypoxia signaling promotes invasion and metastasis become clear, c-MET has emerged as an important determinant of pancreatic cancer malignancy and a potential pharmacological target. This manuscript provides the most current findings on the role of hypoxia and HGF/c-MET expression in the treatment of pancreatic cancer.
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6
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Yan W, Steele NG, Kemp SB, Menjivar RE, Du W, Carpenter ES, Donahue KL, Brown KL, Irizarry-Negron V, Yang S, Burns WR, Zhang Y, di Magliano MP, Bednar F. Notch signaling regulates immunosuppressive tumor-associated macrophage function in pancreatic cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.11.523584. [PMID: 36711890 PMCID: PMC9882066 DOI: 10.1101/2023.01.11.523584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDA) continues to have a dismal prognosis. The poor survival of patients with PDA has been attributed to a high rate of early metastasis and low efficacy of current therapies, which partly result from its complex immunosuppressive tumor microenvironment. Previous studies from our group and others have shown that tumor-associated macrophages (TAMs) are instrumental in maintaining immunosuppression in PDA. Here, we explored the role of Notch signaling, a key regulator of immune response, within the PDA microenvironment. We identified Notch pathway components in multiple immune cell types within human and mouse pancreatic cancer. TAMs, the most abundant immune cell population in the tumor microenvironment, express high levels of Notch receptors with cognate ligands such as JAG1 expressed on tumor epithelial cells, endothelial cells and fibroblasts. TAMs with activated Notch signaling expressed higher levels of immunosuppressive mediators including arginase 1 (Arg1) suggesting that Notch signaling plays a role in macrophage polarization within the PDA microenvironment. Combination of Notch inhibition with PD-1 blockade resulted in increased cytotoxic T cell infiltration, tumor cell apoptosis, and smaller tumor size. Our work implicates macrophage Notch signaling in the establishment of immunosuppression and indicates that targeting the Notch pathway may improve the efficacy of immune-based therapies in PDA patients.
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Affiliation(s)
- Wei Yan
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
| | - Nina G. Steele
- Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Samantha B. Kemp
- Molecular and Cellular Pathology Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA
| | - Rosa E. Menjivar
- Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Wenting Du
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
| | - Eileen S. Carpenter
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor Ml 48109, USA
| | - Katelyn L. Donahue
- Cancer Biology Program, University of Michigan, Ann Arbor, MI 48109, USA
| | - Kristee L. Brown
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
| | | | - Sion Yang
- College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, MI 48109, USA
| | - William R. Burns
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
| | - Yaqing Zhang
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
| | - Marina Pasca di Magliano
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
- Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
| | - Filip Bednar
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
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Chung WC, Xu K. Notch signaling pathway in pancreatic tumorigenesis. Adv Cancer Res 2023. [DOI: 10.1016/bs.acr.2023.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/04/2023]
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Blaauboer A, Van Koetsveld PM, Mustafa DAM, Dumas J, Dogan F, Van Zwienen S, Van Eijck CHJ, Hofland LJ. Immunomodulatory antitumor effect of interferon‑beta combined with gemcitabine in pancreatic cancer. Int J Oncol 2022; 61:97. [PMID: 35795999 DOI: 10.3892/ijo.2022.5387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Accepted: 04/06/2022] [Indexed: 11/06/2022] Open
Abstract
Resistance to gemcitabine is common and critically limits its therapeutic efficacy in patients with pancreatic cancer. Interferon‑beta (IFN‑β) induces numerous antitumor effects and synergizes with gemcitabine treatment. The immunomodulatory effects of this treatment regimen have not yet been described. In the present study, the antitumor effect of IFN‑β combined with gemcitabine was investigated in immune competent mice. Mouse KPC3 cells were used in all experiments. Treatment effects were determined with cell proliferation assay. Reverse transcription‑quantitative PCR was used to measure gene expression. For in vivo experiments, cells were subcutaneously injected in immune competent mice. For immune profiling, NanoString analysis was performed on tumor samples of treated and untreated mice. Baseline expression of Ifnar‑1 and Ifnar‑2c in KPC3 cells was 1.42±0.16 and 1.50±0.17, respectively. IC50 value of IFN‑β on cell growth was high (>1,000 IU/ml). IFN‑β pre‑treatment increased the in vitro response to gemcitabine (1.3‑fold decrease in EC50; P<0.001). In vivo, tumor size was not statistically significant smaller in mice treated with IFN‑β plus gemcitabine (707±92 mm3 vs. 1,239±338 mm3 in vehicle‑treated mice; P=0.16). IFN‑β alone upregulated expression of numerous immune‑related genes. This effect was less pronounced when combined with gemcitabine. For the first time, to the best of our knowledge, the immunomodulatory effects of IFN‑β, alone and combined with gemcitabine, in pancreatic cancer were reported. Prognostic markers for predicting effective responses to IFN‑β therapy are urgently needed.
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Affiliation(s)
- Amber Blaauboer
- Department of Surgery, Erasmus Medical Center, 3015 CN Rotterdam, The Netherlands
| | - Peter M Van Koetsveld
- Department of Internal Medicine, Division of Endocrinology, Erasmus Medical Center, 3015 CN Rotterdam, The Netherlands
| | - Dana A M Mustafa
- Department of Pathology, The Tumor Immuno‑Pathology Laboratory, Erasmus Medical Center, 3015 CN Rotterdam, The Netherlands
| | - Jasper Dumas
- Department of Pathology, The Tumor Immuno‑Pathology Laboratory, Erasmus Medical Center, 3015 CN Rotterdam, The Netherlands
| | - Fadime Dogan
- Department of Internal Medicine, Division of Endocrinology, Erasmus Medical Center, 3015 CN Rotterdam, The Netherlands
| | - Suzanne Van Zwienen
- Department of Internal Medicine, Division of Endocrinology, Erasmus Medical Center, 3015 CN Rotterdam, The Netherlands
| | - Casper H J Van Eijck
- Department of Surgery, Erasmus Medical Center, 3015 CN Rotterdam, The Netherlands
| | - Leo J Hofland
- Department of Internal Medicine, Division of Endocrinology, Erasmus Medical Center, 3015 CN Rotterdam, The Netherlands
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9
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Notch signaling pathway: architecture, disease, and therapeutics. Signal Transduct Target Ther 2022; 7:95. [PMID: 35332121 PMCID: PMC8948217 DOI: 10.1038/s41392-022-00934-y] [Citation(s) in RCA: 529] [Impact Index Per Article: 176.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 02/16/2022] [Accepted: 02/16/2022] [Indexed: 02/07/2023] Open
Abstract
The NOTCH gene was identified approximately 110 years ago. Classical studies have revealed that NOTCH signaling is an evolutionarily conserved pathway. NOTCH receptors undergo three cleavages and translocate into the nucleus to regulate the transcription of target genes. NOTCH signaling deeply participates in the development and homeostasis of multiple tissues and organs, the aberration of which results in cancerous and noncancerous diseases. However, recent studies indicate that the outcomes of NOTCH signaling are changeable and highly dependent on context. In terms of cancers, NOTCH signaling can both promote and inhibit tumor development in various types of cancer. The overall performance of NOTCH-targeted therapies in clinical trials has failed to meet expectations. Additionally, NOTCH mutation has been proposed as a predictive biomarker for immune checkpoint blockade therapy in many cancers. Collectively, the NOTCH pathway needs to be integrally assessed with new perspectives to inspire discoveries and applications. In this review, we focus on both classical and the latest findings related to NOTCH signaling to illustrate the history, architecture, regulatory mechanisms, contributions to physiological development, related diseases, and therapeutic applications of the NOTCH pathway. The contributions of NOTCH signaling to the tumor immune microenvironment and cancer immunotherapy are also highlighted. We hope this review will help not only beginners but also experts to systematically and thoroughly understand the NOTCH signaling pathway.
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Selvanesan BC, Chandra D, Quispe-Tintaya W, Jahangir A, Patel A, Meena K, Alves Da Silva RA, Friedman M, Gabor L, Khouri O, Libutti SK, Yuan Z, Li J, Siddiqui S, Beck A, Tesfa L, Koba W, Chuy J, McAuliffe JC, Jafari R, Entenberg D, Wang Y, Condeelis J, DesMarais V, Balachandran V, Zhang X, Lin K, Gravekamp C. Listeria delivers tetanus toxoid protein to pancreatic tumors and induces cancer cell death in mice. Sci Transl Med 2022; 14:eabc1600. [PMID: 35320003 PMCID: PMC9031812 DOI: 10.1126/scitranslmed.abc1600] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease. Tumors are poorly immunogenic and immunosuppressive, preventing T cell activation in the tumor microenvironment. Here, we present a microbial-based immunotherapeutic treatment for selective delivery of an immunogenic tetanus toxoid protein (TT856-1313) into PDAC tumor cells by attenuated Listeria monocytogenes. This treatment reactivated preexisting TT-specific memory T cells to kill infected tumor cells in mice. Treatment of KrasG12D,p53R172H, Pdx1-Cre (KPC) mice with Listeria-TT resulted in TT accumulation inside tumor cells, attraction of TT-specific memory CD4 T cells to the tumor microenvironment, and production of perforin and granzyme B in tumors. Low doses of gemcitabine (GEM) increased immune effects of Listeria-TT, turning immunologically cold into hot tumors in mice. In vivo depletion of T cells from Listeria-TT + GEM-treated mice demonstrated a CD4 T cell-mediated reduction in tumor burden. CD4 T cells from TT-vaccinated mice were able to kill TT-expressing Panc-02 tumor cells in vitro. In addition, peritumoral lymph node-like structures were observed in close contact with pancreatic tumors in KPC mice treated with Listeria-TT or Listeria-TT + GEM. These structures displayed CD4 and CD8 T cells producing perforin and granzyme B. Whereas CD4 T cells efficiently infiltrated the KPC tumors, CD8 T cells did not. Listeria-TT + GEM treatment of KPC mice with advanced PDAC reduced tumor burden by 80% and metastases by 87% after treatment and increased survival by 40% compared to nontreated mice. These results suggest that Listeria-delivered recall antigens could be an alternative to neoantigen-mediated cancer immunotherapy.
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Affiliation(s)
- Benson Chellakkan Selvanesan
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Forchheimer Building, 1300 Morris Park Avenue, Bronx, NY 10461, USA
| | - Dinesh Chandra
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Forchheimer Building, 1300 Morris Park Avenue, Bronx, NY 10461, USA
| | - Wilber Quispe-Tintaya
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Forchheimer Building, 1300 Morris Park Avenue, Bronx, NY 10461, USA
| | - Arthee Jahangir
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Forchheimer Building, 1300 Morris Park Avenue, Bronx, NY 10461, USA
| | - Ankur Patel
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Forchheimer Building, 1300 Morris Park Avenue, Bronx, NY 10461, USA
| | - Kiran Meena
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Forchheimer Building, 1300 Morris Park Avenue, Bronx, NY 10461, USA
| | - Rodrigo Alberto Alves Da Silva
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Forchheimer Building, 1300 Morris Park Avenue, Bronx, NY 10461, USA
| | - Madeline Friedman
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Forchheimer Building, 1300 Morris Park Avenue, Bronx, NY 10461, USA
| | - Lisa Gabor
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Forchheimer Building, 1300 Morris Park Avenue, Bronx, NY 10461, USA
- Division of Gynecologic Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, 1695 Eastchester Road, Bronx, NY 10461, USA
| | - Olivia Khouri
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Forchheimer Building, 1300 Morris Park Avenue, Bronx, NY 10461, USA
- Division of Gynecologic Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, 1695 Eastchester Road, Bronx, NY 10461, USA
| | - Steven K. Libutti
- Rutgers University, Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08854, USA
| | - Ziqiang Yuan
- Rutgers University, Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08854, USA
| | - Jenny Li
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Forchheimer Building, 1300 Morris Park Avenue, Bronx, NY 10461, USA
| | - Sarah Siddiqui
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Forchheimer Building, 1300 Morris Park Avenue, Bronx, NY 10461, USA
| | - Amanda Beck
- Department of Pathology, Albert Einstein College of Medicine, Michael F. Price Center, 1301 Morris Park Avenue, Room 158, Bronx, NY 10461, USA
| | - Lydia Tesfa
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Jack and Pearl Resnick Campus, 1300 Morris Park Avenue, Chanin Building, Room 309, Bronx, NY 10461, USA
| | - Wade Koba
- Department of Radiology, Albert Einstein College of Medicine, MRRC, 1300 Morris Park Avenue, Bronx, NY 10461, USA
| | - Jennifer Chuy
- Department of Medical Oncology, Montefiore/Einstein Center for Cancer Care, 1695 Eastchester Road, 2nd Floor, Bronx, NY 10461, USA
| | - John C. McAuliffe
- Department of Surgery, Montefiore Medical Center, 1521 Jarrett Place, 2nd Floor, Bronx, NY 10461, USA
| | - Rojin Jafari
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Michael F. Price Center, 1301 Morris Park Avenue, Bronx, NY 10461, USA
| | - David Entenberg
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Michael F. Price Center, 1301 Morris Park Avenue, Bronx, NY 10461, USA
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Michael F. Price Center, 1301 Morris Park Avenue, Bronx, NY 10461, USA
- Integrated Imaging Program, Albert Einstein College of Medicine, Michael F. Price Center, 1301 Morris Park Avenue, Bronx, NY 10461, USA
| | - Yarong Wang
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Michael F. Price Center, 1301 Morris Park Avenue, Bronx, NY 10461, USA
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Michael F. Price Center, 1301 Morris Park Avenue, Bronx, NY 10461, USA
- Integrated Imaging Program, Albert Einstein College of Medicine, Michael F. Price Center, 1301 Morris Park Avenue, Bronx, NY 10461, USA
| | - John Condeelis
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Michael F. Price Center, 1301 Morris Park Avenue, Bronx, NY 10461, USA
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Michael F. Price Center, 1301 Morris Park Avenue, Bronx, NY 10461, USA
- Integrated Imaging Program, Albert Einstein College of Medicine, Michael F. Price Center, 1301 Morris Park Avenue, Bronx, NY 10461, USA
| | - Vera DesMarais
- Department of Anatomy and Structural Biology, Analytical Imaging Facility, Albert Einstein College of Medicine, 1300 Morris Park Ave, Room F641, Bronx, NY 10461, USA
| | - Vinod Balachandran
- Departments of Hepatopancreatobiliary Service and Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
| | - Xusheng Zhang
- Computational Genomics Core, Albert Einstein College of Medicine, Michael F. Price Center, 1301 Morris Park Avenue, Bronx, NY 10461, USA
| | - Ken Lin
- Division of Gynecologic Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, 1695 Eastchester Road, Bronx, NY 10461, USA
| | - Claudia Gravekamp
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Forchheimer Building, 1300 Morris Park Avenue, Bronx, NY 10461, USA
- Corresponding author.
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11
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The Class I HDAC Inhibitor Valproic Acid Strongly Potentiates Gemcitabine Efficacy in Pancreatic Cancer by Immune System Activation. Biomedicines 2022; 10:biomedicines10030517. [PMID: 35327319 PMCID: PMC8945828 DOI: 10.3390/biomedicines10030517] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 01/26/2022] [Accepted: 02/16/2022] [Indexed: 01/01/2023] Open
Abstract
Background: Gemcitabine efficacy in pancreatic cancer is often impaired due to limited intracellular uptake and metabolic activation. Epi-drugs target gene expression patterns and represent a promising approach to reverse chemoresistance. In this study, we investigate the chemosensitizing effect of different epi-drugs when combined with gemcitabine in pancreatic cancer. Methods: Mouse KPC3 cells were used for all experiments. Five different epi-drugs were selected for combination therapy: 5-aza-2′-deoxycytidine, hydralazine, mocetinostat, panobinostat, and valproic acid (VPA). Treatment effects were determined by cell proliferation and colony forming assays. Expression of genes were assessed by real-time quantitative PCR. The most promising epi-drug for combination therapy was studied in immune competent mice. Intratumor changes were defined using NanoString PanCancer panel IO360. Results: All epi-drugs, except hydralazine, potentiated the gemcitabine response in KPC3 cells (range decrease IC50 value 1.7−2-fold; p < 0.001). On colony formation, the cytotoxic effect of 0.5 ng/mL gemcitabine was 1.4 to 6.3 times stronger (p < 0.01). Two out of three drug-transporter genes were strongly upregulated following epi-drug treatment (a range fold increase of 17−124 and 9−60 for Slc28a1 and Slc28a3, respectively; all p < 0.001). VPA combined with gemcitabine significantly reduced tumor size with 74% compared to vehicle-treated mice and upregulated expression of immune-related pathways (range pathway score 0.86−1.3). Conclusions: These results provide a strong rationale for combining gemcitabine with VPA treatment. For the first time, we present intratumor changes and show activation of the immune system. Clinical trials are warranted to assess efficacy and safety of this novel combination in pancreatic cancer patients.
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12
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Hyun J, Lee M, Rehman J, Pajcini KV, Malik AB. Notch1 promotes ordered revascularization through Semaphorin 3g modulation of downstream vascular patterning signalling factors. J Physiol 2022; 600:509-530. [PMID: 34921404 PMCID: PMC9305962 DOI: 10.1113/jp282286] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Accepted: 11/29/2021] [Indexed: 11/12/2022] Open
Abstract
Here we genetically and functionally addressed potential pathways of Notch signalling in mediating vascular regeneration in mouse models. We first used transgenic adult mice with either gain- or loss-of-function Notch signalling in vascular endothelial cells and monitored perfusion in the hindlimb following ischaemia induced by femoral artery ligation. Mice deficient in Notch signalling showed defective perfusion recovery and expansion of collateral arteries. Transcriptomics analysis of arterial endothelial cells in the Notch mutants identified the guidance factor Sema3g as a candidate gene mediating reperfusion downstream of Notch. Studies in the retinal circulation showed the central role of SEMA3G downstream of Notch signalling in the orderly regulation of vascular patterning. These studies in multiple vascular beds show the primacy of Notch signalling and downstream generation of guidance peptides such as SEMA3G in promoting well-ordered vascular regeneration. KEY POINTS: Notch signalling is a critical mediator of revascularization. Yet the cellular processes activated during recovery following vascular injury are incompletely understood. Here we used genetic and cellular approaches in two different vascular beds and cultured endothelial cells to address the generalizability of mechanisms. By utilizing a highly reproducible murine model of hindlimb ischaemia in transgenic mice in which Notch signalling was inhibited at the transcriptional level, we demonstrated the centrality of Notch signalling in perfusion recovery and revascularization. RNA-sequencing of Notch mutants identified class 3 Semaphorins regulated by Notch signalling as downstream targets. Studies in retinal vessels and endothelial cells showed an essential role of guidance peptide Sema3g as a modulator of angiogenesis and orderly vascular patterning. The Notch to Sema3g signalling axis functions as a feedback mechanism to sculpt the growing vasculature in multiple beds.
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Affiliation(s)
- James Hyun
- Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, IL, USA
| | - Monica Lee
- Department of Physiology and Biophysics, University of Illinois College of Medicine, Chicago, IL, USA
| | - Jalees Rehman
- Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, IL, USA
| | - Kostandin V Pajcini
- Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, IL, USA
| | - Asrar B Malik
- Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, IL, USA
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13
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Zhdanovskaya N, Firrincieli M, Lazzari S, Pace E, Scribani Rossi P, Felli MP, Talora C, Screpanti I, Palermo R. Targeting Notch to Maximize Chemotherapeutic Benefits: Rationale, Advanced Strategies, and Future Perspectives. Cancers (Basel) 2021; 13:cancers13205106. [PMID: 34680255 PMCID: PMC8533696 DOI: 10.3390/cancers13205106] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/03/2021] [Accepted: 10/06/2021] [Indexed: 12/15/2022] Open
Abstract
Simple Summary The Notch signaling pathway regulates cell proliferation, apoptosis, stem cell self-renewal, and differentiation in a context-dependent fashion both during embryonic development and in adult tissue homeostasis. Consistent with its pleiotropic physiological role, unproper activation of the signaling promotes or counteracts tumor pathogenesis and therapy response in distinct tissues. In the last twenty years, a wide number of studies have highlighted the anti-cancer potential of Notch-modulating agents as single treatment and in combination with the existent therapies. However, most of these strategies have failed in the clinical exploration due to dose-limiting toxicity and low efficacy, encouraging the development of novel agents and the design of more appropriate combinations between Notch signaling inhibitors and chemotherapeutic drugs with improved safety and effectiveness for distinct types of cancer. Abstract Notch signaling guides cell fate decisions by affecting proliferation, apoptosis, stem cell self-renewal, and differentiation depending on cell and tissue context. Given its multifaceted function during tissue development, both overactivation and loss of Notch signaling have been linked to tumorigenesis in ways that are either oncogenic or oncosuppressive, but always context-dependent. Notch signaling is critical for several mechanisms of chemoresistance including cancer stem cell maintenance, epithelial-mesenchymal transition, tumor-stroma interaction, and malignant neovascularization that makes its targeting an appealing strategy against tumor growth and recurrence. During the last decades, numerous Notch-interfering agents have been developed, and the abundant preclinical evidence has been transformed in orphan drug approval for few rare diseases. However, the majority of Notch-dependent malignancies remain untargeted, even if the application of Notch inhibitors alone or in combination with common chemotherapeutic drugs is being evaluated in clinical trials. The modest clinical success of current Notch-targeting strategies is mostly due to their limited efficacy and severe on-target toxicity in Notch-controlled healthy tissues. Here, we review the available preclinical and clinical evidence on combinatorial treatment between different Notch signaling inhibitors and existent chemotherapeutic drugs, providing a comprehensive picture of molecular mechanisms explaining the potential or lacking success of these combinations.
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Affiliation(s)
- Nadezda Zhdanovskaya
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
| | - Mariarosaria Firrincieli
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
- Center for Life Nano Science, Istituto Italiano di Tecnologia, 00161 Rome, Italy
| | - Sara Lazzari
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
| | - Eleonora Pace
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
| | - Pietro Scribani Rossi
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
| | - Maria Pia Felli
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy;
| | - Claudio Talora
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
| | - Isabella Screpanti
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
- Correspondence: (I.S.); (R.P.)
| | - Rocco Palermo
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
- Center for Life Nano Science, Istituto Italiano di Tecnologia, 00161 Rome, Italy
- Correspondence: (I.S.); (R.P.)
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14
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KalantarMotamedi Y, Choi RJ, Koh SB, Bramhall JL, Fan TP, Bender A. Prediction and identification of synergistic compound combinations against pancreatic cancer cells. iScience 2021; 24:103080. [PMID: 34585118 PMCID: PMC8456050 DOI: 10.1016/j.isci.2021.103080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 07/28/2021] [Accepted: 08/31/2021] [Indexed: 11/30/2022] Open
Abstract
Resistance to current therapies is common for pancreatic cancer and hence novel treatment options are urgently needed. In this work, we developed and validated a computational method to select synergistic compound combinations based on transcriptomic profiles from both the disease and compound side, combined with a pathway scoring system, which was then validated prospectively by testing 30 compounds (and their combinations) on PANC-1 cells. Some compounds selected as single agents showed lower GI50 values than the standard of care, gemcitabine. Compounds suggested as combination agents with standard therapy gemcitabine based on the best performing scoring system showed on average 2.82-5.18 times higher synergies compared to compounds that were predicted to be active as single agents. Examples of highly synergistic in vitro validated compound pairs include gemcitabine combined with Entinostat, thioridazine, loperamide, scriptaid and Saracatinib. Hence, the computational approach presented here was able to identify synergistic compound combinations against pancreatic cancer cells.
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Affiliation(s)
- Yasaman KalantarMotamedi
- Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
| | - Ran Joo Choi
- Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
| | - Siang-Boon Koh
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK
| | - Jo L. Bramhall
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK
| | - Tai-Ping Fan
- Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK
| | - Andreas Bender
- Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
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15
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Alzhrani R, Alsaab HO, Vanamal K, Bhise K, Tatiparti K, Barari A, Sau S, Iyer AK. Overcoming the Tumor Microenvironmental Barriers of Pancreatic Ductal Adenocarcinomas for Achieving Better Treatment Outcomes. ADVANCED THERAPEUTICS 2021; 4:2000262. [PMID: 34212073 PMCID: PMC8240487 DOI: 10.1002/adtp.202000262] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Indexed: 02/06/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with the lowest survival rate among all solid tumors. The lethality of PDAC arises from late detection and propensity of the tumor to metastasize and develop resistance against chemo and radiation therapy. A highly complex tumor microenvironment composed of dense stroma, immune cells, fibroblast, and disorganized blood vessels, is the main obstacle to current PDAC therapy. Despite the tremendous success of immune checkpoint inhibitors (ICIs) in cancers, PDAC remains one of the poorest responders of ICIs therapy. The immunologically "cold" phenotype of PDAC is attributed to the low mutational burden, high infiltration of myeloid-derived suppressor cells and T-regs, contributing to a significant immunotherapy resistance mechanism. Thus, the development of innovative strategies for turning immunologically "cold" tumor into "hot" ones is an unmet need to improve the outcome of PDAC ICIs therapies. Other smart strategies, such as nanomedicines, sonic Hedgehog inhibitor, or smoothened inhibitor, are discussed to enhance chemotherapeutic agents' efficiency by disrupting the PDAC stroma. This review highlights the current challenges and various preclinical and clinical strategies to overcome current PDAC therapy difficulties, thus significantly advancing PDAC research knowledge.
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Affiliation(s)
- Rami Alzhrani
- Use-Inspired Biomaterials and Integrated Nano Delivery Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit 48201, United States
- Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, Taif University, Taif 21944, Saudi Arabia
| | - Hashem O. Alsaab
- Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, Taif University, Taif 21944, Saudi Arabia
| | - Kushal Vanamal
- Use-Inspired Biomaterials and Integrated Nano Delivery Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit 48201, United States
| | - Ketki Bhise
- Use-Inspired Biomaterials and Integrated Nano Delivery Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit 48201, United States
| | - Katyayani Tatiparti
- Use-Inspired Biomaterials and Integrated Nano Delivery Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit 48201, United States
| | - Ayatakshi Barari
- Use-Inspired Biomaterials and Integrated Nano Delivery Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit 48201, United States
| | - Samaresh Sau
- Use-Inspired Biomaterials and Integrated Nano Delivery Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit 48201, United States
| | - Arun K. Iyer
- Use-Inspired Biomaterials and Integrated Nano Delivery Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit 48201, United States
- Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, MI, United States
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16
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Orzechowska M, Anusewicz D, Bednarek AK. Functional Gene Expression Differentiation of the Notch Signaling Pathway in Female Reproductive Tract Tissues-A Comprehensive Review With Analysis. Front Cell Dev Biol 2021; 8:592616. [PMID: 33384996 PMCID: PMC7770115 DOI: 10.3389/fcell.2020.592616] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 11/11/2020] [Indexed: 12/13/2022] Open
Abstract
The Notch pathway involves evolutionarily conserved signaling regulating the development of the female tract organs such as breast, ovary, cervix, and uterine endometrium. A great number of studies revealed Notch aberrancies in association with their carcinogenesis and disease progression, the management of which is still challenging. The present study is a comprehensive review of the available literature on Notch signaling during the normal development and carcinogenesis of the female tract organs. The review has been enriched with our analyses of the TCGA data including breast, cervical, ovarian, and endometrial carcinomas concerning the effects of Notch signaling at two levels: the core components and downstream effectors, hence filling the lack of global overview of Notch-driven carcinogenesis and disease progression. Phenotype heterogeneity regarding Notch signaling was projected in two uniform manifold approximation and projection algorithm dimensions, preceded by the principal component analysis step reducing the data burden. Additionally, overall and disease-free survival analyses were performed with the optimal cutpoint determination by Evaluate Cutpoints software to establish the character of particular Notch components in tumorigenesis. In addition to the review, we demonstrated separate models of the examined cancers of the Notch pathway and its targets, although expression profiles of all normal tissues were much more similar to each other than to its cancerous compartments. Such Notch-driven cancerous differentiation resulted in a case of opposite association with DFS and OS. As a consequence, target genes also show very distinct profiles including genes associated with cell proliferation and differentiation, energy metabolism, or the EMT. In conclusion, the observed Notch associations with the female tract malignancies resulted from differential expression of target genes. This may influence a future analysis to search for new therapeutic targets based on specific Notch pathway profiles.
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Affiliation(s)
| | - Dorota Anusewicz
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz, Poland
| | - Andrzej K Bednarek
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz, Poland
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17
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Li KY, Yuan JL, Trafton D, Wang JX, Niu N, Yuan CH, Liu XB, Zheng L. Pancreatic ductal adenocarcinoma immune microenvironment and immunotherapy prospects. Chronic Dis Transl Med 2020; 6:6-17. [PMID: 32226930 PMCID: PMC7096327 DOI: 10.1016/j.cdtm.2020.01.002] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Indexed: 02/08/2023] Open
Abstract
The tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) is non-immunogenic, which consists of the stellate cells, fibroblasts, immune cells, extracellular matrix, and some other immune suppressive molecules. This low tumor perfusion microenvironment with physical dense fibrotic stroma shields PDAC from traditional antitumor therapies like chemotherapy and various strategies that have been proven successful in other types of cancer. Immunotherapy has the potential to treat minimal and residual diseases and prevent recurrence with minimal toxicity, and studies in patients with metastatic and nonresectable disease have shown some efficacy. In this review, we highlighted the main components of the pancreatic tumor microenvironment, and meanwhile, summarized the advances of some promising immunotherapies for PDAC, including checkpoint inhibitors, chimeric antigen receptors T cells, and cancer vaccines. Based on our previous researches, we specifically discussed how granulocyte-macrophage colony stimulating factor based pancreatic cancer vaccine prime the pancreatic tumor microenvironment, and introduced some novel immunoadjuvants, like the stimulator of interferon genes.
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Affiliation(s)
- Ke-Yu Li
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Department of Oncology, Sidney Kimmel Cancer Center at Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
| | - Jia-Long Yuan
- School of Basic Medical Science, Capital Medical University, Beijing 100069, China
| | - Diego Trafton
- Department of Oncology, Sidney Kimmel Cancer Center at Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
| | - Jian-Xin Wang
- Department of Oncology, Sidney Kimmel Cancer Center at Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
- Department of Hepatic-biliary-pancreatic Surgery, First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310000, China
| | - Nan Niu
- Department of Oncology, Sidney Kimmel Cancer Center at Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
- Department of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, China
| | - Chun-Hui Yuan
- Department of General Surgery, Peking University Third Hospital, Beijing 100191, China
| | - Xu-Bao Liu
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Lei Zheng
- Department of Oncology, Sidney Kimmel Cancer Center at Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
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18
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Shaping of the Tumor Microenvironment by Notch Signaling. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1223:1-16. [PMID: 32030682 DOI: 10.1007/978-3-030-35582-1_1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The tumor microenvironment (TME) has become a major concern of cancer research both from a basic and a therapeutic point of view. Understanding the effect of a signaling pathway-and thus the effect of its targeting-in every aspect of the microenvironment is a prerequisite to predict and analyze the effect of a therapy. The Notch signaling pathway is involved in every component of the TME as well as in the interaction between the different parts of the TME. This review aims at describing how Notch signaling is impacting the TME and the consequences this may have when modulating Notch signaling in a therapeutic perspective.
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19
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Wang WQ, Liu L, Xu JZ, Yu XJ. Reflections on depletion of tumor stroma in pancreatic cancer. Biochim Biophys Acta Rev Cancer 2019; 1871:267-272. [PMID: 30738097 DOI: 10.1016/j.bbcan.2019.01.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Revised: 01/21/2019] [Accepted: 01/22/2019] [Indexed: 12/18/2022]
Abstract
Pancreatic cancer characteristically has an extremely dense stroma, which facilitates chemoresistance by creating physical and biological barriers to therapeutic agents. Thus, stroma-depleting agents may enhance the delivery and efficacy of chemotherapy drugs. However, stroma-targeting therapy for pancreatic cancer is a double-edged sword, as the stroma can also inhibit tumor metastasis and malignancy. In-depth understanding of the critical role of the stroma in cancer metastasis may improve therapeutic approaches by allowing them to harness specific features of the stroma to treat pancreatic cancer.
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Affiliation(s)
- Wen-Quan Wang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, Shanghai, China; Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Liang Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, Shanghai, China; Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Jin-Zhi Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, Shanghai, China; Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xian-Jun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, Shanghai, China; Pancreatic Cancer Institute, Fudan University, Shanghai, China.
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20
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Meurette O, Mehlen P. Notch Signaling in the Tumor Microenvironment. Cancer Cell 2018; 34:536-548. [PMID: 30146333 DOI: 10.1016/j.ccell.2018.07.009] [Citation(s) in RCA: 463] [Impact Index Per Article: 66.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Revised: 04/30/2018] [Accepted: 07/24/2018] [Indexed: 12/18/2022]
Abstract
The Notch signaling pathway regulates many aspects of cancer biology. Most attention has been given to its role in the transformed cell. However, it is now clear that cancer progression and metastasis depend on the bidirectional interactions between cancer cells and their environment, forming the tumor microenvironment (TME). These interactions are mediated and constantly evolve through paracrine and juxtacrine signaling. In this review, we discuss how Notch signaling takes an important part in regulating the crosstalk between the different compartments of the TME. We also address the consequences of the Notch-TME involvement from a therapeutic perspective.
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Affiliation(s)
- Olivier Meurette
- Apoptosis, Cancer and Development Laboratory- Equipe Labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France.
| | - Patrick Mehlen
- Apoptosis, Cancer and Development Laboratory- Equipe Labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France
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21
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Giaimo BD, Borggrefe T. Introduction to Molecular Mechanisms in Notch Signal Transduction and Disease Pathogenesis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1066:3-30. [DOI: 10.1007/978-3-319-89512-3_1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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22
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Yu X, Kogan S, Chen Y, Tsang AT, Withers T, Lin H, Gilleran J, Buckley B, Moore D, Bertino J, Chan C, Kimball SD, Loh SN, Carpizo DR. Zinc Metallochaperones Reactivate Mutant p53 Using an ON/OFF Switch Mechanism: A New Paradigm in Cancer Therapeutics. Clin Cancer Res 2018; 24:4505-4517. [PMID: 29914895 DOI: 10.1158/1078-0432.ccr-18-0822] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Revised: 05/17/2018] [Accepted: 06/04/2018] [Indexed: 01/04/2023]
Abstract
Purpose: Zinc metallochaperones (ZMC) are a new class of anticancer drugs that reactivate zinc-deficient mutant p53 by raising and buffering intracellular zinc levels sufficiently to restore zinc binding. In vitro pharmacodynamics of ZMCs indicate that p53-mutant activity is ON by 4-6 hours and is OFF by 24. We sought to understand the mechanism of this regulation and to translate these findings preclinically. We further sought to innovate the formulation of ZMCs to improve efficacy.Experimental Design: We performed in vitro mechanistic studies to determine the role of cellular zinc homeostatic mechanisms in the transient pharmacodynamics of ZMCs. We conducted preclinical pharmacokinetic, pharmacodynamic, and efficacy studies using a genetically engineered murine pancreatic cancer model (KPC) to translate these mechanistic findings and investigate a novel ZMC formulation.Results:In vitro, cellular zinc homeostatic mechanisms that restore zinc to its physiologic levels function as the OFF switch in ZMC pharmacodynamics. In vivo pharmacokinetic studies indicate that ZMCs have a short half-life (< 30 minutes), which is sufficient to significantly improve survival in mice expressing a zinc-deficient allele (p53R172H) while having no effect in mice expressing a non-zinc-deficient allele (p53R270H). We synthesized a novel formulation of the drug in complex with zinc and demonstrate this significantly improves survival over ZMC1.Conclusions: Cellular zinc homeostatic mechanisms function as an OFF switch in ZMC pharmacodynamics, indicating that a brief period of p53-mutant reactivation is sufficient for on-target efficacy. ZMCs synthesized in complex with zinc are an improved formulation. Clin Cancer Res; 24(18); 4505-17. ©2018 AACR.
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Affiliation(s)
- Xin Yu
- Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey.,Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey
| | - Samuel Kogan
- Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey.,Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.,Department of Pharmacology, Rutgers University, Piscataway, New Jersey
| | - Ying Chen
- Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey
| | - Ashley T Tsang
- Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey.,Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.,Mount Sinai St. Luke's Roosevelt General Surgery Residency Program, New York, New York
| | - Tracy Withers
- Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey.,Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey
| | - Hongxia Lin
- Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey
| | - John Gilleran
- Department of Medicinal Chemistry, Rutgers Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey
| | - Brian Buckley
- Rutgers Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, New Jersey
| | - Dirk Moore
- Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.,Department of Biostatistics. Rutgers School of Public Health, Rutgers University, New Brunswick, New Jersey
| | - Joseph Bertino
- Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.,Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
| | - Chang Chan
- Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.,Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
| | - S David Kimball
- Mount Sinai St. Luke's Roosevelt General Surgery Residency Program, New York, New York.,Rutgers Translational Sciences, Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey.,Z53 Therapeutics, Inc, Holmdel, New Jersey
| | - Stewart N Loh
- Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, New York
| | - Darren R Carpizo
- Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey. .,Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.,Department of Pharmacology, Rutgers University, Piscataway, New Jersey.,Z53 Therapeutics, Inc, Holmdel, New Jersey
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23
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Cook N, Basu B, Smith DM, Gopinathan A, Evans J, Steward WP, Palmer D, Propper D, Venugopal B, Hategan M, Anthoney DA, Hampson LV, Nebozhyn M, Tuveson D, Farmer-Hall H, Turner H, McLeod R, Halford S, Jodrell D. A phase I trial of the γ-secretase inhibitor MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma. Br J Cancer 2018; 118:793-801. [PMID: 29438372 PMCID: PMC5877439 DOI: 10.1038/bjc.2017.495] [Citation(s) in RCA: 90] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Revised: 12/18/2017] [Accepted: 12/20/2017] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND The Notch pathway is frequently activated in cancer. Pathway inhibition by γ-secretase inhibitors has been shown to be effective in pre-clinical models of pancreatic cancer, in combination with gemcitabine. METHODS A multi-centre, non-randomised Bayesian adaptive design study of MK-0752, administered per os weekly, in combination with gemcitabine administered intravenously on days 1, 8 and 15 (28 day cycle) at 800 or 1000 mg m-2, was performed to determine the safety of combination treatment and the recommended phase 2 dose (RP2D). Secondary and tertiary objectives included tumour response, plasma and tumour MK-0752 concentration, and inhibition of the Notch pathway in hair follicles and tumour. RESULTS Overall, 44 eligible patients (performance status 0 or 1 with adequate organ function) received gemcitabine and MK-0752 as first or second line treatment for pancreatic cancer. RP2Ds of MK-0752 and gemcitabine as single agents could be combined safely. The Bayesian algorithm allowed further dose escalation, but pharmacokinetic analysis showed no increase in MK-0752 AUC (area under the curve) beyond 1800 mg once weekly. Tumour response evaluation was available in 19 patients; 13 achieved stable disease and 1 patient achieved a confirmed partial response. CONCLUSIONS Gemcitabine and a γ-secretase inhibitor (MK-0752) can be combined at their full, single-agent RP2Ds.
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Affiliation(s)
- Natalie Cook
- Cancer Research UK, Cambridge Research Institute, University of Cambridge Robinson Way, Cambridge CB2 0RE, UK
- Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0RE, UK
| | - Bristi Basu
- Cancer Research UK, Cambridge Research Institute, University of Cambridge Robinson Way, Cambridge CB2 0RE, UK
- Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0RE, UK
| | - Donna-Michelle Smith
- Cancer Research UK, Cambridge Research Institute, University of Cambridge Robinson Way, Cambridge CB2 0RE, UK
| | - Aarthi Gopinathan
- Cancer Research UK, Cambridge Research Institute, University of Cambridge Robinson Way, Cambridge CB2 0RE, UK
| | - Jeffry Evans
- Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow G12 0YN, United Kingdom
| | - William P Steward
- Department of Oncology, University of Leicester, Leicester LE2 7LX, UK
| | - Daniel Palmer
- Clatterbridge Cancer Centre, Clatterbridge Road, Bebington, Wirral CH63 4JY, UK
| | - David Propper
- Bart’s Cancer Institute, Queen Mary University of London EC1M 6BQ, London, UK
| | - Balaji Venugopal
- Cancer Research UK, Centre for Drug Development, Angel Building, 407 St. John Street, London EC1V 4AD, UK
| | - Mirela Hategan
- Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0RE, UK
| | - D Alan Anthoney
- St James Institute of Oncology, University of Leeds & Leeds Teaching Hospitals Trust, Leeds LS9 7TF, UK
| | - Lisa V Hampson
- Department of Mathematics and Statistics, Fylde College, Lancaster University, Lancaster LA1 4YF, UK
| | | | - David Tuveson
- Cold Spring Harbor Laboratories, Cold Spring Harbor, NY 11724, USA
| | - Hayley Farmer-Hall
- Cancer Research UK, Centre for Drug Development, Angel Building, 407 St. John Street, London EC1V 4AD, UK
| | - Helen Turner
- Cancer Research UK, Centre for Drug Development, Angel Building, 407 St. John Street, London EC1V 4AD, UK
| | - Robert McLeod
- Cancer Research UK, Centre for Drug Development, Angel Building, 407 St. John Street, London EC1V 4AD, UK
| | - Sarah Halford
- Cancer Research UK, Centre for Drug Development, Angel Building, 407 St. John Street, London EC1V 4AD, UK
| | - Duncan Jodrell
- Cancer Research UK, Cambridge Research Institute, University of Cambridge Robinson Way, Cambridge CB2 0RE, UK
- Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0RE, UK
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24
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Zhao J, Wang H, Hsiao CH, Chow DSL, Koay EJ, Kang Y, Wen X, Huang Q, Ma Y, Bankson JA, Ullrich SE, Overwijk W, Maitra A, Piwnica-Worms D, Fleming JB, Li C. Simultaneous inhibition of hedgehog signaling and tumor proliferation remodels stroma and enhances pancreatic cancer therapy. Biomaterials 2018; 159:215-228. [PMID: 29331808 PMCID: PMC6203960 DOI: 10.1016/j.biomaterials.2018.01.014] [Citation(s) in RCA: 91] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Revised: 01/08/2018] [Accepted: 01/08/2018] [Indexed: 02/07/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. It has an excessive desmoplastic stroma that can limit the intratumoral delivery of chemotherapy drugs, and protect tumor cells against radiotherapy. Therefore, both stromal and tumor compartments need to be addressed in order to effectively treat PDAC. We hereby co-deliver a sonic hedgehog inhibitor, cyclopamine (CPA), and a cytotoxic chemotherapy drug paclitaxel (PTX) with a polymeric micelle formulation (M-CPA/PTX). CPA can deplete the stroma-producing cancer-associated fibroblasts (CAFs), while PTX can inhibit tumor proliferation. Here we show that in clinically relevant PDAC models, M-CPA effectively modulates stroma by increasing microvessel density, alleviating hypoxia, reducing matrix stiffness while maintaining the tumor-restraining function of extracellular matrix. M-CPA/PTX also significantly extends animal survival by suppressing tumor growth and lowering the percentages of poorly to moderately differentiated tumor phenotypes. Our study suggests that using multifunctional nanoparticles to simultaneously target stromal and tumor compartments is a promising strategy for PDAC therapy.
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Affiliation(s)
- Jun Zhao
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Huamin Wang
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Cheng-Hui Hsiao
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77030, USA
| | - Diana S-L Chow
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77030, USA
| | - Eugene J Koay
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Yaan Kang
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Xiaoxia Wen
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Qian Huang
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Ying Ma
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - James A Bankson
- Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Stephen E Ullrich
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Willem Overwijk
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Anirban Maitra
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - David Piwnica-Worms
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Jason B Fleming
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Chun Li
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
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25
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Contemporary Management of Localized Resectable Pancreatic Cancer. Cancers (Basel) 2018; 10:cancers10010024. [PMID: 29361690 PMCID: PMC5789374 DOI: 10.3390/cancers10010024] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Revised: 01/16/2018] [Accepted: 01/18/2018] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is the third most common cause of cancer deaths in the United States. Surgical resection with negative margins still constitutes the cornerstone of potentially curative therapy, but is possible only in 15–20% of patients at the time of initial diagnosis. Accumulating evidence suggests that the neoadjuvant approach may improve R0 resection rate in localized resectable and borderline resectable diseases, and potentially downstage locally advanced disease to achieve surgical resection, though the impact on survival is to be determined. Despite advancements in the last decade in developing effective combinational chemo-radio therapeutic options, preoperative treatment strategies, and better peri-operative care, pancreatic cancer continues to carry a dismal prognosis in the majority. Prodigious efforts are currently being made in optimizing the neoadjuvant therapy with a better toxicity profile, developing novel agents, imaging techniques, and identification of biomarkers for the disease. Advancement in our understanding of the tumor microenvironment and molecular pathology is urgently needed to facilitate the development of novel targeted and immunotherapies for this setting. In this review, we detail the current literature on contemporary management of resectable, borderline resectable and locally advanced pancreatic cancer with a focus on future directions in the field.
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26
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Ruess DA, Görgülü K, Wörmann SM, Algül H. Pharmacotherapeutic Management of Pancreatic Ductal Adenocarcinoma: Current and Emerging Concepts. Drugs Aging 2017; 34:331-357. [PMID: 28349415 DOI: 10.1007/s40266-017-0453-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Pancreatic ductal adenocarcinoma is a devastating malignancy, which is the result of late diagnosis, aggressive disease, and a lack of effective treatment options. Thus, pancreatic ductal adenocarcinoma is projected to become the second leading cause of cancer-related death by 2030. This review summarizes recent developments of oncological therapy in the palliative setting of metastatic pancreatic ductal adenocarcinoma. It further compiles novel targets and therapeutic approaches as well as promising treatment combinations, which are presently in preclinical evaluation, covering several aspects of the hallmarks of cancer. Finally, challenges to the implementation of an individualized therapy approach in the context of precision medicine are discussed.
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Affiliation(s)
- Dietrich A Ruess
- Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany.
| | - Kivanc Görgülü
- Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany
| | - Sonja M Wörmann
- Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany
| | - Hana Algül
- Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany.
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27
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Lin S, Negulescu A, Bulusu S, Gibert B, Delcros JG, Ducarouge B, Rama N, Gadot N, Treilleux I, Saintigny P, Meurette O, Mehlen P. Non-canonical NOTCH3 signalling limits tumour angiogenesis. Nat Commun 2017; 8:16074. [PMID: 28719575 PMCID: PMC5520050 DOI: 10.1038/ncomms16074] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2016] [Accepted: 05/25/2017] [Indexed: 01/22/2023] Open
Abstract
Notch signalling is a causal determinant of cancer and efforts have been made to develop targeted therapies to inhibit the so-called canonical pathway. Here we describe an unexpected pro-apoptotic role of Notch3 in regulating tumour angiogenesis independently of the Notch canonical pathway. The Notch3 ligand Jagged-1 is upregulated in a fraction of human cancer and our data support the view that Jagged-1, produced by cancer cells, is inhibiting the apoptosis induced by the aberrant Notch3 expression in tumour vasculature. We thus present Notch3 as a dependence receptor inducing endothelial cell death while this pro-apoptotic activity is blocked by Jagged-1. Along this line, using Notch3 mutant mice, we demonstrate that tumour growth and angiogenesis are increased when Notch3 is silenced in the stroma. Consequently, we show that the well-documented anti-tumour effect mediated by γ-secretase inhibition is at least in part dependent on the apoptosis triggered by Notch3 in endothelial cells. Notch signalling is deregulated in several cancers; therefore, strategies targeting this pathway are currently being explored. Here the authors report a pro-apoptotic function of Notch3 in endothelial cells; consequently, when Notch3 is silenced in stroma cells, tumour growth and angiogenesis are increased.
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Affiliation(s)
- Shuheng Lin
- Apoptosis, Cancer and Development Laboratory-Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France
| | - Ana Negulescu
- Apoptosis, Cancer and Development Laboratory-Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France
| | - Sirisha Bulusu
- Apoptosis, Cancer and Development Laboratory-Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France
| | - Benjamin Gibert
- Apoptosis, Cancer and Development Laboratory-Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France
| | - Jean-Guy Delcros
- Apoptosis, Cancer and Development Laboratory-Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France
| | - Benjamin Ducarouge
- Apoptosis, Cancer and Development Laboratory-Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France
| | - Nicolas Rama
- Apoptosis, Cancer and Development Laboratory-Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France
| | - Nicolas Gadot
- Department of Translational Research and Innovation, Centre Léon Bérard, 69008 Lyon, France
| | - Isabelle Treilleux
- Department of Translational Research and Innovation, Centre Léon Bérard, 69008 Lyon, France
| | - Pierre Saintigny
- Department of Translational Research and Innovation, Centre Léon Bérard, 69008 Lyon, France
| | - Olivier Meurette
- Apoptosis, Cancer and Development Laboratory-Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France
| | - Patrick Mehlen
- Apoptosis, Cancer and Development Laboratory-Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France.,Department of Translational Research and Innovation, Centre Léon Bérard, 69008 Lyon, France
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28
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Khan MAA, Azim S, Zubair H, Bhardwaj A, Patel GK, Khushman M, Singh S, Singh AP. Molecular Drivers of Pancreatic Cancer Pathogenesis: Looking Inward to Move Forward. Int J Mol Sci 2017; 18:ijms18040779. [PMID: 28383487 PMCID: PMC5412363 DOI: 10.3390/ijms18040779] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Revised: 03/28/2017] [Accepted: 03/30/2017] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) continues to rank among the most lethal cancers. The consistent increase in incidence and mortality has made it the seventh leading cause of cancer-associated deaths globally and the third in the United States. The biggest challenge in combating PC is our insufficient understanding of the molecular mechanism(s) underlying its complex biology. Studies during the last several years have helped identify several putative factors and events, both genetic and epigenetic, as well as some deregulated signaling pathways, with implications in PC onset and progression. In this review article, we make an effort to summarize our current understanding of molecular and cellular events involved in the pathogenesis of pancreatic malignancy. Specifically, we provide up-to-date information on the genetic and epigenetic changes that occur during the initiation and progression of PC and their functional involvement in the pathogenic processes. We also discuss the impact of the tumor microenvironment on the molecular landscape of PC and its role in aggressive disease progression. It is envisioned that a better understanding of these molecular factors and the mechanisms of their actions can help unravel novel diagnostic and prognostic biomarkers and can also be exploited for future targeted therapies.
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Affiliation(s)
- Mohammad Aslam Aslam Khan
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
| | - Shafquat Azim
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
| | - Haseeb Zubair
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
| | - Arun Bhardwaj
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
| | - Girijesh Kumar Patel
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
| | - Moh'd Khushman
- Departments of Interdisciplinary Clinical Oncology, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
| | - Seema Singh
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
- Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36604, USA.
| | - Ajay Pratap Singh
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
- Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36604, USA.
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29
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Abstract
The Notch signalling cascade is an evolutionarily conserved pathway that has a crucial role in regulating development and homeostasis in various tissues. The cellular processes and events that it controls are diverse, and continued investigation over recent decades has revealed how the role of Notch signalling is multifaceted and highly context dependent. Consistent with the far-reaching impact that Notch has on development and homeostasis, aberrant activity of the pathway is also linked to the initiation and progression of several malignancies, and Notch can in fact be either oncogenic or tumour suppressive depending on the tissue and cellular context. The Notch pathway therefore represents an important target for therapeutic agents designed to treat many types of cancer. In this Review, we focus on the latest developments relating specifically to the tumour-suppressor activity of Notch signalling and discuss the potential mechanisms by which Notch can inhibit carcinogenesis in various tissues. Potential therapeutic strategies aimed at restoring or augmenting Notch-mediated tumour suppression will also be highlighted.
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Affiliation(s)
- Craig S Nowell
- CMU, Department for Pathology and Immunology, University of Geneva, Rue Michel Servet, 1211 Geneva 4, Switzerland
| | - Freddy Radtke
- Ecole Polytechnique Fédérale de Lausanne, School of Life Sciences, Swiss Institute for Experimental Cancer Research, Lausanne, Vaud 1015, Switzerland
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30
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Polireddy K, Chen Q. Cancer of the Pancreas: Molecular Pathways and Current Advancement in Treatment. J Cancer 2016; 7:1497-514. [PMID: 27471566 PMCID: PMC4964134 DOI: 10.7150/jca.14922] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Accepted: 04/26/2016] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is one of the most lethal cancers among all malignances, with a median overall survival of <1 year and a 5-year survival of ~5%. The dismal survival rate and prognosis are likely due to lack of early diagnosis, fulminant disease course, high metastasis rate, and disappointing treatment outcome. Pancreatic cancers harbor a variety of genetic alternations that render it difficult to treat even with targeted therapy. Recent studies revealed that pancreatic cancers are highly enriched with a cancer stem cell (CSC) population, which is resistant to chemotherapeutic drugs, and therefore escapes chemotherapy and promotes tumor recurrence. Cancer cell epithelial to mesenchymal transition (EMT) is highly associated with metastasis, generation of CSCs, and treatment resistance in pancreatic cancer. Reviewed here are the molecular biology of pancreatic cancer, the major signaling pathways regulating pancreatic cancer EMT and CSCs, and the advancement in current clinical and experimental treatments for pancreatic cancer.
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Affiliation(s)
- Kishore Polireddy
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, USA 66160
| | - Qi Chen
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, USA 66160
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31
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Kleeff J, Korc M, Apte M, La Vecchia C, Johnson CD, Biankin AV, Neale RE, Tempero M, Tuveson DA, Hruban RH, Neoptolemos JP. Pancreatic cancer. Nat Rev Dis Primers 2016; 2:16022. [PMID: 27158978 DOI: 10.1038/nrdp.2016.22] [Citation(s) in RCA: 1304] [Impact Index Per Article: 144.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Pancreatic cancer is a major cause of cancer-associated mortality, with a dismal overall prognosis that has remained virtually unchanged for many decades. Currently, prevention or early diagnosis at a curable stage is exceedingly difficult; patients rarely exhibit symptoms and tumours do not display sensitive and specific markers to aid detection. Pancreatic cancers also have few prevalent genetic mutations; the most commonly mutated genes are KRAS, CDKN2A (encoding p16), TP53 and SMAD4 - none of which are currently druggable. Indeed, therapeutic options are limited and progress in drug development is impeded because most pancreatic cancers are complex at the genomic, epigenetic and metabolic levels, with multiple activated pathways and crosstalk evident. Furthermore, the multilayered interplay between neoplastic and stromal cells in the tumour microenvironment challenges medical treatment. Fewer than 20% of patients have surgically resectable disease; however, neoadjuvant therapies might shift tumours towards resectability. Although newer drug combinations and multimodal regimens in this setting, as well as the adjuvant setting, appreciably extend survival, ∼80% of patients will relapse after surgery and ultimately die of their disease. Thus, consideration of quality of life and overall survival is important. In this Primer, we summarize the current understanding of the salient pathophysiological, molecular, translational and clinical aspects of this disease. In addition, we present an outline of potential future directions for pancreatic cancer research and patient management.
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Affiliation(s)
- Jorg Kleeff
- NIHR Pancreas Biomedical Research Unit, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Duncan Building, Daulby Street, Liverpool L69 3GA, UK
- Department of General, Visceral and Pediatric Surgery, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
| | - Murray Korc
- Departments of Medicine, and Biochemistry and Molecular Biology, Indiana University School of Medicine, the Melvin and Bren Simon Cancer Center, and the Pancreatic Cancer Signature Center, Indianapolis, Indiana, USA
| | - Minoti Apte
- SWS Clinical School, University of New South Wales, and Ingham Institute for Applied Medical Research, Sydney, New South Wales, Australia
| | - Carlo La Vecchia
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Colin D Johnson
- University Surgical Unit, University Hospital Southampton, Southampton, UK
| | - Andrew V Biankin
- Institute of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Garscube Estate, Bearsden, Glasgow, Scotland, UK
| | - Rachel E Neale
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Margaret Tempero
- UCSF Pancreas Center, University of California San Francisco - Mission Bay Campus/Mission Hall, San Francisco, California, USA
| | - David A Tuveson
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, New York, USA
| | - Ralph H Hruban
- The Sol Goldman Pancreatic Cancer Research Center, Departments of Pathology and Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - John P Neoptolemos
- NIHR Pancreas Biomedical Research Unit, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Duncan Building, Daulby Street, Liverpool L69 3GA, UK
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Baines A, Martin P, Rorie C. Current and Emerging Targeting Strategies for Treatment of Pancreatic Cancer. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2016; 144:277-320. [DOI: 10.1016/bs.pmbts.2016.09.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Knudsen ES, O’Reilly EM, Brody JR, Witkiewicz AK. Genetic Diversity of Pancreatic Ductal Adenocarcinoma and Opportunities for Precision Medicine. Gastroenterology 2016; 150:48-63. [PMID: 26385075 PMCID: PMC5010785 DOI: 10.1053/j.gastro.2015.08.056] [Citation(s) in RCA: 85] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Revised: 08/23/2015] [Accepted: 08/25/2015] [Indexed: 12/20/2022]
Abstract
Patients with pancreatic ductal adenocarcinoma (PDA) have a poor prognosis despite new treatments; approximately 7% survive for 5 years. Although there have been advances in systemic, primarily cytotoxic, therapies, it has been a challenge to treat patients with PDA using targeted therapies. Sequence analyses have provided a wealth of information about the genetic features of PDA and have identified potential therapeutic targets. Preclinical and early-phase clinical studies have found specific pathways could be rationally targeted; it might also be possible to take advantage of the genetic diversity of PDAs to develop therapeutic agents. The genetic diversity and instability of PDA cells have long been thought of as obstacles to treatment, but are now considered exploitable features. We review the latest findings in pancreatic cancer genetics and the promise of targeted approaches in PDA therapy.
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Affiliation(s)
- Erik S. Knudsen
- Simmons Cancer Center, University of Texas Southwestern Medical Center, TX,Department of Pathology, University of Texas Southwestern Medical Center, TX,CORRESPONDENCE, Erik Knudsen, PHD, UTSW, Dallas TX, , Agnieszka Witkiewicz, UTSW, Dallas TX,
| | - Eileen M. O’Reilly
- Department of Medicine, Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, NY
| | - Jonathan R. Brody
- Department of Surgery, Jefferson Pancreatic, Biliary, and Related Cancer Center, Thomas Jefferson University, PA
| | - Agnieszka K. Witkiewicz
- Simmons Cancer Center, University of Texas Southwestern Medical Center, TX,Department of Pathology, University of Texas Southwestern Medical Center, TX,CORRESPONDENCE, Erik Knudsen, PHD, UTSW, Dallas TX, , Agnieszka Witkiewicz, UTSW, Dallas TX,
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Jia Y, Xie J. Promising molecular mechanisms responsible for gemcitabine resistance in cancer. Genes Dis 2015; 2:299-306. [PMID: 30258872 PMCID: PMC6150077 DOI: 10.1016/j.gendis.2015.07.003] [Citation(s) in RCA: 119] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2015] [Accepted: 07/20/2015] [Indexed: 01/18/2023] Open
Abstract
Gemcitabine is the first-line treatment for pancreatic ductual adenocarcinoma (PDAC) as well as acts against a wide range of other solid tumors. Patients usually have a good initial response to gemcitabine-based chemotherapy but would eventually develop resistance. To improve survival and prognosis of cancer patients, better understanding of the mechanisms responsible for gemcitabine resistance and discovery of new therapeutic strategies are in great need. Amounting evidence indicate that the developmental pathways, such as Hedgehog (Hh), Wnt and Notch, become reactivated in gemcitabine-resistant cancer cells. Thus, the strategies for targeting these pathways may sensitize cancer cells to gemcitabine treatment. In this review, we will summarize recent development in this area of research and discuss strategies to overcome gemcitabine resistance. Given the cross-talk between these three developmental signaling pathways, designing clinical trials using a cocktail of inhibitory agents targeting all these pathways may be more effective. Ultimately, our hope is that targeting these developmental pathways may be an effective way to improve the gemcitabine treatment outcome in cancer patients.
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Affiliation(s)
- Yanfei Jia
- Central Laboratory, Jinan Central Hospital Affiliated to Shandong University, Jinan 250013, China
| | - Jingwu Xie
- Division of Hematology and Oncology, Department of Pediatrics, Wells Center for Pediatric Research, Indiana University Simon Cancer Center, Indiana University, Indianapolis, IN 46202, USA
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35
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Takai E, Yachida S. Genomic alterations in pancreatic cancer and their relevance to therapy. World J Gastrointest Oncol 2015; 7:250-258. [PMID: 26483879 PMCID: PMC4606179 DOI: 10.4251/wjgo.v7.i10.250] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2015] [Revised: 07/28/2015] [Accepted: 09/16/2015] [Indexed: 02/05/2023] Open
Abstract
Pancreatic cancer is a highly lethal cancer type, for which there are few viable therapeutic options. But, with the advance of sequencing technologies for global genomic analysis, the landscape of genomic alterations in pancreatic cancer is becoming increasingly well understood. In this review, we summarize current knowledge of genomic alterations in 12 core signaling pathways or cellular processes in pancreatic ductal adenocarcinoma, which is the most common type of malignancy in the pancreas, including four commonly mutated genes and many other genes that are mutated at low frequencies. We also describe the potential implications of these genomic alterations for development of novel therapeutic approaches in the context of personalized medicine.
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Gopinathan A, Morton JP, Jodrell DI, Sansom OJ. GEMMs as preclinical models for testing pancreatic cancer therapies. Dis Model Mech 2015; 8:1185-200. [PMID: 26438692 PMCID: PMC4610236 DOI: 10.1242/dmm.021055] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Pancreatic ductal adenocarcinoma is the most common form of pancreatic tumour, with a very limited survival rate and currently no available disease-modifying treatments. Despite recent advances in the production of genetically engineered mouse models (GEMMs), the development of new therapies for pancreatic cancer is still hampered by a lack of reliable and predictive preclinical animal models for this disease. Preclinical models are vitally important for assessing therapies in the first stages of the drug development pipeline, prior to their transition to the clinical arena. GEMMs carry mutations in genes that are associated with specific human diseases and they can thus accurately mimic the genetic, phenotypic and physiological aspects of human pathologies. Here, we discuss different GEMMs of human pancreatic cancer, with a focus on the Lox-Stop-Lox (LSL)-Kras(G12D); LSL-Trp53(R172H); Pdx1-cre (KPC) model, one of the most widely used preclinical models for this disease. We describe its application in preclinical research, highlighting its advantages and disadvantages, its potential for predicting clinical outcomes in humans and the factors that can affect such outcomes, and, finally, future developments that could advance the discovery of new therapies for pancreatic cancer.
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Affiliation(s)
- Aarthi Gopinathan
- Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge, CB2 0RE, UK
| | | | - Duncan I Jodrell
- Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge, CB2 0RE, UK
| | - Owen J Sansom
- Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK
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Notch signaling: an emerging therapeutic target for cancer treatment. Cancer Lett 2015; 369:20-7. [PMID: 26341688 DOI: 10.1016/j.canlet.2015.07.048] [Citation(s) in RCA: 298] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2015] [Revised: 07/28/2015] [Accepted: 07/31/2015] [Indexed: 12/14/2022]
Abstract
The Notch pathway is involved in cell proliferation, differentiation and survival. The Notch signaling pathway is one of the most commonly activated signaling pathways in cancer. Alterations include activating mutations and amplification of the Notch pathway, which play key roles in the progression of cancer. Accumulating evidence suggests that the pharmacological inhibition of this pathway can overcome chemoresistance. Efforts have been taken to develop Notch inhibitors as a single agent or in combination with clinically used chemotherapeutics to treat cancer. Some Notch inhibitors have been demonstrated to have therapeutic efficacy in preclinical studies. This review summarizes the recent studies and clinical evaluations of the Notch inhibitors in cancer.
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Neesse A, Algül H, Tuveson DA, Gress TM. Stromal biology and therapy in pancreatic cancer: a changing paradigm. Gut 2015; 64:1476-84. [PMID: 25994217 DOI: 10.1136/gutjnl-2015-309304] [Citation(s) in RCA: 415] [Impact Index Per Article: 41.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Accepted: 03/20/2015] [Indexed: 12/12/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDA) exhibits one of the poorest prognosis of all solid tumours and poses an unsolved problem in cancer medicine. Despite the recent success of two combination chemotherapies for palliative patients, the modest survival benefits are often traded against significant side effects and a compromised quality of life. Although the molecular events underlying the initiation and progression of PDA have been intensively studied and are increasingly understood, the reasons for the poor therapeutic response are hardly apprehended. One leading hypothesis over the last few years has been that the pronounced tumour microenvironment in PDA not only promotes carcinogenesis and tumour progression but also mediates therapeutic resistance. To this end, targeting of various stromal components and pathways was considered a promising strategy to biochemically and biophysically enhance therapeutic response. However, none of the efforts have yet led to efficacious and approved therapies in patients. Additionally, recent data have shown that tumour-associated fibroblasts may restrain rather than promote tumour growth, reinforcing the need to critically revisit the complexity and complicity of the tumour-stroma with translational implications for future therapy and clinical trial design.
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Affiliation(s)
- Albrecht Neesse
- Department of Gastroenterology and Gastrointestinal Oncology, University Medical Centre Goettingen, Georg August University Goettingen, Goettingen, Germany
| | - Hana Algül
- II. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - David A Tuveson
- Cold Spring Harbor Laboratory, Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York, USA
| | - Thomas M Gress
- Department of Gastroenterology, Endocrinology, Infectiology and Metabolism, Philipps-University, Marburg, Germany
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Cao F, Li J, Sun H, Liu S, Cui Y, Li F. HES 1 is essential for chemoresistance induced by stellate cells and is associated with poor prognosis in pancreatic cancer. Oncol Rep 2015; 33:1883-9. [PMID: 25672829 DOI: 10.3892/or.2015.3789] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Accepted: 01/07/2015] [Indexed: 11/06/2022] Open
Abstract
The role of pancreatic stellate cells (PSCs) has been established in many studies. However, the potential mechanism for the chemoresistance induced by PSCs has not been fully elucidated. In the present study, human pancreatic cancer cell lines were directly or indirectly co-cultured with PSCs. The inhibition rate and IC50 values were assessed to determine the ability of chemoresistance. RT-PCR and western blot analysis were used to evaluate Hes 1 and Jagged 1 expression before and after co-culture with PSCs. To determine the relationship between Hes 1 expression and survival in pancreatic cancer patients, Kaplan-Meier survival analysis was performed. PSCs promoted the expression of Hes 1 in both PANC-1 and BxPC-3 cell lines and induced chemoresistance to gemcitabine. A Notch signaling pathway inhibitor (L1790) and Hes 1 siRNA reversed the chemoresistance induced by PSCs. In 72 resected pancreatic cancer patients, high Hes 1 expression was observed in 34 patients with shorter overall and progression-free survival times. In conclusion, Hes 1 is essential for chemoresistance induced by PSCs and is associated with poor prognosis in pancreatic cancer patients. Therapy targeting the Notch signaling pathway may reverse chemoresistance and improve survival in patients with pancreatic cancer.
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Affiliation(s)
- Feng Cao
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, P.R. China
| | - Jia Li
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, P.R. China
| | - Haichen Sun
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, P.R. China
| | - Shuang Liu
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, P.R. China
| | - Yeqing Cui
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, P.R. China
| | - Fei Li
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, P.R. China
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40
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Hidalgo M, Cascinu S, Kleeff J, Labianca R, Löhr JM, Neoptolemos J, Real FX, Van Laethem JL, Heinemann V. Addressing the challenges of pancreatic cancer: future directions for improving outcomes. Pancreatology 2015; 15:8-18. [PMID: 25547205 DOI: 10.1016/j.pan.2014.10.001] [Citation(s) in RCA: 365] [Impact Index Per Article: 36.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2014] [Revised: 10/01/2014] [Accepted: 10/03/2014] [Indexed: 12/11/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC), which accounts for more than 90% of all pancreatic tumours, is a devastating malignancy with an extremely poor prognosis, as shown by a 1-year survival rate of around 18% for all stages of the disease. The low survival rates associated with PDAC primarily reflect the fact that tumours progress rapidly with few specific symptoms and are thus at an advanced stage at diagnosis in most patients. As a result, there is an urgent need to develop accurate markers of pre-invasive pancreatic neoplasms in order to facilitate prediction of cancer risk and to help diagnose the disease at an earlier stage. However, screening for early diagnosis of prostate cancer remains challenging and identifying a highly accurate, low-cost screening test for early PDAC for use in clinical practice remains an important unmet need. More effective therapies are also crucial in PDAC, since progress in identifying novel therapies has been hampered by the genetic complexity of the disease and treatment remains a major challenge. Presently, the greatest step towards improved treatment efficacy has been made in the field of palliative chemotherapy by introducing FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan and oxaliplatin) and gemcitabine/nab-paclitaxel. Strategies designed to raise the profile of PDAC in research and clinical practice are a further requirement in order to ensure the best treatment for patients. This article proposes a number of approaches that may help to accelerate progress in treating patients with PDAC, which, in turn, may be expected to improve the quality of life and survival for those suffering from this devastating disease.
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Affiliation(s)
- Manuel Hidalgo
- Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
| | - Stefano Cascinu
- Department of Medical Oncology, University of Ancona, Ancona, Italy
| | - Jörg Kleeff
- Department of General Surgery, Technische Universität München, Munich, Germany
| | | | - J-Matthias Löhr
- Department of Clinical Science, Intervention and Technology, Karolinska Institute, Stockholm, Sweden
| | - John Neoptolemos
- National Institutes of Health Research Liverpool Pancreas Biomedical Research Unit and Cancer Research UK Liverpool Clinical Trials Unit Director, University of Liverpool and Royal Liverpool University Hospital, Liverpool, UK
| | - Francisco X Real
- Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid and Universitat Pompeu Fabra, Barcelona, Spain
| | - Jean-Luc Van Laethem
- Department of Gastroenterology-GI Cancer Unit, Erasme University Hospital, Brussels, Belgium
| | - Volker Heinemann
- Comprehensive Cancer Centre Munich, Klinikum der Universität München, Munich, Germany
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41
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Abstract
PURPOSE OF REVIEW Recent advances in sequencing technology have led to a deeper and more comprehensive understanding of the molecular biology of pancreatic ductal adenocarcinoma. This timely review seeks to summarize these recent advances which will provide a foundation for future studies in the field. RECENT FINDINGS Stereotypical genetic alterations have been identified and confirmed. However, additional alterations have highlighted the importance and complexity of a number of intracellular signaling pathways that present unique opportunities for therapeutic targeting. SUMMARY A genetic signature of pancreatic ductal adenocarcinoma has been identified. This recent and important work is currently in the process of being applied in many clinical applications from early diagnostics to customized therapeutic regimens for this disease. A fundamental understanding of these findings will thus be of utmost importance for future research in the field and in the clinical care of patients with this lethal disease.
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Abstract
Intratumoral hypoxia is a common feature of solid tumors. Recent advances in cancer biology indicate that hypoxia is not only a consequence of unrestrained tumor growth, but also plays an active role in promoting tumor progression, malignancy, and resistance to therapy. Hypoxia signaling is mediated by the hypoxia-inducible factors (HIFs), which are not only stabilized under hypoxia, but also by activated oncogenes or inactivated tumor suppressors under normoxia. Hypoxia is a prominent feature of the tumor microenvironment of pancreatic tumors, also characterized by the presence of a fibrotic reaction that promotes, and is also modulated by, hypoxia. As the mechanisms by which hypoxia signaling impacts invasion and metastasis in pancreatic cancer are being elucidated, hypoxia is emerging as a key determinant of pancreatic cancer malignancy as well as an important target for therapy. Herein we present an overview of recent advances in the understanding of the impact that hypoxia has in pancreatic cancer invasion and metastasis.
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Affiliation(s)
- Angela Yuen
- Tumor Microenvironment and Metastasis Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA
| | - Begoña Díaz
- Tumor Microenvironment and Metastasis Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA
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43
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Samore WR, Gondi CS. Brief overview of selected approaches in targeting pancreatic adenocarcinoma. Expert Opin Investig Drugs 2014; 23:793-807. [PMID: 24673265 DOI: 10.1517/13543784.2014.902933] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
INTRODUCTION Pancreatic adenocarcinoma (PDAC) has the worst prognosis of any major malignancy, with 5-year survival painfully inadequate at under 5%. Investigators have struggled to target and exploit PDAC unique biology, failing to bring meaningful results from bench to bedside. Nonetheless, in recent years, several promising targets have emerged. AREAS COVERED This review will discuss novel drug approaches in development for use in PDAC. The authors examine the continued efforts to target Kirsten rat sarcoma viral oncogene homolog (KRas), which have recently been successfully abated using novel small interfering RNA (siRNA) eluting devices. The authors also discuss other targets relevant to PDAC including those downstream of mutated KRas, such as MAPK kinase and phosphatidylinositol 3-kinase. EXPERT OPINION Although studies into novel biomarkers and advanced imaging have highlighted the potential new avenues toward discovering localized tumors earlier, the current therapeutic options highlight the fact that PDAC is a highly metastatic and chemoresistant cancer that often must be fought with virulent, systemic therapies. Several newer approaches, including siRNA targeting of mutated KRas and enzymatic depletion of hyaluronan with PEGylated hyaluronidase are particularly exciting given their early stage results. Further research should help in elucidating their potential impact as therapeutic options.
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Affiliation(s)
- Wesley R Samore
- M3 student, University of Illinois College of Medicine , One Illini Drive Peoria, IL 61605 , USA
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44
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Palagani V, Bozko P, El Khatib M, Belahmer H, Giese N, Sipos B, Malek NP, Plentz RR. Combined inhibition of Notch and JAK/STAT is superior to monotherapies and impairs pancreatic cancer progression. Carcinogenesis 2014; 35:859-866. [DOI: 10.1093/carcin/bgt394] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023] Open
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Ntziachristos P, Lim JS, Sage J, Aifantis I. From fly wings to targeted cancer therapies: a centennial for notch signaling. Cancer Cell 2014; 25:318-34. [PMID: 24651013 PMCID: PMC4040351 DOI: 10.1016/j.ccr.2014.02.018] [Citation(s) in RCA: 292] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2014] [Revised: 01/21/2014] [Accepted: 02/21/2014] [Indexed: 12/21/2022]
Abstract
Since Notch phenotypes in Drosophila melanogaster were first identified 100 years ago, Notch signaling has been extensively characterized as a regulator of cell-fate decisions in a variety of organisms and tissues. However, in the past 20 years, accumulating evidence has linked alterations in the Notch pathway to tumorigenesis. In this review, we discuss the protumorigenic and tumor-suppressive functions of Notch signaling, and dissect the molecular mechanisms that underlie these functions in hematopoietic cancers and solid tumors. Finally, we link these mechanisms and observations to possible therapeutic strategies targeting the Notch pathway in human cancers.
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Affiliation(s)
- Panagiotis Ntziachristos
- Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, NY 10016, USA; NYU Cancer Institute and Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, NY 10016, USA
| | - Jing Shan Lim
- Departments of Pediatrics and Genetics, Stanford University, Stanford, CA 94305, USA
| | - Julien Sage
- Departments of Pediatrics and Genetics, Stanford University, Stanford, CA 94305, USA.
| | - Iannis Aifantis
- Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, NY 10016, USA; NYU Cancer Institute and Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, NY 10016, USA.
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46
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Cassidy LD, Liau SS, Venkitaraman AR. Chromosome instability and carcinogenesis: insights from murine models of human pancreatic cancer associated with BRCA2 inactivation. Mol Oncol 2014; 8:161-8. [PMID: 24268522 PMCID: PMC3989051 DOI: 10.1016/j.molonc.2013.10.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2013] [Revised: 10/07/2013] [Accepted: 10/13/2013] [Indexed: 01/01/2023] Open
Abstract
Chromosomal instability is a hallmark of human cancer cells, but its role in carcinogenesis remains poorly resolved. Insights into this role have emerged from studies on the tumour suppressor BRCA2, whose inactivation in human cancers causes chromosomal instability through the loss of essential functions of the BRCA2 protein in the normal mechanisms responsible for the replication, repair and segregation of DNA during cell division. Humans who carry heterozygous germline mutations in the BRCA2 gene are highly predisposed to cancers of the breast, ovary, pancreas, prostate and other tissues. Here, we review recent studies that describe genetically engineered mouse models (GEMMs) for pancreatic cancer associated with BRCA2 mutations. These studies not only surprisingly show that BRCA2 does not follow the classical Knudson "two hit" paradigm for tumour suppression, but also highlight features of the interplay between TP53 inactivation and carcinogenesis in the context of BRCA2 deficiency. Thus, the models reveal novel aspects of cancer evolution in carriers of germline BRCA2 mutations, provide new insights into the tumour suppressive role of BRCA2, and establish valuable new preclinical settings for testing approaches to pancreatic cancer therapy; together, these features emphasize the value of GEMMs in cancer research.
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Affiliation(s)
- Liam D Cassidy
- University of Cambridge, Medical Research Council Cancer Cell Unit, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 0XZ, United Kingdom
| | - Siong-Seng Liau
- University of Cambridge, Medical Research Council Cancer Cell Unit, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 0XZ, United Kingdom
| | - Ashok R Venkitaraman
- University of Cambridge, Medical Research Council Cancer Cell Unit, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 0XZ, United Kingdom.
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47
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Olive KP, Politi K. Translational therapeutics in genetically engineered mouse models of cancer. Cold Spring Harb Protoc 2014; 2014:131-143. [PMID: 24492770 DOI: 10.1101/pdb.top069997] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
Advances in knowledge of the molecular alterations of human cancers, refinements in technologies for the generation of genetically engineered mouse models (GEMMs), and the development of cancer therapies have accelerated in recent years. Progress in these fields provides the foundation for clinically relevant studies to be performed in GEMMs, through which it is possible to glean information on drug efficacy and to identify determinants of sensitivity and resistance to drugs and drug combinations. GEMMs used in pre-, co-, and postclinical studies must closely recapitulate the genetics, histopathology, and response to therapy of the human disease. Prevention and intervention trials can be designed in GEMMs to test the effects of drugs on tumor initiation, regression, and progression. Given their complexity, careful consideration of the infrastructure requirements and practical aspects of each individual experiment, including enrollment, tumor monitoring, and dose and schedule, must be considered in the design of therapeutic studies in GEMMs. Advantages of GEMMs include the ability to rapidly perform drug efficacy studies in a defined genetic background, the ease of pharmacodynamic and pharmacokinetic assessments, and the possibility of experimentally manipulating model systems to address questions that cannot be addressed in patients. In light of these features, GEMMs are useful tools for translational studies to inform clinical trials in cancer patients.
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Affiliation(s)
- Kenneth P Olive
- Departments of Medicine and Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York 10032
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Tremblay I, Paré E, Arsenault D, Douziech M, Boucher MJ. The MEK/ERK pathway promotes NOTCH signalling in pancreatic cancer cells. PLoS One 2013; 8:e85502. [PMID: 24392017 PMCID: PMC3877363 DOI: 10.1371/journal.pone.0085502] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2013] [Accepted: 11/27/2013] [Indexed: 12/28/2022] Open
Abstract
Activation of the NOTCH receptors relies on their intracellular proteolysis by the gamma-secretase complex. This cleavage liberates the NOTCH intracellular domain (NIC) thereby allowing the translocation of NIC towards the nucleus to assemble into a transcriptional platform. Little information is available regarding the regulatory steps operating on NIC following its release from the transmembrane receptor up to its association with transcriptional partners. Interfering with these regulatory steps might potentially influences the nuclear outcome of NOTCH signalling. Herein, we exploited a reliable model to study the molecular events occurring subsequent to NOTCH1 cleavage. In pancreatic cancer cells, pulse of NOTCH1 activation led to increased expression of NOTCH target genes namely HES1 and c-MYC. We uncovered that, upon its release, the NOTCH1 intracellular domain, NIC1, undergoes a series of post-translational modifications that include phosphorylation. Most interestingly, we found that activation of the MEK/ERK pathway promotes HES1 expression. Inhibition of the gamma-secretase complex prevented the MEK/ERK-induced HES1 expression suggesting a NOTCH-dependent mechanism. Finally, higher levels of NIC1 were found associated with its transcriptional partners [CBF1, Su(H) and LAG-1] (CSL) and MASTERMIND-LIKE 1 (MAML1) upon MEK/ERK activation providing a potential mechanism whereby the MEK/ERK pathway promotes expression of NOTCH target genes. For the first time, our data exposed a signalling pathway, namely the MEK/ERK pathway that positively impacts on NOTCH nuclear outcome.
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Affiliation(s)
- Isabelle Tremblay
- Department of Medicine, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Emanuel Paré
- Department of Medicine, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Dominique Arsenault
- Department of Medicine, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Mélanie Douziech
- Department of Medicine, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Marie-Josée Boucher
- Department of Medicine, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, Canada
- * E-mail:
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Neesse A, Krug S, Gress TM, Tuveson DA, Michl P. Emerging concepts in pancreatic cancer medicine: targeting the tumor stroma. Onco Targets Ther 2013; 7:33-43. [PMID: 24379681 PMCID: PMC3872146 DOI: 10.2147/ott.s38111] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Pancreatic ductal adenocarcinoma is a stroma-rich and highly challenging cancer to treat. Over recent years, it has become increasingly evident that the complex network of soluble cytokines, growth factors, proteases, and components of the extracellular matrix collaboratively interact within the tumor microenvironment, sustaining and driving cancer cell proliferation, invasion, and early metastasis. More recently, the tumor microenvironment has also been appreciated to mediate therapeutic resistance in pancreatic ductal adenocarcinoma, thus opening numerous avenues for novel therapeutic explorations. Inert and soluble components of the tumor stroma have been targeted in order to break down the extracellular matrix scaffold, relieve vessel compression, and increase drug delivery to hypovascular tumors. Moreover, targeting of antiapoptotic, immunosuppressive, and pro-proliferative effects of the tumor stroma provides novel vantage points of attack. This review focuses on current and future developments in pancreatic cancer medicine, with a particular emphasis on biophysical and biochemical approaches that target the tumor microenvironment.
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Affiliation(s)
- Albrecht Neesse
- Department of Gastroenterology, Endocrinology, Infectiology and Metabolism, Philipps University Marburg, Marburg, Germany
| | - Sebastian Krug
- Department of Gastroenterology, Endocrinology, Infectiology and Metabolism, Philipps University Marburg, Marburg, Germany
| | - Thomas M Gress
- Department of Gastroenterology, Endocrinology, Infectiology and Metabolism, Philipps University Marburg, Marburg, Germany
| | | | - Patrick Michl
- Department of Gastroenterology, Endocrinology, Infectiology and Metabolism, Philipps University Marburg, Marburg, Germany
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Du X, Zhao YP, Zhang TP, Zhou L, Chen G, Wang TX, You L, Shu H. Alteration of the intrinsic apoptosis pathway is involved in Notch-induced chemoresistance to gemcitabine in pancreatic cancer. Arch Med Res 2013; 45:15-20. [PMID: 24316112 DOI: 10.1016/j.arcmed.2013.10.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2013] [Accepted: 09/27/2013] [Indexed: 01/26/2023]
Abstract
BACKGROUND AND AIMS Chemoresistance is a major challenge in pancreatic cancer (PC) treatment. Limited data have shown that members of the Notch signaling pathway are involved in resistance to gemcitabine (GEM) in PC. However, further evidence is needed and the underlying mechanisms remain to be elucidated. The current study aims to investigate the role of alterations of the intrinsic apoptosis pathway in Notch-induced GEM resistance of PC. METHODS The Notch signaling pathway was inhibited or activated in three PC cell lines (AsPC-1, BxPC-3, and MIA PaCa-2) by γ-secretase inhibition and Notch intracellular domain (NICD) overexpression, respectively. Subsequent analyses included inhibition rates of cell proliferation by GEM, cell apoptosis, and expression of proteins involved in the intrinsic apoptosis pathway. RESULTS Hes-1 expression was significantly elevated after GEM treatment, indicating Notch activation. Inhibition of the Notch signaling pathway by DAPT, a γ-secretase inhibitor, resulted in a significant increase of the inhibition rates by GEM in all PC cell lines. In addition, there was more frequent apoptosis, higher caspase-3 activity, up-regulation of Bax, and down-regulation of Bcl-2 and Bcl-xL. Conversely, transient transfection of NICD, which enhances the activity of the Notch signaling, caused a remarkable decrease of the chemosensitivity to GEM. CONCLUSIONS An alteration of the intrinsic apoptosis pathway is involved in Notch-induced chemoresistance to GEM in PC cells.
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Affiliation(s)
- Xiao Du
- Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Yu-Pei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Beijing, China; National Laboratory of Medical Molecular Biology, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing, China.
| | - Tai-Ping Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Li Zhou
- Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Ge Chen
- Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Tian-Xiao Wang
- Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Lei You
- Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Hong Shu
- Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
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