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Wang D, Wang L, Zhang W, Xu K, Chen L, Guo Z, Wu K, Huang D, Zhao Y, Yao M, Zheng L, Ye C, Ran J, Zhou W, Liu X, Xu J. Extracellular vesicle-mediated gene therapy targets BRAF V600E-mutant colorectal cancer by inhibiting the MEK1/2-ERK1/2 pathway. J Nanobiotechnology 2025; 23:129. [PMID: 39979881 PMCID: PMC11843959 DOI: 10.1186/s12951-025-03205-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 02/05/2025] [Indexed: 02/22/2025] Open
Abstract
BACKGROUND Patients with colorectal cancer (CRC) harboring BRAF mutation have a poor prognosis. The median survival time for patients with advanced BRAFV600E-mutant CRC is only approximately one year. Owing to the insensitivity to standard chemotherapy, there are still no effective and highly specific treatment strategies available in clinical practice for CRC patients with BRAF mutation. Therefore, targeting the BRAFV600E mutation site, researching and exploring novel targeted therapies are essential to improve the survival rate of patients with this CRC subtype. AIM This study aims to develop a precise therapeutic system for BRAFV600E CRC, based on the carrier properties of extracellular vesicles (EVs) and gene therapy targeting BRAFV600E. METHOD We first obtained engineered cells capable of stably producing EVs loaded with BRAFV600E nucleic acid drugs (siBRAFV600E). Next, BRAFV600E-mutant and wild-type CRC cell lines, as well as corresponding subcutaneous and metastasis models, were used to evaluate the therapeutic efficacy of EVs-siBRAFV600E and explored the mechanism. Notably, patient-derived xenograft (PDX) models, which share the same molecular characteristics, pathological features, and heterogeneity as patients do, were utilized to further explore the therapeutic efficacy and mechanisms. RESULT EVs-siBRAFV600E specifically inhibited BRAFV600E CRC but didn't affect BRAF wild-type CRC in vitro and vivo. EVs-siBRAFV600E exerts its therapeutic effect by regulating the MEK1/2-ERK1/2 pathway, and it has demonstrated excellent therapeutic efficacy in PDX models. CONCLUSION The therapeutic EVs we constructed are effective and specific for the BRAFV600E-mutant CRC. This study provides a novel strategy for the treatment of CRC patients with BRAFV600E mutation.
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Affiliation(s)
- Di Wang
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
| | - Liwei Wang
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
| | - Wei Zhang
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, PR China
| | - Kaicheng Xu
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
| | - Liang Chen
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
| | - Ziye Guo
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
| | - Kaile Wu
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
| | - Donghua Huang
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
| | - Yubin Zhao
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
| | - Minjun Yao
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
| | - Liming Zheng
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
| | - Chenyi Ye
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
| | - Jisheng Ran
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
| | - Wei Zhou
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, PR China.
| | - Xin Liu
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, PR China.
| | - Jianbin Xu
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, PR China.
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, 310009, PR China.
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China.
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China.
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Jobu Y, Nishigawa M, Furihata K, Furihata M, Uchida K, Taniuchi K. Inhibitory effects of the combination of rapamycin with gemcitabine plus paclitaxel on the growth of pancreatic cancer tumors. Hum Cell 2025; 38:44. [PMID: 39794664 PMCID: PMC11723851 DOI: 10.1007/s13577-024-01165-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 12/16/2024] [Indexed: 01/13/2025]
Abstract
We previously examined the antitumor effects of short interfering RNA nanoparticles targeting mammalian target of rapamycin (mTOR) in an orthotopic pancreatic cancer mouse model. We herein report the inhibitory effects of the mTOR inhibitor rapamycin on tumor growth in a novel established mouse model of pancreatic cancer using human pancreatic cancer cell line-derived organoids. Gemcitabine, 5-fluorouracil, and gemcitabine plus nab-paclitaxel are clinically used to treat advanced pancreatic cancer. In vitro assays showed that rapamycin strongly inhibited cell invasion, while gemcitabine, 5-fluorouracil, and gemcitabine plus paclitaxel primarily inhibited cell proliferation with minimal effects on invasion. In vivo mouse experiments demonstrated that rapamycin exhibited superior antitumor activity to S-1 (a metabolically activated prodrug of 5-fluorouracil) and another mTOR inhibitor, everolimus, while its efficacy was similar to that of gemcitabine plus paclitaxel (which was used instead of nab-paclitaxel due to concerns about allergic reactions in mice to human albumin) in a mouse model of pancreatic cancer using human pancreatic cancer cell line-derived organoids. Furthermore, the combination of rapamycin with gemcitabine plus paclitaxel exerted synergistic inhibitory effects on the growth of pancreatic cancer tumors. Although the inhibition of tumor growth was significantly stronger in everolimus-treated mice than in control mice, there were no additive anti-growth effects when combined with gemcitabine plus paclitaxel. The present results suggest that the combination of rapamycin with gemcitabine plus paclitaxel achieved the greatest reduction in tumor volumes in the mouse xenograft model and, thus, has significant clinical promise.
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Affiliation(s)
- Yuri Jobu
- Department of Gastroenterology and Hepatology, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan
| | - Miki Nishigawa
- Department of Gastroenterology and Hepatology, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan
| | - Kaoru Furihata
- Department of Pathology, Kochi Medical School, Kochi University, Nankoku, Kochi, 783-8505, Japan
| | - Mutsuo Furihata
- Department of Pathology, Kochi Medical School, Kochi University, Nankoku, Kochi, 783-8505, Japan
| | - Kazushige Uchida
- Department of Gastroenterology and Hepatology, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan
| | - Keisuke Taniuchi
- Department of Gastroenterology and Hepatology, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan.
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Gayibov E, Sychra T, Spálenková A, Souček P, Oliverius M. The use of patient-derived xenografts and patient-derived organoids in the search for new therapeutic regimens for pancreatic carcinoma. A review. Biomed Pharmacother 2025; 182:117750. [PMID: 39689516 DOI: 10.1016/j.biopha.2024.117750] [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: 09/06/2024] [Revised: 12/02/2024] [Accepted: 12/08/2024] [Indexed: 12/19/2024] Open
Abstract
Patient-derived organoids (PDOs) and xenografts (PDXs) are powerful tools for personalized medicine in pancreatic cancer (PC) research. This study explores the complementary strengths of PDOs and PDXs in terms of practicality, genetic fidelity, cost, and labor considerations. Among other models like 2D cell cultures, spheroids, cancer-on-chip systems, cell line-derived xenografts (CDX), and genetically engineered mouse models (GEMMs), PDOs and PDXs uniquely balance genetic fidelity and personalized medicine potential, offering distinct advantages over the simplicity of 2D cultures and the advanced, but often resource-intensive, GEMMs and cancer-on-chip systems. PDOs excel in high-throughput drug screening due to their ease of use, lower cost, and shorter experimental timelines. However, they lack a complete tumor microenvironment. Conversely, PDXs offer a more complex microenvironment that closely reflects patient tumors, potentially leading to more clinically relevant results. Despite limitations in size, number of specimens, and engraftment success, PDXs demonstrate significant concordance with patient responses to treatment, highlighting their value in personalized medicine. Both models exhibit significant genetic fidelity, making them suitable for drug sensitivity testing. The choice between PDOs and PDXs depends on the research focus, resource availability, and desired level of microenvironment complexity. PDOs are advantageous for high-throughput screening of a diverse array of potential therapeutic agents due to their relative ease of culture and scalability. PDXs, on the other hand, offer a more physiologically relevant model, allowing for a comprehensive evaluation of drug efficacy and mechanisms of action.
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Affiliation(s)
- Emin Gayibov
- 3rd Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Tomáš Sychra
- 3rd Faculty of Medicine, Charles University, Prague, Czech Republic; Centre of Toxicology and Health Safety, National Institute of Public Health, Prague, Czech Republic; Department of General Surgery, 3rd Faculty of Medicine, Charles University and University Hospital Královské Vinohrady, Prague, Czech Republic
| | - Alžběta Spálenková
- Centre of Toxicology and Health Safety, National Institute of Public Health, Prague, Czech Republic; Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
| | - Pavel Souček
- Centre of Toxicology and Health Safety, National Institute of Public Health, Prague, Czech Republic; Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic.
| | - Martin Oliverius
- 3rd Faculty of Medicine, Charles University, Prague, Czech Republic; Department of General Surgery, 3rd Faculty of Medicine, Charles University and University Hospital Královské Vinohrady, Prague, Czech Republic.
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Ouissam AJ, Hind C, Sami Aziz B, Said A. Inhibition of the PI3K/AKT/mTOR pathway in pancreatic cancer: is it a worthwhile endeavor? Ther Adv Med Oncol 2024; 16:17588359241284911. [PMID: 39399412 PMCID: PMC11468005 DOI: 10.1177/17588359241284911] [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: 04/19/2024] [Accepted: 09/03/2024] [Indexed: 10/15/2024] Open
Abstract
Pancreatic cancer (PC) is an aggressive disease that is challenging to treat and is associated with a high mortality rate. The most common type of PC is pancreatic ductal adenocarcinoma (PDAC), and the existing treatment options are insufficient for PDAC patients. Due to the complexity and heterogeneity of PDAC, personalized medicine is necessary for effectively treating this illness. To achieve this, it is essential to understand the mechanism of PDAC carcinogenesis. Targeted therapies are a promising strategy to improve patient outcomes. Aberrant activation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway plays a crucial role in PC pathogenesis, from initiation to progression. This review provides a comprehensive overview of the current state of knowledge regarding the PI3K pathway in PDAC, summarizes clinical data on PI3K pathway inhibition in PDAC, and explores potential effective combinations that are a promising direction requiring further investigation in PDAC.
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Affiliation(s)
- Al Jarroudi Ouissam
- Department of Medical Oncology, Mohammed VI University Hospital, Oujda, Morocco
- Faculty of Medicine and Pharmacy, Mohammed Ist University, Oujda, Morocco
| | - Chibani Hind
- Department of Medical Oncology, Mohammed VI University Hospital, Oujda, Morocco
- Faculty of Medicine and Pharmacy, Mohammed Ist University, Oujda, Morocco
| | - Brahmi Sami Aziz
- Department of Medical Oncology, Mohammed VI University Hospital, Oujda, Morocco
- Faculty of Medicine and Pharmacy, Mohammed Ist University, Oujda, Morocco
| | - Afqir Said
- Department of Medical Oncology, Mohammed VI University Hospital, Oujda, Morocco
- Faculty of Medicine and Pharmacy, Mohammed Ist University, Oujda, Morocco
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Cocco E, de Stanchina E. Patient-Derived-Xenografts in Mice: A Preclinical Platform for Cancer Research. Cold Spring Harb Perspect Med 2024; 14:a041381. [PMID: 37696659 PMCID: PMC11216185 DOI: 10.1101/cshperspect.a041381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/13/2023]
Abstract
The use of patient-derived xenografts (PDXs) has dramatically improved drug development programs. PDXs (1) reproduce the pathological features and the genomic profile of the parental tumors more precisely than other preclinical models, and (2) more faithfully predict therapy response. However, PDXs have limitations. These include the inability to completely capture tumor heterogeneity and the role of the immune system, the low engraftment efficiency of certain tumor types, and the consequences of the human-host interactions. Recently, the use of novel mouse strains and specialized engraftment techniques has enabled the generation of "humanized" PDXs, partially overcoming such limitations. Importantly, establishing, characterizing, and maintaining PDXs is costly and requires a significant regulatory, administrative, clinical, and laboratory infrastructure. In this review, we will retrace the historical milestones that led to the implementation of PDXs for cancer research, review the most recent innovations in the field, and discuss future avenues to tackle deficiencies that still exist.
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Affiliation(s)
- Emiliano Cocco
- University of Miami, Miller School of Medicine, Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, Miami, Florida 33136, USA
| | - Elisa de Stanchina
- Antitumor Assessment Core Facility, Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
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Jiménez DJ, Javed A, Rubio-Tomás T, Seye-Loum N, Barceló C. Clinical and Preclinical Targeting of Oncogenic Pathways in PDAC: Targeted Therapeutic Approaches for the Deadliest Cancer. Int J Mol Sci 2024; 25:2860. [PMID: 38474109 DOI: 10.3390/ijms25052860] [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: 12/21/2023] [Revised: 01/22/2024] [Accepted: 01/30/2024] [Indexed: 03/14/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related death worldwide. It is commonly diagnosed in advanced stages and therapeutic interventions are typically constrained to systemic chemotherapy, which yields only modest clinical outcomes. In this review, we examine recent developments in targeted therapy tailored to address distinct molecular pathway alteration required for PDAC. Our review delineates the principal signaling pathways and molecular mechanisms implicated in the initiation and progression of PDAC. Subsequently, we provide an overview of prevailing guidelines, ongoing investigations, and prospective research trajectories related to targeted therapeutic interventions, drawing insights from randomized clinical trials and other pertinent studies. This review focus on a comprehensive examination of preclinical and clinical data substantiating the efficacy of these therapeutic modalities, emphasizing the potential of combinatorial regimens and novel therapies to enhance the quality of life for individuals afflicted with PDAC. Lastly, the review delves into the contemporary application and ongoing research endeavors concerning targeted therapy for PDAC. This synthesis serves to bridge the molecular elucidation of PDAC with its clinical implications, the evolution of innovative therapeutic strategies, and the changing landscape of treatment approaches.
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Affiliation(s)
- Diego J Jiménez
- Translational Pancreatic Cancer Oncogenesis Group, Health Research Institute of the Balearic Islands (IdISBa), Hospital Universitari Son Espases, 07120 Palma de Mallorca, Spain
| | - Aadil Javed
- Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Teresa Rubio-Tomás
- School of Medicine, University of Crete, 70013 Herakleion, Crete, Greece
| | - Ndioba Seye-Loum
- Translational Pancreatic Cancer Oncogenesis Group, Health Research Institute of the Balearic Islands (IdISBa), Hospital Universitari Son Espases, 07120 Palma de Mallorca, Spain
| | - Carles Barceló
- Translational Pancreatic Cancer Oncogenesis Group, Health Research Institute of the Balearic Islands (IdISBa), Hospital Universitari Son Espases, 07120 Palma de Mallorca, Spain
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Zhou K, Liu Y, Yuan S, Zhou Z, Ji P, Huang Q, Wen F, Li Q. Signalling in pancreatic cancer: from pathways to therapy. J Drug Target 2023; 31:1013-1026. [PMID: 37869884 DOI: 10.1080/1061186x.2023.2274806] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Accepted: 10/18/2023] [Indexed: 10/24/2023]
Abstract
Pancreatic cancer (PC) is a common malignant tumour in the digestive system. Due to the lack of sensitive diagnostic markers, strong metastasis ability, and resistance to anti-cancer drugs, the prognosis of PC is inferior. In the past decades, increasing evidence has indicated that the development of PC is closely related to various signalling pathways. With the exploration of RAS-driven, epidermal growth factor receptor, Hedgehog, NF-κB, TGF-β, and NOTCH signalling pathways, breakthroughs have been made to explore the mechanism of pancreatic carcinogenesis, as well as the novel therapies. In this review, we discussed the signalling pathways involved in PC and summarised current targeted agents in the treatment of PC. Furthermore, opportunities and challenges in the exploration of potential therapies targeting signalling pathways were also highlighted.
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Affiliation(s)
- Kexun Zhou
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yingping Liu
- The Second Clinical Medical College of Lanzhou University, Lanzhou University, Lanzhou, China
| | | | - Ziyu Zhou
- The Second Clinical Medical College of Lanzhou University, Lanzhou University, Lanzhou, China
| | - Pengfei Ji
- The Second Clinical Medical College of Lanzhou University, Lanzhou University, Lanzhou, China
| | - Qianhan Huang
- School of Public Health, Xuzhou Medical University, Xuzhou, China
| | - Feng Wen
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Qiu Li
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
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Targeting PI3K/AKT/mTOR Signaling Pathway in Pancreatic Cancer: From Molecular to Clinical Aspects. Int J Mol Sci 2022; 23:ijms231710132. [PMID: 36077529 PMCID: PMC9456549 DOI: 10.3390/ijms231710132] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/01/2022] [Accepted: 09/01/2022] [Indexed: 02/06/2023] Open
Abstract
Although pancreatic cancer (PC) was considered in the past an orphan cancer type due to its low incidence, it may become in the future one of the leading causes of cancer death. Pancreatic ductal adenocarcinoma (PDAC) is the most frequent type of PC, being a highly aggressive malignancy and having a 5-year survival rate of less than 10%. Non-modifiable (family history, age, genetic susceptibility) and modifiable (smoking, alcohol, acute and chronic pancreatitis, diabetes mellitus, intestinal microbiota) risk factors are involved in PC pathogenesis. Chronic inflammation induced by various factors plays crucial roles in PC development from initiation to metastasis. In multiple malignant conditions such as PC, cytokines, chemokines, and growth factors activate the class I phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) (PI3K/AKT/mTOR) signaling pathway, which plays key roles in cell growth, survival, proliferation, metabolism, and motility. Currently, mTOR, AKT, and PI3K inhibitors are used in clinical studies. Moreover, PI3K/mTOR dual inhibitors are being tested in vitro and in vivo with promising results for PC patients. The main aim of this review is to present PC incidence, risk factors, tumor microenvironment development, and PI3K/AKT/mTOR dysregulation and inhibitors used in clinical, in vivo, and in vitro studies.
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Sun Y, Xie J, Cai S, Wang Q, Feng Z, Li Y, Lu JJ, Chen W, Ye Z. Elevated expression of nuclear receptor-binding SET domain 3 promotes pancreatic cancer cell growth. Cell Death Dis 2021; 12:913. [PMID: 34615858 PMCID: PMC8494902 DOI: 10.1038/s41419-021-04205-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Revised: 09/13/2021] [Accepted: 09/22/2021] [Indexed: 12/28/2022]
Abstract
The nuclear receptor-binding SET domain 3 (NSD3) catalyzes methylation of histone H3 at lysine 36 (H3K36), and promotes malignant transformation and progression of human cancer. Its expression, potential functions and underlying mechanisms in pancreatic cancer are studied. Bioinformatics studies and results from local human tissues show that NSD3 is upregulated in human pancreatic cancer tissues, which is correlated with poor overall survival. In primary and established pancreatic cancer cells, NSD3 silencing (by shRNAs) or CRISPR/Cas9-induced NSD3 knockout potently inhibited cell proliferation, migration and invasion, while provoking cell cycle arrest and apoptosis. Conversely, ectopic expression of NSD3-T1232A mutation significantly accelerated proliferation, migration, and invasion of pancreatic cancer cells. H3K36 dimethylation, expression of NSD3-dependent genes (Prkaa2, Myc, Irgm1, Adam12, and Notch3), and mTOR activation (S6K1 phosphorylation) were largely inhibited by NSD3 silencing or knockout. In vivo, intratumoral injection of adeno-associated virus (AAV)-packed NSD3 shRNA potently inhibited pancreatic cancer xenograft growth in nude mice. These results suggest that elevated NSD3 could be an important driver for the malignant progression of pancreatic cancer.
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Affiliation(s)
- Yihui Sun
- Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Jiaming Xie
- Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Shang Cai
- Department of Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Qian Wang
- Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Zhenyu Feng
- Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Yecheng Li
- Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Jing-Jing Lu
- Department of Radiotherapy and Oncology, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, China.
| | - Wei Chen
- Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China.
| | - Zhenyu Ye
- Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China.
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Miyabayashi K, Nakagawa H, Koike K. Molecular and Phenotypic Profiling for Precision Medicine in Pancreatic Cancer: Current Advances and Future Perspectives. Front Oncol 2021; 11:682872. [PMID: 34249730 PMCID: PMC8260689 DOI: 10.3389/fonc.2021.682872] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 06/04/2021] [Indexed: 12/14/2022] Open
Abstract
Pancreatic cancer is the most common lethal malignancy, with little improvement in patient outcomes over the decades. The development of early detection methods and effective therapeutic strategies are needed to improve the prognosis of patients with this disease. Recent advances in cancer genomics have revealed the genetic landscape of pancreatic cancer, and clinical trials are currently being conducted to match the treatment to underlying mutations. Liquid biopsy-based diagnosis is a promising method to start personalized treatment. In addition to genome-based medicine, personalized models have been studied as a tool to test candidate drugs to select the most efficacious treatment. The innovative three-dimensional organoid culture platform, as well as patient-derived xenografts can be used to conduct genomic and functional studies to enable personalized treatment approaches. Combining genome-based medicine with drug screening based on personalized models may fulfill the promise of precision medicine for pancreatic cancer.
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Affiliation(s)
| | - Hayato Nakagawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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Pham TND, Shields MA, Spaulding C, Principe DR, Li B, Underwood PW, Trevino JG, Bentrem DJ, Munshi HG. Preclinical Models of Pancreatic Ductal Adenocarcinoma and Their Utility in Immunotherapy Studies. Cancers (Basel) 2021; 13:cancers13030440. [PMID: 33503832 PMCID: PMC7865443 DOI: 10.3390/cancers13030440] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Revised: 01/13/2021] [Accepted: 01/20/2021] [Indexed: 12/18/2022] Open
Abstract
Simple Summary Immune checkpoint blockade has provided durable clinical responses in a number of human malignancies, but not in patients with pancreatic cancer. Efforts to understand mechanisms of resistance and increase efficacy of immune checkpoint blockade in pancreatic cancer require the use of appropriate preclinical models in the laboratory. Here, we discuss the benefits, caveats, and potentials for improvement of the most commonly used models, including murine-based and patient-derived models. Abstract The advent of immunotherapy has transformed the treatment landscape for several human malignancies. Antibodies against immune checkpoints, such as anti-PD-1/PD-L1 and anti-CTLA-4, demonstrate durable clinical benefits in several cancer types. However, checkpoint blockade has failed to elicit effective anti-tumor responses in pancreatic ductal adenocarcinoma (PDAC), which remains one of the most lethal malignancies with a dismal prognosis. As a result, there are significant efforts to identify novel immune-based combination regimens for PDAC, which are typically first tested in preclinical models. Here, we discuss the utility and limitations of syngeneic and genetically-engineered mouse models that are currently available for testing immunotherapy regimens. We also discuss patient-derived xenograft mouse models, human PDAC organoids, and ex vivo slice cultures of human PDAC tumors that can complement murine models for a more comprehensive approach to predict response and resistance to immunotherapy regimens.
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Affiliation(s)
- Thao N. D. Pham
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; (M.A.S.); (C.S.)
- Jesse Brown VA Medical Center, Chicago, IL 60612, USA;
- Correspondence: (T.N.D.P.); (H.G.M.); Tel.: +1-312-503-0312 (T.N.D.P.); +1-312-503-2301 (H.G.M.)
| | - Mario A. Shields
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; (M.A.S.); (C.S.)
- Robert H. Lurie Comprehensive Cancer Center, Chicago, IL 60611, USA
| | - Christina Spaulding
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; (M.A.S.); (C.S.)
- Jesse Brown VA Medical Center, Chicago, IL 60612, USA;
| | - Daniel R. Principe
- Medical Scientist Training Program, University of Illinois, Chicago, IL 60612, USA;
| | - Bo Li
- Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA;
| | - Patrick W. Underwood
- Department of Surgery, University of Florida, Gainesville, FL 32611, USA; (P.W.U.); (J.G.T.)
| | - Jose G. Trevino
- Department of Surgery, University of Florida, Gainesville, FL 32611, USA; (P.W.U.); (J.G.T.)
| | - David J. Bentrem
- Jesse Brown VA Medical Center, Chicago, IL 60612, USA;
- Robert H. Lurie Comprehensive Cancer Center, Chicago, IL 60611, USA
- Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA;
| | - Hidayatullah G. Munshi
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; (M.A.S.); (C.S.)
- Jesse Brown VA Medical Center, Chicago, IL 60612, USA;
- Robert H. Lurie Comprehensive Cancer Center, Chicago, IL 60611, USA
- Correspondence: (T.N.D.P.); (H.G.M.); Tel.: +1-312-503-0312 (T.N.D.P.); +1-312-503-2301 (H.G.M.)
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12
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Liu Y, Feng M, Chen H, Yang G, Qiu J, Zhao F, Cao Z, Luo W, Xiao J, You L, Zheng L, Zhang T. Mechanistic target of rapamycin in the tumor microenvironment and its potential as a therapeutic target for pancreatic cancer. Cancer Lett 2020; 485:1-13. [PMID: 32428662 DOI: 10.1016/j.canlet.2020.05.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 04/21/2020] [Accepted: 05/04/2020] [Indexed: 02/07/2023]
Abstract
Pancreatic cancer(PC) is a devastating disease with a poor prognosis; however, few treatment options are available and the search continues for feasible molecular therapeutic targets, both in the tumor itself and in the tumor microenvironment. The mechanistic target of rapamycin (mTOR) signaling pathway has emerged as an attractive target due to its regulatory role in multiple cellular processes, including metabolism, proliferation, survival, and differentiation, under physiological and pathological conditions. Although mTOR-regulated events in tumor cells and the tumor microenvironment are known to restrict the development and growth of tumor cells, monotherapy with mTOR inhibitors has shown limited efficacy against PC to date, suggesting the need for alternative approaches. In this review, we describe the mechanisms by which mTOR modulates the PC microenvironment and suggest ways its function in immune cells might be exploited for the treatment of PC. We also discuss preclinical and clinical studies with mTOR inhibitors in combination with other therapeutic strategies, most notably immunotherapy. Finally, we highlight the promise that mTOR combinatorial therapy may hold for the treatment of PC in the near future.
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Affiliation(s)
- Yueze Liu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Mengyu Feng
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, 100142, China; Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Hao Chen
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Gang Yang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Jiangdong Qiu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Fangyu Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Zhe Cao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Wenhao Luo
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Jianchun Xiao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Lei You
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Lianfang Zheng
- Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Taiping Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; Clinical Immunology Center, Chinese Academy of Medical Sciences, Beijing, 100730, China.
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13
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Wang CF, Shi XJ. Generation and application of patient-derived xenograft models in pancreatic cancer research. Chin Med J (Engl) 2019; 132:2729-2736. [PMID: 31725451 PMCID: PMC6940092 DOI: 10.1097/cm9.0000000000000524] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE Pancreatic ductal adenocarcinoma cancer (PDAC) is one of the leading causes of cancer-related death worldwide. Hence, the development of effective anti-PDAC therapies is urgently required. Patient-derived xenograft (PDX) models are useful models for developing anti-cancer therapies and screening drugs for precision medicine. This review aimed to provide an updated summary of using PDX models in PDAC. DATA SOURCES The author retrieved information from the PubMed database up to June 2019 using various combinations of search terms, including PDAC, pancreatic carcinoma, pancreatic cancer, patient-derived xenografts or PDX, and patient-derived tumor xenografts or PDTX. STUDY SELECTION Original articles and review articles relevant to the review's theme were selected. RESULTS PDX models are better than cell line-derived xenograft and other models. PDX models consistently demonstrate retained tumor morphology and genetic stability, are beneficial in cancer research, could enhance drug discovery and oncologic mechanism development of PDAC, allow an improved understanding of human cancer cell biology, and help guide personalized treatment. CONCLUSIONS In this review, we outline the status and application of PDX models in both basic and pre-clinical pancreatic cancer researches. PDX model is one of the most appropriate pre-clinical tools that can improve the prognosis of patients with pancreatic cancer in the future.
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Affiliation(s)
- Cheng-Fang Wang
- Department of Hepato-Biliary Surgery, The General Hospital of People's Liberation Army (301 hospital), Beijing 100853, China
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14
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Gemcitabine Combined with the mTOR Inhibitor Temsirolimus in Patients with Locally Advanced or Metastatic Pancreatic Cancer. A Hellenic Cooperative Oncology Group Phase I/II Study. Target Oncol 2019; 13:715-724. [PMID: 30488350 DOI: 10.1007/s11523-018-0605-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND The prognosis of patients with advanced pancreatic cancer is dismal, and there is a need for novel and effective treatments. OBJECTIVES Tο determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of a novel gemcitabine (G) and temsirolimus (T) combination (phase I) and estimate the 6-month progression-free survival (PFS) in patients treated with the T + G combination (phase II). PATIENTS AND METHODS Eligible patients with histologically confirmed inoperable or metastatic pancreatic carcinoma (MPC) were entered into the trial. G was given bi-weekly and T weekly in a 4-week cycle. The first dose level was set at G 800 mg/m2 and T 10 mg. G was escalated in increments of 200 mg/m2 and T in increments of 5 mg until DLT was reached, and the recommended dose was used for the phase II part. RESULTS Thirty patients were enrolled in the phase I component at the pre-planned six dose levels; one bilirubin DLT of grade III occurred at the first dose level. The MTD was established as the approved doses of both drugs. Fifty-five patients were entered into the phase II component. Median relative dose intensities administered in the first cycle were 0.75 for T and 0.99 for G. Grade 3-4 hematological toxicities were recorded in 87.3% of patients. The most common non-hematological adverse events were metabolic disorders (81.8%) followed by gastrointestinal disorders (63.6%). Median PFS was 2.69 months (95% CI 1.74-4.95) and median OS was 4.95 months (95% CI 3.54-6.85), while the 6-month PFS rate was 30.9%. CONCLUSIONS Combination of G and T is feasible in patients with locally advanced or MPC with manageable side effects, but lacks clinical efficacy. The study was registered in the Australian New Zealand Clinical Trials Registry (ACTRN12611000643976).
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15
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Parkin A, Man J, Timpson P, Pajic M. Targeting the complexity of Src signalling in the tumour microenvironment of pancreatic cancer: from mechanism to therapy. FEBS J 2019; 286:3510-3539. [PMID: 31330086 PMCID: PMC6771888 DOI: 10.1111/febs.15011] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2019] [Revised: 05/26/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023]
Abstract
Pancreatic cancer, a disease with extremely poor prognosis, has been notoriously resistant to virtually all forms of treatment. The dynamic crosstalk that occurs between tumour cells and the surrounding stroma, frequently mediated by intricate Src/FAK signalling, is increasingly recognised as a key player in pancreatic tumourigenesis, disease progression and therapeutic resistance. These important cues are fundamental for defining the invasive potential of pancreatic tumours, and several components of the Src and downstream effector signalling have been proposed as potent anticancer therapeutic targets. Consequently, numerous agents that block this complex network are being extensively investigated as potential antiinvasive and antimetastatic therapeutic agents for this disease. In this review, we will discuss the latest evidence of Src signalling in PDAC progression, fibrotic response and resistance to therapy. We will examine future opportunities for the development and implementation of more effective combination regimens, targeting key components of the oncogenic Src signalling axis, and in the context of a precision medicine-guided approach.
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Affiliation(s)
- Ashleigh Parkin
- The Kinghorn Cancer CentreThe Garvan Institute of Medical ResearchSydneyAustralia
| | - Jennifer Man
- The Kinghorn Cancer CentreThe Garvan Institute of Medical ResearchSydneyAustralia
| | - Paul Timpson
- The Kinghorn Cancer CentreThe Garvan Institute of Medical ResearchSydneyAustralia
- Faculty of MedicineSt Vincent's Clinical SchoolUniversity of NSWSydneyAustralia
| | - Marina Pajic
- The Kinghorn Cancer CentreThe Garvan Institute of Medical ResearchSydneyAustralia
- Faculty of MedicineSt Vincent's Clinical SchoolUniversity of NSWSydneyAustralia
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16
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Jeon J, Cheong JH. Clinical Implementation of Precision Medicine in Gastric Cancer. J Gastric Cancer 2019; 19:235-253. [PMID: 31598369 PMCID: PMC6769368 DOI: 10.5230/jgc.2019.19.e25] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Accepted: 07/28/2019] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer (GC) is one of the deadliest malignancies in the world. Currently, clinical treatment decisions are mostly made based on the extent of the tumor and its anatomy, such as tumor-node-metastasis staging. Recent advances in genome-wide molecular technology have enabled delineation of the molecular characteristics of GC. Based on this, efforts have been made to classify GC into molecular subtypes with distinct prognosis and therapeutic response. Simplified algorithms based on protein and RNA expressions have been proposed to reproduce the GC classification in the clinical field. Furthermore, a recent study established a single patient classifier (SPC) predicting the prognosis and chemotherapy response of resectable GC patients based on a 4-gene real-time polymerase chain reaction assay. GC patient stratification according to SPC will enable personalized therapeutic strategies in adjuvant settings. At the same time, patient-derived xenografts and patient-derived organoids are now emerging as novel preclinical models for the treatment of GC. These models recapitulate the complex features of the primary tumor, which is expected to facilitate both drug development and clinical therapeutic decision making. An integrated approach applying molecular patient stratification and patient-derived models in the clinical realm is considered a turning point in precision medicine in GC.
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Affiliation(s)
- Jaewook Jeon
- Yonsei University College of Medicine, Seoul, Korea
| | - Jae-Ho Cheong
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea.,Yonsei Biomedical Research Institute, Yonsei University College of Medicine, Seoul, Korea.,Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.,Department of Biochemistry & Molecular Biology, Yonsei University College of Medicine, Seoul, Korea.,Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Korea
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EMT and Stemness-Key Players in Pancreatic Cancer Stem Cells. Cancers (Basel) 2019; 11:cancers11081136. [PMID: 31398893 PMCID: PMC6721598 DOI: 10.3390/cancers11081136] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2019] [Revised: 08/01/2019] [Accepted: 08/06/2019] [Indexed: 12/15/2022] Open
Abstract
Metastasis and tumor progression are the major cause of death in patients suffering from pancreatic ductal adenocarcinoma. Tumor growth and especially dissemination are typically associated with activation of an epithelial-to-mesenchymal transition (EMT) program. This phenotypic transition from an epithelial to a mesenchymal state promotes migration and survival both during development and in cancer progression. When re-activated in pathological contexts such as cancer, this type of developmental process confers additional stemness properties to specific subsets of cells. Cancer stem cells (CSCs) are a subpopulation of cancer cells with stem-like features that are responsible for the propagation of the tumor as well as therapy resistance and cancer relapse, but also for circulating tumor cell release and metastasis. In support of this concept, EMT transcription factors generate cells with stem cell properties and mediate chemoresistance. However, their role in pancreatic ductal adenocarcinoma metastasis remains controversial. As such, a better characterization of CSC populations will be crucial in future development of therapies targeting these cells. In this review, we will discuss the latest updates on the mechanisms common to pancreas development and CSC-mediated tumor progression.
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Abstract
Immunotherapy is one of the most exciting recent breakthroughs in the field of cancer treatment. Many different approaches are being developed and a number have already gained regulatory approval or are under investigation in clinical trials. However, learning from the past, preclinical animal models often insufficiently reflect the physiological situation in humans, which subsequently causes treatment failures in clinical trials. Due to species-specific differences in most parts of the immune system, the transfer of knowledge from preclinical studies to clinical trials is eminently challenging. Human tumor cell line-based or patient-derived xenografts in immunocompromised mice have been successfully applied in the preclinical testing of cytotoxic or molecularly targeted agents, but naturally these systems lack the human immune system counterpart. The co-transplantation of human peripheral blood mononuclear cells or hematopoietic stem cells is employed to overcome this limitation. This review summarizes some important aspects of the different available tumor xenograft mouse models, their history, and their implementation in drug development and personalized therapy. Moreover, recent progress, opportunities and limitations of different humanized mouse models will be discussed.
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Wu CX, Wang XQ, Chok SH, Man K, Tsang SHY, Chan ACY, Ma KW, Xia W, Cheung TT. Blocking CDK1/PDK1/β-Catenin signaling by CDK1 inhibitor RO3306 increased the efficacy of sorafenib treatment by targeting cancer stem cells in a preclinical model of hepatocellular carcinoma. Theranostics 2018; 8:3737-3750. [PMID: 30083256 PMCID: PMC6071527 DOI: 10.7150/thno.25487] [Citation(s) in RCA: 145] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2018] [Accepted: 05/20/2018] [Indexed: 12/31/2022] Open
Abstract
Rationale: Hepatocellular carcinoma (HCC) is an aggressive malignant solid tumor wherein CDK1/PDK1/β-Catenin is activated, suggesting that inhibition of this pathway may have therapeutic potential. Methods: CDK1 overexpression and clinicopathological parameters were analyzed. HCC patient-derived xenograft (PDX) tumor models were treated with RO3306 (4 mg/kg) or sorafenib (30 mg/kg), alone or in combination. The relevant signaling of CDK1/PDK1/β-Catenin was measured by western blot. Silencing of CDK1 with shRNA and corresponding inhibitors was performed for mechanism and functional studies. Results: We found that CDK1 was frequently augmented in up to 46% (18/39) of HCC tissues, which was significantly associated with poor overall survival (p=0.008). CDK1 inhibitor RO3306 in combination with sorafenib treatment significantly decreased tumor growth in PDX tumor models. Furthermore, the combinatorial treatment could overcome sorafenib resistance in the HCC case #10 PDX model. Western blot results demonstrated the combined administration resulted in synergistic down-regulation of CDK1, PDK1 and β-Catenin as well as concurrent decreases of pluripotency proteins Oct4, Sox2 and Nanog. Decreased CDK1/PDK1/β-Catenin was associated with suppression of epithelial mesenchymal transition (EMT). In addition, a low dose of RO3306 and sorafenib combination could inhibit 97H CSC growth via decreasing the S phase and promoting cells to enter into a Sub-G1 phase. Mechanistic and functional studies silencing CDK1 with shRNA and RO3306 combined with sorafenib abolished oncogenic function via downregulating CDK1, with downstream PDK1 and β-Catenin inactivation. Conclusion: Anti-CDK1 treatment can boost sorafenib antitumor responses in PDX tumor models, providing a rational combined treatment to increase sorafenib efficacy in the clinic.
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Affiliation(s)
- Chuan Xing Wu
- Department of Surgery, The University of Hong Kong, Hong Kong
| | - Xiao Qi Wang
- Department of Surgery, The University of Hong Kong, Hong Kong
- Department of Medicine, The University of Hong Kong, Hong Kong
| | - Siu Ho Chok
- Department of Surgery, The University of Hong Kong, Hong Kong
| | - Kwan Man
- Department of Surgery, The University of Hong Kong, Hong Kong
| | | | | | - Ka Wing Ma
- Department of Surgery, The University of Hong Kong, Hong Kong
| | - Wei Xia
- Department of Surgery, The University of Hong Kong, Hong Kong
| | - Tan To Cheung
- Department of Surgery, The University of Hong Kong, Hong Kong
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Izumchenko E, Paz K, Ciznadija D, Sloma I, Katz A, Vasquez-Dunddel D, Ben-Zvi I, Stebbing J, McGuire W, Harris W, Maki R, Gaya A, Bedi A, Zacharoulis S, Ravi R, Wexler LH, Hoque MO, Rodriguez-Galindo C, Pass H, Peled N, Davies A, Morris R, Hidalgo M, Sidransky D. Patient-derived xenografts effectively capture responses to oncology therapy in a heterogeneous cohort of patients with solid tumors. Ann Oncol 2018; 28:2595-2605. [PMID: 28945830 DOI: 10.1093/annonc/mdx416] [Citation(s) in RCA: 227] [Impact Index Per Article: 32.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Background While patient-derived xenografts (PDXs) offer a powerful modality for translational cancer research, a precise evaluation of how accurately patient responses correlate with matching PDXs in a large, heterogeneous population is needed for assessing the utility of this platform for preclinical drug-testing and personalized patient cancer treatment. Patients and methods Tumors obtained from surgical or biopsy procedures from 237 cancer patients with a variety of solid tumors were implanted into immunodeficient mice and whole-exome sequencing was carried out. For 92 patients, responses to anticancer therapies were compared with that of their corresponding PDX models. Results We compared whole-exome sequencing of 237 PDX models with equivalent information in The Cancer Genome Atlas database, demonstrating that tumorgrafts faithfully conserve genetic patterns of the primary tumors. We next screened PDXs established for 92 patients with various solid cancers against the same 129 treatments that were administered clinically and correlated patient outcomes with the responses in corresponding models. Our analysis demonstrates that PDXs accurately replicate patients' clinical outcomes, even as patients undergo several additional cycles of therapy over time, indicating the capacity of these models to correctly guide an oncologist to treatments that are most likely to be of clinical benefit. Conclusions Integration of PDX models as a preclinical platform for assessment of drug efficacy may allow a higher success-rate in critical end points of clinical benefit.
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Affiliation(s)
- E Izumchenko
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, R&D, Baltimore
| | - K Paz
- Champions Oncology, R&D, Baltimore, USA
| | | | - I Sloma
- Champions Oncology, R&D, Baltimore, USA
| | - A Katz
- Champions Oncology, R&D, Baltimore, USA
| | | | - I Ben-Zvi
- Champions Oncology, R&D, Baltimore, USA
| | - J Stebbing
- Department of Surgery & Cancer, Imperial College, London, UK
| | - W McGuire
- Department of Internal Medicine, Division of Hematology/Oncology, Virginia Commonwealth University, Massey Cancer Center, Virginia Commonwealth University, Richmond
| | - W Harris
- Department of Medicine, Division of Oncology, University of Washington, Seattle
| | - R Maki
- Department of Pediatric Hematology Oncology, Mount Sinai School of Medicine, New York, USA
| | - A Gaya
- Guy's and St Thomas' Cancer Center, London
| | - A Bedi
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, R&D, Baltimore
| | - S Zacharoulis
- Department of Pediatric Oncology, The Royal Marsden Hospital, Harley Street Clinic, Sutton, UK
| | - R Ravi
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, R&D, Baltimore
| | - L H Wexler
- Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York
| | - M O Hoque
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, R&D, Baltimore
| | | | - H Pass
- Department of Cardiothoracic Surgery, New York University Langone Medical Center, New York, USA
| | - N Peled
- Research and Detection Unit for Thoracic malignancies, Sheba Medical Center, Tel Aviv, Israel
| | - A Davies
- Champions Oncology, R&D, Baltimore, USA
| | - R Morris
- Champions Oncology, R&D, Baltimore, USA
| | - M Hidalgo
- Division of Hematology-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA
| | - D Sidransky
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, R&D, Baltimore.
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Sereti E, Karagianellou T, Kotsoni I, Magouliotis D, Kamposioras K, Ulukaya E, Sakellaridis N, Zacharoulis D, Dimas K. Patient Derived Xenografts (PDX) for personalized treatment of pancreatic cancer: emerging allies in the war on a devastating cancer? J Proteomics 2018; 188:107-118. [PMID: 29398619 DOI: 10.1016/j.jprot.2018.01.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2017] [Revised: 01/10/2018] [Accepted: 01/19/2018] [Indexed: 12/14/2022]
Abstract
The prognosis of pancreatic ductal adenocarcinoma (PDAC), the eighth most lethal cancer for men and ninth for women worldwide, remains dismal. The increasing rates of deaths by PDAC indicate that the overall management of the disease in 21st century is still insufficient. Thus it is obvious that there is an unmet need to improve management of PDAC by finding new biomarkers to screen high risk patients, confirm diagnosis, and predict response to treatment as well more efficacious and safer treatments. Patient Derived Xenografts (PDX) have been developed as a new promising tool in an effort to mirror genetics, tumor heterogeneity and cancer microenvironment of the primary tumor. Herein we aim to give an updated overview of the current status and the perspectives of PDX in the search for the identification of novel biomarkers and improved therapeutic outcomes for PDAC but also their use as a valuable tool towards individualized treatments to improve the outcome of the disease. Furthermore, we critically review the applications, advantages, limitations, and perspectives of PDX in the research towards an improved management of PDAC. SIGNIFICANCE This review provides a comprehensive overview of the current status and the potential role as well as the challenges of PDX in the road to fight one of the most lethal cancers in the developed countries, pancreatic ductal adenocarcinoma.
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Affiliation(s)
- Evangelia Sereti
- Department of Pharmacology, Faculty of Medicine, University of Thessaly, Larissa, Greece
| | | | - Ioanna Kotsoni
- Department of Pharmacology, Faculty of Medicine, University of Thessaly, Larissa, Greece
| | - Dimitrios Magouliotis
- Department of Pharmacology, Faculty of Medicine, University of Thessaly, Larissa, Greece; Department of Surgery, University Hospital of Larissa, Larissa, Greece
| | - Konstantinos Kamposioras
- Department of Medical Oncology, The Mid Yorkshire Hospitals NHS Trust, Wakefield, United Kingdom
| | - Engin Ulukaya
- Istinye University, Faculty of Medicine, Department of Clinical Biochemistry, Istanbul, Turkey
| | - Nikos Sakellaridis
- Department of Pharmacology, Faculty of Medicine, University of Thessaly, Larissa, Greece
| | | | - Konstantinos Dimas
- Department of Pharmacology, Faculty of Medicine, University of Thessaly, Larissa, Greece.
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22
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Hassan Z, Schneeweis C, Wirth M, Veltkamp C, Dantes Z, Feuerecker B, Ceyhan GO, Knauer SK, Weichert W, Schmid RM, Stauber R, Arlt A, Krämer OH, Rad R, Reichert M, Saur D, Schneider G. MTOR inhibitor-based combination therapies for pancreatic cancer. Br J Cancer 2018; 118:366-377. [PMID: 29384525 PMCID: PMC5808033 DOI: 10.1038/bjc.2017.421] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Revised: 10/25/2017] [Accepted: 10/26/2017] [Indexed: 12/13/2022] Open
Abstract
Background: Although the mechanistic target of rapamycin (MTOR) kinase, included in the mTORC1 and mTORC2 signalling hubs, has been demonstrated to be active in a significant fraction of patients with pancreatic ductal adenocarcinoma (PDAC), the value of the kinase as a therapeutic target needs further clarification. Methods: We used Mtor floxed mice to analyse the function of the kinase in context of the pancreas at the genetic level. Using a dual-recombinase system, which is based on the flippase-FRT (Flp-FRT) and Cre-loxP recombination technologies, we generated a novel cellular model, allowing the genetic analysis of MTOR functions in tumour maintenance. Cross-species validation and pharmacological intervention studies were used to recapitulate genetic data in human models, including primary human 3D PDAC cultures. Results: Genetic deletion of the Mtor gene in the pancreas results in exocrine and endocrine insufficiency. In established murine PDAC cells, MTOR is linked to metabolic pathways and maintains the glucose uptake and growth. Importantly, blocking MTOR genetically as well as pharmacologically results in adaptive rewiring of oncogenic signalling with activation of canonical extracellular signal-regulated kinase and phosphoinositide 3-kinase-AKT pathways. We provide evidence that interfering with such adaptive signalling in murine and human PDAC models is important in a subgroup. Conclusions: Our data suggest developing dual MTORC1/TORC2 inhibitor-based therapies for subtype-specific intervention.
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Affiliation(s)
- Zonera Hassan
- Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University Munich, 81675 München, Germany
| | - Christian Schneeweis
- Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University Munich, 81675 München, Germany
| | - Matthias Wirth
- Institute of Pathology, Heinrich-Heine University and University Hospital Düsseldorf, 40225 Düsseldorf, Germany
| | - Christian Veltkamp
- Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University Munich, 81675 München, Germany
| | - Zahra Dantes
- Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University Munich, 81675 München, Germany
| | - Benedikt Feuerecker
- Department of Nuclear Medicine, Klinikum rechts der Isar, Technical University Munich, 81675 München, Germany.,German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
| | - Güralp O Ceyhan
- Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, 81675 München, Germany
| | - Shirley K Knauer
- Molecular Biology, Centre for Medical Biotechnology (ZMB), University Duisburg-Essen, 45141 Essen, Germany
| | - Wilko Weichert
- Institute of Pathology, Technische Universität München, 81675 München, Germany
| | - Roland M Schmid
- Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University Munich, 81675 München, Germany
| | - Roland Stauber
- Molecular and Cellular Oncology/ENT, University Medical Center Mainz, Langenbeckstrasse 1, Mainz 55131, Germany
| | - Alexander Arlt
- Laboratory of Molecular Gastroenterology and Hepatology, 1st Department of Internal Medicine, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Oliver H Krämer
- Department of Toxicology, University of Mainz Medical Center, Mainz 55131, Germany
| | - Roland Rad
- Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University Munich, 81675 München, Germany.,German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
| | - Maximilian Reichert
- Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University Munich, 81675 München, Germany.,Division of Gastroenterology and Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Dieter Saur
- Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University Munich, 81675 München, Germany.,German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
| | - Günter Schneider
- Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University Munich, 81675 München, Germany.,German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
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23
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Zhang JW, Zhao F, Sun Q. Metformin synergizes with rapamycin to inhibit the growth of pancreatic cancer in vitro and in vivo. Oncol Lett 2017; 15:1811-1816. [PMID: 29434877 DOI: 10.3892/ol.2017.7444] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Accepted: 10/13/2017] [Indexed: 01/28/2023] Open
Abstract
Previous studies have suggested that metformin may improve the survival rate of patients with pancreatic cancer (PC) by regulating the adenosine monophosphate-activated protein kinase/mammalian target of rapamycin (mTOR) signaling pathway. Rapamycin specifically targets mTOR. In the present study, the efficacy of metformin and rapamycin in isolation and combination were investigated for the treatment of PC. The efficacy of metformin and rapamycin in reducing the proliferation of PC cell line SW1990 in vitro and in vivo was evaluated. It was revealed that metformin (10 mmol/l) + rapamycin (2 ng/ml), metformin (15 mmol/l) + rapamycin (20 ng/ml) and metformin (20 mmol/l) + rapamycin (200 ng/ml) significantly inhibited the viability of PC cells compared with untreated cells. Additionally, metformin (20 mmol/l) + rapamycin (200 ng/ml) significantly suppressed the expression of phosphorylated mTOR compared with metformin or rapamycin alone. Using a xenograft tumor model, it was revealed that combination treatment significantly inhibited the growth of PC cells compared with monotherapy. The present study revealed that a combination of metformin and rapamycin synergistically inhibited the growth of PC in vitro and in vivo and may be a potential treatment option for patients with PC.
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Affiliation(s)
- Jia-Wei Zhang
- Department of Oncology, Wuxi No. 2 People's Hospital, Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214000, P.R. China
| | - Fan Zhao
- Department of Oncology, Wuxi No. 2 People's Hospital, Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214000, P.R. China
| | - Qing Sun
- Department of Oncology, Wuxi No. 2 People's Hospital, Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214000, P.R. China
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24
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Jung J, Seol HS, Chang S. The Generation and Application of Patient-Derived Xenograft Model for Cancer Research. Cancer Res Treat 2017; 50:1-10. [PMID: 28903551 PMCID: PMC5784646 DOI: 10.4143/crt.2017.307] [Citation(s) in RCA: 198] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Accepted: 09/08/2017] [Indexed: 12/26/2022] Open
Abstract
Establishing an appropriate preclinical model is crucial for translational cancer research. The most common way that has been adopted by far is grafting cancer cell lines, derived from patients. Although this xenograft model is easy to generate, but has several limitations because this cancer model could not represent the unique features of each cancer patient sufficiently. Moreover, accumulating evidences demonstrate cancer is a highly heterogeneous disease so that a tumor is comprised of cancer cells with diverse characteristics. In attempt to avoid these discrepancies between xenograft model and patients' tumor, a patient-derived xenograft (PDX) model has been actively generated and applied. The PDX model can be developed by the implantation of cancerous tissue from a patient's tumor into an immune-deficient mouse directly, thereby it preserves both cell-cell interactions and tumor microenvironment. In addition, the PDX model has shown advantages as a preclinical model in drug screening, biomarker development and co-clinical trial. In this review, we will summarize the methodology and applications of PDX in detail, and cover critical issues for the development of this model for preclinical research.
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Affiliation(s)
- Jaeyun Jung
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hyang Sook Seol
- Asan Institute for Life Science, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Suhwan Chang
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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25
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Harris AL, Joseph RW, Copland JA. Patient-derived tumor xenograft models for melanoma drug discovery. Expert Opin Drug Discov 2017; 11:895-906. [PMID: 27454070 DOI: 10.1080/17460441.2016.1216968] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
INTRODUCTION Cutaneous metastatic melanoma (MM) is an aggressive form of skin cancer, with treatment providing cures to a minority of patients. The multiple risk factors that contribute to MM development suggest that cutaneous melanomas embody a repertoire of altered genetic events requiring studies to better understand its biology in order to develop novel therapies. AREAS COVERED Patient-derived tumor xenograft (PDTX) mouse models are noted to be superior for novel drug discovery and tumor biology studies due to their ability to maintain tumor heterogeneity and their use as real-time individualized patient models. In this review, the authors highlight the utility of PDTX models in advancing treatment options for patients with MM by creating invaluable preclinical models that exhibit patient-relevant treatment outcomes. EXPERT OPINION There is a strong necessity to reassess current approaches in which preclinical experiments are designed and executed in order to minimize unwarranted clinical trials. With rigorously performed preclinical studies, PDTX models have the capability to effectively confirm or deny drug effective outcomes. The ability to do this, however, will demand better aids to guide experimental design, the redefining of preclinical efficacy, and the understanding that these models should be viewed as complementary to other drug prediction and efficacy tools.
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Affiliation(s)
- Antoneicka L Harris
- a Center for Clinical and Translational Sciences , Mayo Clinic College of Medicine , Rochester , MN , USA
| | - Richard W Joseph
- b Division of Hematology/Oncology, Department of Medicine , Mayo Clinic , Jacksonville , FL , USA
| | - John A Copland
- c Department of Cancer Biology , Mayo Clinic Florida , Jacksonville , FL , USA
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26
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Roife D, Dai B, Kang Y, Perez MVR, Pratt M, Li X, Fleming JB. Ex Vivo Testing of Patient-Derived Xenografts Mirrors the Clinical Outcome of Patients with Pancreatic Ductal Adenocarcinoma. Clin Cancer Res 2016; 22:6021-6030. [PMID: 27259561 PMCID: PMC5136340 DOI: 10.1158/1078-0432.ccr-15-2936] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Revised: 05/20/2016] [Accepted: 05/25/2016] [Indexed: 01/06/2023]
Abstract
PURPOSE Translation of the patient-derived xenograft (PDX) model into a method for practical personalized cancer treatment is prevented by the intense resources and time necessary to generate and test each tumorgraft. We aimed to develop a high-throughput ex vivo drug testing approach that can be used for personalized cancer treatment design. EXPERIMENTAL DESIGN We developed a unique ex vivo live tissue sensitivity assay (LTSA), in which precision-cut and uniform small tissue slices derived from pancreatic ductal adenocarcinoma PDX tumors were arrayed in a 96-well plate and screened against clinically relevant regimens within 3 to 5 days. The correlation between the sensitivities of tissue slices to the regimens and patients' clinical responses and outcome were statistically analyzed. The results of LTSA assay were further confirmed with biochemical methods in vitro and animal PDX model in vivo RESULTS: The ex vivo tissue slices remain viable for at least 5 days, and the tumor parenchyma, including stroma, vascular structures, and signaling pathways, are all retained. The sensitivities of the ex vivo tissue slices to gemcitabine and irinotecan was consistent with the clinical responses and outcomes of the patients from whom the tumorgrafts were derived (r = 0.77; P = 0.0002). Retrospective analysis showed that the patients who received LTSA-sensitive regimens had remarkably longer progression-free survival than patients who received LTSA-resistant regimens (16.33 vs. 3.8 months; n = 18, P = 0.011). CONCLUSIONS The results from these PDX and LTSA methods reflect clinical patients' responses and could be used as a personalized strategy for improving systemic therapy effectiveness in patients with pancreatic cancer. Clin Cancer Res; 22(24); 6021-30. ©2016 AACR.
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Affiliation(s)
- David Roife
- Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA
| | - Bingbing Dai
- Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA
| | - Ya'an Kang
- Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA
| | - Mayrim V. Rios Perez
- Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA
| | - Michael Pratt
- Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA
| | - Xinqun Li
- Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA
| | - Jason B. Fleming
- Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA
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27
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Vijayvergia N, Cohen SJ. Personalized medicine in sporadic pancreatic cancer without homologous recombination-deficiency: are we any closer? J Gastrointest Oncol 2016; 7:727-737. [PMID: 27747087 PMCID: PMC5056260 DOI: 10.21037/jgo.2016.08.01] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Accepted: 06/14/2016] [Indexed: 12/12/2022] Open
Abstract
Pancreatic adenocarcinoma is the fourth leading cause of cancer related death in the United States. Most patients are diagnosed at a late stage and despite recent advances in chemotherapeutic approaches, outcomes are poor. With the introduction of combination chemotherapy, novel biomarkers are clearly needed to identify subsets of patients likely to benefit from these therapies. Advances in our understanding of the molecular drivers of pancreatic cancer offer the hope of personalized therapy that may benefit our patients. In this review, we summarize the current knowledge about the biology of pancreatic cancer and its implication for treatment. We discuss recent advances in targeted therapies and the role of potential biomarkers in predicting response to established therapies. We also review novel therapeutic approaches that may be able to fulfill the promise of personalized therapy for pancreatic cancer.
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Affiliation(s)
- Namrata Vijayvergia
- Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| | - Steven J Cohen
- Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
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28
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Kaida H, Azuma K, Kawahara A, Yasunaga M, Kitasato Y, Hattori S, Taira T, Ureshino H, Kage M, Ishii K, Murakami T, Ishibashi M. The correlation between FDG uptake and biological molecular markers in pancreatic cancer patients. Eur J Radiol 2016; 85:1804-1810. [PMID: 27666620 DOI: 10.1016/j.ejrad.2016.08.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2016] [Revised: 08/08/2016] [Accepted: 08/09/2016] [Indexed: 12/18/2022]
Abstract
PURPOSE We examined whether fluorine-18 fluorodeoxyglucose (FDG) uptake is related to the mammalian target of rapamycin (mTOR) signal pathway and its related proteins in pancreatic cancer patients. METHODS We retrospectively studied 53 pancreatic cancer patients who underwent FDG positron emission tomography (PET) or FDG PET/CT, and complete curative surgical resection. The SUV max, the tumor to nontumor activity of pancreas [T/N (P)] ratio and the T/N of liver [T/N (L)] ratio were calculated. The expressions of glucose transporter-1(Glut-1) and mTOR pathway proteins in pancreas cell lines were examined by immune blots. Excised tumor tissue was analyzed by immunohistochemistry using monoclonal antibodies for Glut-1, epidermal growth factor receptor (EGFR), mTOR, p70S6kinase (p70S6) and S6 ribosomal protein (S6). RESULTS The expressions of Glut-1, EGFR and p70S6 were significantly correlated with the SUV max, T/N (P) ratio and T/N (L) ratio. The expressions of mTOR and S6 were not correlated with all parameters. The expression of Glut-1 was positively correlated with the expressions of EGFR and p70S6, but not with mTOR or S6. S6 was positively correlated with p70S6. CONCLUSIONS Glut-1, EGFR and p70S6 expressions are associated with the FDG uptake mechanism of pancreatic cancer. FDG uptake may predict the levels of EGFR and p70S6 expressions, and FDG uptake reflects glucose metabolism and cancer progression.
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Affiliation(s)
- Hayato Kaida
- Department of Radiology, Kindai University Faculty of Medicine, Osakasayama City, Osaka, 589-8511, Japan.
| | - Koichi Azuma
- Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume City, Fukuoka, 830-0011, Japan
| | - Akihiko Kawahara
- Department of Diagnostic Pathology, Kurume University Hospital, Kurume City, Fukuoka, 830-0011, Japan
| | - Masafumi Yasunaga
- Department of Surgery, Kurume University School of Medicine, Kurume City, Fukuoka, 830-0011, Japan
| | - Yuhei Kitasato
- Department of Surgery, Kurume University School of Medicine, Kurume City, Fukuoka, 830-0011, Japan
| | - Satoshi Hattori
- Biostatic Center, Kurume University School of Medicine, Kurume City, Fukuoka, 830-0011, Japan
| | - Tomoki Taira
- Department of Diagnostic Pathology, Kurume University Hospital, Kurume City, Fukuoka, 830-0011, Japan
| | - Hiroki Ureshino
- Department of Surgery, Kurume University School of Medicine, Kurume City, Fukuoka, 830-0011, Japan
| | - Masayoshi Kage
- Department of Diagnostic Pathology, Kurume University Hospital, Kurume City, Fukuoka, 830-0011, Japan
| | - Kazunari Ishii
- Department of Radiology, Kindai University Faculty of Medicine, Osakasayama City, Osaka, 589-8511, Japan
| | - Takamichi Murakami
- Department of Radiology, Kindai University Faculty of Medicine, Osakasayama City, Osaka, 589-8511, Japan
| | - Masatoshi Ishibashi
- Division of Nuclear Medicine, PET Center, and Department of Radiology, Fukuoka Tokushukai Hospital, Kasuga City, Fukuoka, 816-0864, Japan
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29
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Bousquet G, Janin A. Patient-Derived Xenograft: An Adjuvant Technology for the Treatment of Metastatic Disease. Pathobiology 2016; 83:170-6. [PMID: 27010922 DOI: 10.1159/000444533] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Accepted: 02/08/2016] [Indexed: 11/19/2022] Open
Abstract
The occurrence of metastases severely affects prognosis for patients with cancer, making metastatic disease a daily societal challenge. Because of resistance to drugs, the potential curability with chemotherapy at the metastatic stage remains low. Large genomic analyses to identify new targets have their limitations due to intratumor heterogeneity when they are performed on tumor samples from primary tumors and because the functional value of molecular abnormalities in a cancer is usually not known. Additional tools are thus required for the development of new anticancer agents. The use of preclinical models is a key component of translational research in oncology. For four decades, xenograft models of human cancer cell lines injected subcutaneously in immunocompromised mice have been widely used, with disappointing results for predicting the clinical benefit of a new drug. Patient-derived xenografts are preclinical models rediscovered as innovative pharmacological tools, both for the preclinical development of anticancer drugs and as individual models for personalized treatment of metastatic disease. Here, we review the recent progress reported using patient-derived xenografts for the treatment of metastatic disease, and discuss the feasibility of their implementation in daily oncological care.
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Affiliation(s)
- Guilhem Bousquet
- UMR-S 1165, Laboratoire de Pathologie, Sorbonne Paris Citx00E9;, Universitx00E9; Paris Diderot, Paris, France
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30
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Izumchenko E, Meir J, Bedi A, Wysocki PT, Hoque MO, Sidransky D. Patient-derived xenografts as tools in pharmaceutical development. Clin Pharmacol Ther 2016; 99:612-21. [PMID: 26874468 DOI: 10.1002/cpt.354] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Revised: 02/20/2016] [Accepted: 02/11/2016] [Indexed: 12/16/2022]
Abstract
Successful drug development in oncology is grossly suboptimal, manifested by the very low percentage of new agents being developed that ultimately succeed in clinical approval. This poor success is in part due to the inability of standard cell-line xenograft models to accurately predict clinical success and to tailor chemotherapy specifically to a group of patients more likely to benefit from the therapy. Patient-derived xenografts (PDXs) maintain the histopathological architecture and molecular features of human tumors, and offer a potential solution to maximize drug development success and ultimately generate better outcomes for patients. Although imperfect in mimicking all aspects of human cancer, PDXs are a more predictable platform for preclinical evaluation of treatment effect and in selected cases can guide therapeutic decision making in the clinic. This article summarizes the current status of PDX models, challenges associated with modeling human cancer, and various approaches that have been applied to overcome these challenges and improve the clinical relevance of PDX cancer models.
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Affiliation(s)
- E Izumchenko
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - J Meir
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - A Bedi
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - P T Wysocki
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - M O Hoque
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - D Sidransky
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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31
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Sia D, Moeini A, Labgaa I, Villanueva A. The future of patient-derived tumor xenografts in cancer treatment. Pharmacogenomics 2015; 16:1671-83. [PMID: 26402657 DOI: 10.2217/pgs.15.102] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Over the last decades, major technological advancements have led to a better understanding of the molecular drivers of human malignancies. Nonetheless, this progress only marginally impacted the cancer therapeutic approach, probably due to the limited ability of experimental models to predict efficacy in clinical trials. In an effort to offset this limitation, there has been an increasing interest in the development of patient-derived xenograft (PDX) models where human tumors are xenotransplanted into immunocompromised mice. Considering their high resemblance to human tumors and their stability, PDX models are becoming the preferred translational tools in preclinical studies. Nonetheless, several limitations hamper a wider use of PDX models and tarnish the concept that they might represent the missing piece in the personalized medicine puzzle.
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Affiliation(s)
- Daniela Sia
- Barcelona-Clínic Liver Cancer Group, HCC Translational Research Laboratory, Liver Unit, Hepato-biliary Surgery, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, CIBERehd, Universitat de Barcelona, C/Rossello 153, Barcelona, Catalonia, Spain.,Gastrointestinal Surgery & Liver Transplantation Unit, Department of Surgery, National Cancer Institute, via Venezian, 1, Milan, Italy.,Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue NY 10029, USA
| | - Agrin Moeini
- Barcelona-Clínic Liver Cancer Group, HCC Translational Research Laboratory, Liver Unit, Hepato-biliary Surgery, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, CIBERehd, Universitat de Barcelona, C/Rossello 153, Barcelona, Catalonia, Spain.,Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue NY 10029, USA
| | - Ismail Labgaa
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue NY 10029, USA
| | - Augusto Villanueva
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue NY 10029, USA.,Division of Hematology & Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, NY, USA
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32
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Zhang D, Xia H, Zhang W, Fang B. The anti-ovarian cancer activity by WYE-132, a mTORC1/2 dual inhibitor. Tumour Biol 2015; 37:1327-36. [PMID: 26293898 DOI: 10.1007/s13277-015-3922-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Accepted: 08/11/2015] [Indexed: 11/24/2022] Open
Abstract
Epithelial ovarian cancer is the most common and lethal gynecological cancer in USA and around the world, causing major mortality annually. In the current study, we investigated the potential anti-ovarian cancer activity of WYE-132, a mammalian target of rapamycin (mTOR) complex 1/2 (mTORC1/2) dual inhibitor. Our results showed that WYE-132 potently inhibited proliferation of primary and established human ovarian cancer cells. Meanwhile, WYE-132 induced caspase-dependent apoptosis in ovarian cancer cells. At the molecular level, WYE-132 blocked mTORC1/2 activation and inhibited expression of mTOR-regulated genes (cyclin D1 and hypoxia-inducible factor 1α). Interestingly, introducing a constitutively active AKT (caAKT), which restored mTORC1/2 activation in WYE-132-treated ovarian cancer cells, only mitigated (but not abolished) WYE-132-mediated growth inhibition and apoptosis. Further studies showed that WYE-132 inhibited sphingosine kinase-1 (SphK1) activity, leading to pro-apoptotic ceramide production in ovarian cancer cells. Meanwhile, WYE-132-induced cytotoxicity against ovarian cancer cells was inhibited by sphingosine-1-phosphate (S1P) but was aggravated by SphK1 inhibitor SKI-II or C6 ceramide. In vivo, WYE-132 inhibited ovarian cancer cell growth, and its activity was further enhanced when co-administrated with paclitaxel (Taxol). These results demonstrate that WYE-132 inhibits ovarian cancer cell proliferation through mTOR-dependent and mTOR-independent mechanisms and indicate a potential value of WYE-132 in ovarian cancer treatment.
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Affiliation(s)
- Dan Zhang
- Department of Obstetrics and Gynecology, Ruijin Hospital affiliated to Shanghai Jiaotong University, Shanghai, China.,Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Hexia Xia
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Wei Zhang
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Bo Fang
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
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33
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Chen B, Xu M, Zhang H, Xu MZ, Wang XJ, Tang QH, Tang JY. The Antipancreatic Cancer Activity of OSI-027, a Potent and Selective Inhibitor of mTORC1 and mTORC2. DNA Cell Biol 2015; 34:610-7. [PMID: 26284306 DOI: 10.1089/dna.2015.2886] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
In the present study, we investigated the potential activity of OSI-027, a potent and selective mammalian target of rapamycin (mTOR) complex 1/2 (mTORC1/2) dual inhibitor, against pancreatic cancer cells both in vitro and in vivo. We demonstrated that OSI-027 inhibited survival and growth of both primary and transformed (PANC-1 and MIA PaCa-2 lines) human pancreatic cancer cells. Meanwhile, OSI-027 induced caspase-dependent apoptotic death of the pancreatic cancer cells. On the other hand, caspase inhibitors alleviated cytotoxicity by OSI-027. At the molecular level, OSI-027 treatment blocked mTORC1 and mTORC2 activation simultaneously, without affecting ERK-mitogen-activated protein kinase activation. Importantly, OSI-027 activated cytoprotective autophagy in the above cancer cells. Whereas pharmacological blockage of autophagy or siRNA knockdown of Beclin-1 significantly enhanced the OSI-027-induced activity against pancreatic cancer cells. Specifically, a relatively low dose of OSI-027 sensitized gemcitabine-induced pancreatic cancer cell death in vitro. Further, administration of OSI-027 or together with gemcitabine dramatically inhibited PANC-1 xenograft growth in severe combined immunodeficiency mice, leading to significant mice survival improvement. In summary, the preclinical results of this study suggest that targeting mTORC1/2 synchronously by OSI-027 could be further investigated as a valuable treatment for pancreatic cancer.
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Affiliation(s)
- Bo Chen
- 1 Department of Biliary and Pancreatic Surgery, East Hospital Affiliated to Tongji University in Shanghai , Shanghai, China
| | - Ming Xu
- 1 Department of Biliary and Pancreatic Surgery, East Hospital Affiliated to Tongji University in Shanghai , Shanghai, China
| | - Hui Zhang
- 1 Department of Biliary and Pancreatic Surgery, East Hospital Affiliated to Tongji University in Shanghai , Shanghai, China
| | - Ming-zheng Xu
- 2 Department of Emergency, East Hospital Affiliated to Tongji University in Shanghai , Shanghai, China
| | - Xu-jing Wang
- 1 Department of Biliary and Pancreatic Surgery, East Hospital Affiliated to Tongji University in Shanghai , Shanghai, China
| | - Qing-he Tang
- 1 Department of Biliary and Pancreatic Surgery, East Hospital Affiliated to Tongji University in Shanghai , Shanghai, China
| | - Jian-ying Tang
- 2 Department of Emergency, East Hospital Affiliated to Tongji University in Shanghai , Shanghai, China
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Chiorean EG, Coveler AL. Pancreatic cancer: optimizing treatment options, new, and emerging targeted therapies. Drug Des Devel Ther 2015; 9:3529-45. [PMID: 26185420 PMCID: PMC4500614 DOI: 10.2147/dddt.s60328] [Citation(s) in RCA: 134] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Pancreatic cancer is the fourth leading cause of cancer death in the US and is expected to become the second leading cause of cancer-related deaths in the next decade. Despite 5-fluorouracil/leucovorin with irinotecan and oxaliplatin (FOLFIRINOX) and gemcitabine/nab-paclitaxel significantly improving outcomes for metastatic cancer, refractory disease still poses significant challenges. Difficulties with early detection and the inherent chemo- and radio-resistant nature of this malignancy led to attempts to define the sequential biology of pancreatic cancer in order to improve survival outcomes. Pancreatic adenocarcinoma is characterized by several germline or acquired genetic mutations, the most common being KRAS (90%), CDK2NA (90%), TP53 (75%-90%), DPC4/SMAD4 (50%). In addition, the tumor microenvironment, chemoresistant cancer stem cells, and the desmoplastic stroma have been the target of some promising clinical investigations. Among the core pathways reproducibly shown to lead the development and progression of this disease, DNA repair, apoptosis, G1/S cell cycle transition, KRAS, Wnt, Notch, Hedgehog, TGF-beta, and other cell invasion pathways, have been the target of "precision therapeutics". No single molecularly targeted therapeutic though has been uniformly successful, probably due to the tumor heterogeneity, but biomarker research is evolving and it hopes to select more patients likely to benefit. Recent reports note activity with immunotherapies such as CD40 agonists, CCR2 inhibitors, cancer vaccines, and novel combinations against the immunosuppressive tumor milieu are ongoing. While many obstacles still exist, clearly we are making progress in deciphering the heterogeneity within pancreatic cancers. Integrating conventional and immunological targeting will be the key to effective treatment of this deadly disease.
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Affiliation(s)
| | - Andrew L Coveler
- Department of Medicine, Division of Oncology, University of Washington, Seattle, WA, USA
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Baer R, Cintas C, Therville N, Guillermet-Guibert J. Implication of PI3K/Akt pathway in pancreatic cancer: When PI3K isoforms matter? Adv Biol Regul 2015; 59:19-35. [PMID: 26166735 DOI: 10.1016/j.jbior.2015.05.001] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Revised: 05/27/2015] [Accepted: 05/28/2015] [Indexed: 12/18/2022]
Abstract
Pancreatic cancer belongs to the incurable family of solid cancers. Despite of a recent better understanding its molecular biology, and an increased number of clinical trials, there is still a lack for innovative targeted therapies to fight this deadly malignancy. PI3K/Akt signalling is one of the most commonly deregulated signalling pathways in cancer, which explains the massive attention from many pharmaceutical companies over the ten past years on these signalling molecules. The already developed small molecule inhibitors are currently under clinical trial in various cancer types. Class I PI3Ks have 4 isoforms for which the role in physiology starts to be well described in the literature. Data are more unclear for their differential involvement in oncogenesis. In this review, we will discuss about the cognitive and therapeutic potential of targeting this signalling pathway and in particular Class I PI3K isoforms for pancreatic cancer treatment. Isoform-specificity of PI3K inhibitors are currently designed to achieve the same goal as pan-PI3K inhibitors but without potential adverse effects. We will discuss if such strategy is relevant in pancreatic adenocarcinoma.
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Affiliation(s)
- Romain Baer
- Inserm, U1037, Université Toulouse III, Centre de Recherches en Cancérologie de Toulouse, Oncopole de Toulouse, F31037, Toulouse, France
| | - Célia Cintas
- Inserm, U1037, Université Toulouse III, Centre de Recherches en Cancérologie de Toulouse, Oncopole de Toulouse, F31037, Toulouse, France
| | - Nicole Therville
- Inserm, U1037, Université Toulouse III, Centre de Recherches en Cancérologie de Toulouse, Oncopole de Toulouse, F31037, Toulouse, France
| | - Julie Guillermet-Guibert
- Inserm, U1037, Université Toulouse III, Centre de Recherches en Cancérologie de Toulouse, Oncopole de Toulouse, F31037, Toulouse, France.
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Azaro A, Rodon J, Calles A, Braña I, Hidalgo M, Lopez-Casas PP, Munoz M, Westwood P, Miller J, Moser BA, Ohnmacht U, Bumgardner W, Benhadji KA, Calvo E. A first-in-human phase I trial of LY2780301, a dual p70 S6 kinase and Akt Inhibitor, in patients with advanced or metastatic cancer. Invest New Drugs 2015; 33:710-9. [PMID: 25902900 DOI: 10.1007/s10637-015-0241-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2014] [Accepted: 04/10/2015] [Indexed: 12/15/2022]
Abstract
The primary objective of this phase I study of LY2780301, a dual p70 S6 kinase and Akt inhibitor, was to determine the recommended phase II dose as a single agent in patients with advanced cancer. Secondary objectives included safety, pharmacokinetic, and pharmacodynamic analyses, and co-clinical analyses in Avatar models. Eligible patients received total daily doses of LY2780301 100-500 mg, given orally as a single dose or divided into 2 doses for 28-day cycles. Dose escalation followed 3 + 3 design. The primary pharmacodynamic endpoint was inhibition of S6 assessed by skin and tumor biopsy. Thirty-two patients were treated. Common toxicities possibly related to treatment included constipation (19 %), fatigue (13 %), nausea (9 %), and diarrhea (9 %). Grade 3/4 toxicities potentially related to treatment were anemia (n = 2), increased alanine aminotransferase/aspartate aminotransferase (ALT) (n = 1), and increased gamma-glutamyl transpeptidase (GGT) (n = 1). One patient experienced best overall response of prolonged stable disease for 6 cycles. Plasma exposures of LY2780301 exceeded predicted efficacious exposures, but were not dose proportional. Among patients receiving 500 mg daily >50 % exhibited reduced S6 in skin biopsies at Day 8 of treatment, but the effect was not maintained. Plasma concentrations of LY2780301 and/or its metabolites were not correlated with S6 expression in the epidermis. There was minimal antitumor activity against the model, CRC 019. Avatar models showed minimal pharmacodynamic effects consistent with the observed antitumor effects. This study suggests a dose of LY2780301 500 mg QD for future studies.
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Affiliation(s)
- Analia Azaro
- Vall d'Hebron University Hospital and University of Autònoma, Barcelona, Spain
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Abstract
Pancreatic cancer is expected to be the second deadliest malignancy in the USA by 2020. The survival rates for patients with other gastrointestinal malignancies have increased consistently during the past 30 years; unfortunately, however, the outcomes of patients with pancreatic cancer have not changed significantly. Although surgery remains the only curative treatment for pancreatic cancer, therapeutic strategies based on initial resection have not substantially improved the survival of patients with resectable disease over the past 25 years; presently, more than 80% of patients suffer disease relapse after resection. Preclinical evidence that pancreatic cancer is a systemic disease suggests a possible benefit for early administration of systemic therapy in these patients. In locally advanced disease, the role of chemoradiotherapy is increasingly being questioned, particularly considering the results of the LAP-07 trial. Novel biomarkers are clearly needed to identify subsets of patients likely to benefit from chemoradiotherapy. In the metastatic setting, FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, and oxaliplatin), and nab-paclitaxel plus gemcitabine have yielded only modest improvements in survival. Thus, new treatments are urgently needed for patients with pancreatic cancer. Herein, we review the state-of-the-art of pancreatic cancer treatment, and the upcoming novel therapeutics that hold promise in this disease are also discussed.
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Ricci F, Bizzaro F, Cesca M, Guffanti F, Ganzinelli M, Decio A, Ghilardi C, Perego P, Fruscio R, Buda A, Milani R, Ostano P, Chiorino G, Bani MR, Damia G, Giavazzi R. Patient-derived ovarian tumor xenografts recapitulate human clinicopathology and genetic alterations. Cancer Res 2014; 74:6980-90. [PMID: 25304260 DOI: 10.1158/0008-5472.can-14-0274] [Citation(s) in RCA: 105] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. On the basis of its histopathology and molecular-genomic changes, ovarian cancer has been divided into subtypes, each with distinct biology and outcome. The aim of this study was to develop a panel of patient-derived EOC xenografts that recapitulate the molecular and biologic heterogeneity of human ovarian cancer. Thirty-four EOC xenografts were successfully established, either subcutaneously or intraperitoneally, in nude mice. The xenografts were histologically similar to the corresponding patient tumor and comprised all the major ovarian cancer subtypes. After orthotopic transplantation in the bursa of the mouse ovary, they disseminate into the organs of the peritoneal cavity and produce ascites, typical of ovarian cancer. Gene expression analysis and mutation status indicated a high degree of similarity with the original patient and discriminate different subsets of xenografts. They were very responsive, responsive, and resistant to cisplatin, resembling the clinical situation in ovarian cancer. This panel of patient-derived EOC xenografts that recapitulate the recently type I and type II classification serves to study the biology of ovarian cancer, identify tumor-specific molecular markers, and develop novel treatment modalities.
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Affiliation(s)
- Francesca Ricci
- Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
| | - Francesca Bizzaro
- Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
| | - Marta Cesca
- Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
| | - Federica Guffanti
- Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
| | - Monica Ganzinelli
- Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
| | - Alessandra Decio
- Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
| | - Carmen Ghilardi
- Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
| | | | - Robert Fruscio
- Obstetrics and Gynecology Clinic, San Gerardo Hospital, Monza, Italy
| | - Alessandro Buda
- Obstetrics and Gynecology Clinic, San Gerardo Hospital, Monza, Italy
| | - Rodolfo Milani
- Obstetrics and Gynecology Clinic, San Gerardo Hospital, Monza, Italy
| | - Paola Ostano
- Cancer Genomics Laboratory, Fondazione Edo ed Elvo Tempia Valenta, Biella, Italy
| | - Giovanna Chiorino
- Cancer Genomics Laboratory, Fondazione Edo ed Elvo Tempia Valenta, Biella, Italy
| | - Maria Rosa Bani
- Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
| | - Giovanna Damia
- Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
| | - Raffaella Giavazzi
- Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
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Hidalgo M, Amant F, Biankin AV, Budinská E, Byrne AT, Caldas C, Clarke RB, de Jong S, Jonkers J, Mælandsmo GM, Roman-Roman S, Seoane J, Trusolino L, Villanueva A. Patient-derived xenograft models: an emerging platform for translational cancer research. Cancer Discov 2014; 4:998-1013. [PMID: 25185190 PMCID: PMC4167608 DOI: 10.1158/2159-8290.cd-14-0001] [Citation(s) in RCA: 1237] [Impact Index Per Article: 112.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
UNLABELLED Recently, there has been an increasing interest in the development and characterization of patient-derived tumor xenograft (PDX) models for cancer research. PDX models mostly retain the principal histologic and genetic characteristics of their donor tumor and remain stable across passages. These models have been shown to be predictive of clinical outcomes and are being used for preclinical drug evaluation, biomarker identification, biologic studies, and personalized medicine strategies. This article summarizes the current state of the art in this field, including methodologic issues, available collections, practical applications, challenges and shortcomings, and future directions, and introduces a European consortium of PDX models. SIGNIFICANCE PDX models are increasingly used in translational cancer research. These models are useful for drug screening, biomarker development, and the preclinical evaluation of personalized medicine strategies. This review provides a timely overview of the key characteristics of PDX models and a detailed discussion of future directions in the field.
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Affiliation(s)
| | | | - Andrew V Biankin
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow
| | | | | | | | - Robert B Clarke
- Breakthrough Breast Cancer Unit, Institute of Cancer Sciences, University of Manchester, Manchester, United Kingdom
| | | | - Jos Jonkers
- The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | | | | | | | - Livio Trusolino
- Candiolo Cancer Institute - FPO IRCCS; and Department of Oncology, University of Torino, Candiolo, Torino, Italy
| | - Alberto Villanueva
- Catalan Institute of Oncology-Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, Barcelona, Spain
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Rossi ML, Rehman AA, Gondi CS. Therapeutic options for the management of pancreatic cancer. World J Gastroenterol 2014; 20:11142-11159. [PMID: 25170201 PMCID: PMC4145755 DOI: 10.3748/wjg.v20.i32.11142] [Citation(s) in RCA: 92] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2013] [Revised: 01/11/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
Since its initial characterization, pancreatic ductal adenocarcinoma has remained one of the most devastating and difficult cancers to treat. Pancreatic cancer is the fourth leading cause of death in the United States, resulting in an estimated 38460 deaths annually. With few screening tools available to detect this disease at an early stage, 94% of patients will die within five years of diagnosis. Despite decades of research that have led to a better understanding of the molecular and cellular signaling pathways in pancreatic cancer cells, few effective therapies have been developed to target these pathways. Other treatment options have included more sophisticated pancreatic cancer surgeries and combination therapies. While outcomes have improved modestly for these patients, more effective treatments are desperately needed. One of the greatest challenges in the future of treating this malignancy will be to develop therapies that target the tumor microenvironment and surrounding pancreatic cancer stem cells in addition to pancreatic cancer cells. Recent advances in targeting pancreatic stellate cells and the stroma have encouraged researchers to shift their focus to the role of desmoplasia in pancreatic cancer pathobiology in the hopes of developing newer-generation therapies. By combining novel agents with current cytotoxic chemotherapies and radiation therapy and personalizing them to each patient based on specific biomarkers, the goal of prolonging a patient’s life could be achieved. Here we review the most effective therapies that have been used for the treatment of pancreatic cancer and discuss the future potential of therapeutic options.
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Lou HZ, Weng XC, Pan HM, Pan Q, Sun P, Liu LL, Chen B. The novel mTORC1/2 dual inhibitor INK-128 suppresses survival and proliferation of primary and transformed human pancreatic cancer cells. Biochem Biophys Res Commun 2014; 450:973-8. [PMID: 24971544 DOI: 10.1016/j.bbrc.2014.06.081] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2014] [Accepted: 06/17/2014] [Indexed: 11/25/2022]
Abstract
Pancreatic cancer has one of worst prognosis among all human malignancies around the world, the development of novel and more efficient anti-cancer agents against this disease is urgent. In the current study, we tested the potential effect of INK-128, a novel mammalian target of rapamycin (mTOR) complex 1 and 2 (mTORC1/2) dual inhibitor, against pancreatic cancer cells in vitro. Our results demonstrated that INK-128 concentration- and time-dependently inhibited the survival and growth of pancreatic cancer cells (both primary cells and transformed cells). INK-128 induced pancreatic cancer cell apoptosis and necrosis simultaneously. Further, INK-128 dramatically inhibited phosphorylation of 4E-binding protein 1 (4E-BP1), ribosomal S6 kinase 1 (S6K1) and Akt at Ser 473 in pancreatic cancer cells. Meanwhile, it downregulated cyclin D1 expression and caused cell cycle arrest. Finally, we found that a low concentration of INK-128 significantly increased the sensitivity of pancreatic cancer cells to gemcitabine. Together, our in vitro results suggest that INK-128 might be further investigated as a novel anti-cancer agent or chemo-adjuvant for pancreatic cancer treatment.
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Affiliation(s)
- Hai-Zhou Lou
- Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016, China
| | - Xiao-Chuan Weng
- Department of Anesthesiology, Hangzhou Xia-sha Hospital, Hangzhou 310018, China
| | - Hong-Ming Pan
- Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016, China
| | - Qin Pan
- Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016, China
| | - Peng Sun
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China
| | - Li-Li Liu
- Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016, China
| | - Bin Chen
- Department of Hepatopancreatobiliary Surgery, First People's Hospital of Hangzhou, Hangzhou 310006, China.
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Xu XD, Yang L, Zheng LY, Pan YY, Cao ZF, Zhang ZQ, Zhou QS, Yang B, Cao C. Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses vasculogenic mimicry and proliferation of highly aggressive pancreatic cancer PaTu8988 cells. BMC Cancer 2014; 14:373. [PMID: 24886166 PMCID: PMC4047270 DOI: 10.1186/1471-2407-14-373] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2013] [Accepted: 05/16/2014] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Pancreatic cancer is one of the most aggressive human malignancies with a extremely low 5-year survival rate. Hence, the search for more effective anti-pancreatic cancer agents is urgent. METHODS PaTu8988 pancreatic cancer cells were treated with different concentrations of suberoylanilide hydroxamic acid (SAHA), cell survival, proliferation, migration and vasculogenic mimicry (VM) were analyzed. Associated signaling changes were also analyzed by RT-PCR and Western blots. RESULTS Here, we reported that SAHA, a histone deacetylase inhibitor (HDACi), exerted significant inhibitory efficiency against pancreatic cancer cell survival, proliferation, migration and VM. SAHA dose-dependently inhibited PaTu8988 pancreatic cancer cell growth with the IC-50 of 3.4 ± 0. 7 μM. Meanwhile, SAHA suppressed PaTu8988 cell cycle progression through inducing G2/M arrest, which was associated with cyclin-dependent kinase 1 (CDK-1)/cyclin-B1 degradation and p21/p27 upregulation. Further, SAHA induced both apoptotic and non-apoptotic death of PaTu8988 cells. Significantly, SAHA suppressed PaTu8988 cell in vitro migration and cell-dominant tube formation or VM, which was accompanied by semaphorin-4D (Sema-4D) and integrin-β5 down-regulation. Our evidences showed that Akt activation might be important for Sema-4D expression in PaTu8988 cells, and SAHA-induced Sema-4D down-regulation might be associated with Akt inhibition. CONCLUSIONS This study is among the first to report the VM formation in cultured human pancreatic cancer cells. And we provided strong evidence to suggest that SAHA executes significant anti-VM efficiency in the progressive pancreatic cancer cells. Thus, SAHA could be further investigated as a promising anti-pancreatic cancer agent.
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Affiliation(s)
- Xing-dong Xu
- Department of General Surgery, the Third Hospital affiliated to Soochow University, Changzhou City 213003, Jiangsu, China
| | - Lan Yang
- Department of General Surgery, the Third Hospital affiliated to Soochow University, Changzhou City 213003, Jiangsu, China
| | - Li-yun Zheng
- Department of Neurology, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yan-yan Pan
- Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, Jiangsu, China
| | - Zhi-fei Cao
- Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, Jiangsu, China
| | - Zhi-qing Zhang
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, Suzhou 215021, Jiangsu, China
| | - Quan-sheng Zhou
- Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, Jiangsu, China
| | - Bo Yang
- Department of General Surgery, the Third Hospital affiliated to Soochow University, Changzhou City 213003, Jiangsu, China
| | - Cong Cao
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, Suzhou 215021, Jiangsu, China
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Gonzalez-Angulo AM, Meric-Bernstam F, Chawla S, Falchook G, Hong D, Akcakanat A, Chen H, Naing A, Fu S, Wheler J, Moulder S, Helgason T, Li S, Elias I, Desai N, Kurzrock R. Weekly nab-Rapamycin in patients with advanced nonhematologic malignancies: final results of a phase I trial. Clin Cancer Res 2014; 19:5474-84. [PMID: 24089446 DOI: 10.1158/1078-0432.ccr-12-3110] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE This dose-finding phase I study investigated the maximum-tolerated dose (MTD) and safety of weekly nanoparticle albumin-bound rapamycin (nab-rapamycin) in patients with untreatable advanced nonhematologic malignancies. EXPERIMENTAL DESIGN nab-Rapamycin was administered weekly for 3 weeks followed by 1 week of rest, with a starting dose of 45 mg/m(2). Additional doses were 56.25, 100, 150, and 125 mg/m(2). RESULTS Of 27 enrolled patients, 26 were treated. Two dose-limiting toxicities (DLT) occurred at 150 mg/m(2) [grade 3 aspartate aminotransferase (AST) elevation and grade 4 thrombocytopenia], and two DLTs occurred at 125 mg/m(2) (grade 3 suicidal ideation and grade 3 hypophosphatemia). Thus, the MTD was declared at 100 mg/m(2). Most treatment-related adverse events (TRAE) were grade 1/2, including thrombocytopenia (58%), hypokalemia (23%), mucositis (38%), fatigue (27%), rash (23%), diarrhea (23%), nausea (19%), anemia (19%), hypophosphatemia (19%), neutropenia (15%), and hypertriglyceridemia (15%). Only one grade 3 nonhematologic TRAE (dyspnea) and one grade 3 hematologic event (anemia) occurred at the MTD. One patient with kidney cancer had a partial response and 2 patients remained on study for 365 days (patient with mesothelioma) and 238 days (patient with neuroendocrine tumor). The peak concentration (Cmax) and area under the concentration-time curve (AUC) of rapamycin increased with dose between 45 and 150 mg/m(2), except for a relatively low AUC at 125 mg/m(2). nab-Rapamycin significantly inhibited mTOR targets S6K and 4EBP1. CONCLUSIONS The clinical dose of single-agent nab-rapamycin was established at 100 mg/m(2) weekly (3 of 4 weeks) given intravenously, which was well tolerated with preliminary evidence of response and stable disease, and produced a fairly dose-proportional pharmacokinetic profile in patients with unresectable advanced nonhematologic malignancies.
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Affiliation(s)
- Ana M Gonzalez-Angulo
- Authors' Affiliations: Departments of Breast Medical Oncology and Systems Biology, Surgical Oncology, and Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas; Sarcoma Oncology Center, Santa Monica; Division of Hematology-Oncology, University of California, San Diego, California; and Celgene, Summit, New Jersey
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Walker EJ, Ko AH. Beyond first-line chemotherapy for advanced pancreatic cancer: an expanding array of therapeutic options? World J Gastroenterol 2014; 20:2224-36. [PMID: 24605022 PMCID: PMC3942828 DOI: 10.3748/wjg.v20.i9.2224] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2013] [Revised: 12/13/2013] [Accepted: 01/03/2014] [Indexed: 02/06/2023] Open
Abstract
While an increasing number of therapeutic options are now available for the first-line treatment of locally advanced or metastatic pancreatic cancer, the optimal choice for treatment in the second-line setting and beyond is less well defined. A variety of cytotoxic agents, either alone or in combination, have been evaluated, although primarily in the context of small single-arm or retrospective studies. Most regimens have been associated with median progression-free survival rates in the range of 2-4 mo and overall survival rates between 4-8 mo, highlighting the very poor prognosis of patients who are candidates for such treatment. Targeted therapies studied in this chemotherapy-refractory setting, meanwhile, have produced even worse efficacy results. In the current article, we review the clinical evidence for treatment of refractory disease, primarily in patients who have progressed on front-line gemcitabine-based chemotherapy. In the process, we highlight the limitations of the available data to date as well as some of the challenges in designing appropriate clinical trials in this salvage setting, including how to select an appropriate control arm given the absence of a well-established reference standard, and the importance of incorporating predictive biomarkers and quality of life measures whenever possible into study design.
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Xin Y, Shen XD, Cheng L, Hong DF, Chen B. Perifosine inhibits S6K1-Gli1 signaling and enhances gemcitabine-induced anti-pancreatic cancer efficiency. Cancer Chemother Pharmacol 2014; 73:711-9. [PMID: 24519751 DOI: 10.1007/s00280-014-2397-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2013] [Accepted: 01/20/2014] [Indexed: 02/07/2023]
Abstract
PURPOSE The pancreatic cancer has extremely low overall 5-year survival, and gemcitabine is the only approved single agent for pancreatic cancer treatment. METHODS In the present study, we investigated the potential effect of perifosine, a novel Akt inhibitor on gemcitabine-induced anti-pancreatic cancer effect both in vivo and in vitro. RESULTS We showed that sub-cytotoxic low concentration of perifosine dramatically enhanced gemcitabine-induced cytotoxicity in cultured pancreatic cancer cells. Perifosine inhibited Akt-mammalian target of rapamycin and Erk-mitogen-activated protein kinase activation in pancreatic cancer cells. Meanwhile, perifosine suppressed the hedgehog signaling, as it inhibited glioma-associated oncogenes (Gli) 1 activation and decreased its target protein patched 1 (PTCH1) expression. Our data demonstrated that perifosine blocked p70S6K1 (S6K1) activation, thus disrupting S6K1-Gli1 association and subsequent Gli1 activation. The reduction of S6K1 or Gli1 expression by target siRNAs inhibited PTCH1 expression and enhanced gemcitabine-induced cytotoxicity in pancreatic cancer cells. Significantly, perifosine dramatically enhanced gemcitabine-mediated antitumor effect in a PANC-1 xenograft severe combined immunodeficiency mice model. CONCLUSIONS In summary, we conclude that perifosine sensitizes gemcitabine-mediated anti-pancreatic cancer efficiency through regulating multiple signaling pathways.
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Affiliation(s)
- Ying Xin
- Department of Thyroid and Breast Surgery, Zhejiang Provincial People's Hospital, Hangzhou, 310014, Zhejiang, China
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Utomo WK, Narayanan V, Biermann K, van Eijck CHJ, Bruno MJ, Peppelenbosch MP, Braat H. mTOR is a promising therapeutical target in a subpopulation of pancreatic adenocarcinoma. Cancer Lett 2014; 346:309-17. [PMID: 24467966 DOI: 10.1016/j.canlet.2014.01.014] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2013] [Revised: 01/17/2014] [Accepted: 01/20/2014] [Indexed: 12/30/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal disease, unusually resistant against therapy. It is generally felt that stratification of patients for personalized medicine is the way forward. Here, we report that a subpopulation of PDACs shows strong activation of the mTOR signaling cassette. Moreover, we show that inhibition of mTOR in pancreatic cancer cell lines showing high levels of mTOR signaling is associated with cancer cell death. Finally, we show using fine needle biopsies the existence of a subpopulation of PDAC patients with high activation of the mTOR signaling cassette and provide evidence that inhibition of mTOR might be clinically useful for this group. Thus, our results define an unrecognized subpopulation of PDACs, characterized by high activation of mTOR and show that identification of this specific patient group in the early phase of diagnosis is feasible.
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Affiliation(s)
- Wesley K Utomo
- Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands
| | - Vilvapathy Narayanan
- Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands
| | | | | | - Marco J Bruno
- Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands
| | | | - Henri Braat
- Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands
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Garcia PL, Council LN, Christein JD, Arnoletti JP, Heslin MJ, Gamblin TL, Richardson JH, Bjornsti MA, Yoon KJ. Development and histopathological characterization of tumorgraft models of pancreatic ductal adenocarcinoma. PLoS One 2013; 8:e78183. [PMID: 24194913 PMCID: PMC3806809 DOI: 10.1371/journal.pone.0078183] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2013] [Accepted: 09/09/2013] [Indexed: 12/20/2022] Open
Abstract
Pancreatic cancer is the one of the deadliest of all malignancies. The five year survival rate for patients with this disease is 3-5%. Thus, there is a compelling need for novel therapeutic strategies to improve the clinical outcome for patients with pancreatic cancer. Several groups have demonstrated for other types of solid tumors that early passage human tumor xenograft models can be used to define some genetic and molecular characteristics of specific human tumors. Published studies also suggest that murine tumorgraft models (early passage xenografts derived from direct implantation of primary tumor specimens) may be useful in identifying compounds with efficacy against specific tumor types. Because pancreatic cancer is a fatal disease and few well-characterized model systems are available for translational research, we developed and characterized a panel of pancreatic tumorgraft models for biological evaluation and therapeutic drug testing. Of the 41 primary tumor specimens implanted subcutaneously into mice, 35 produced viable tumorgraft models. We document the fidelity of histological and morphological characteristics and of KRAS mutation status among primary (F0), F1, and F2 tumors for the twenty models that have progressed to the F3 generation. Importantly, our procedures produced a take rate of 85%, higher than any reported in the literature. Primary tumor specimens that failed to produce tumorgrafts were those that either contained <10% tumor cells or that were obtained from significantly smaller primary tumors. In view of the fidelity of characteristics of primary tumor specimens through at least the F2 generation in mice, we propose that these tumorgraft models represent a useful tool for identifying critical characteristics of pancreatic tumors and for evaluating potential therapies.
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Affiliation(s)
- Patrick L. Garcia
- Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Leona N. Council
- Division of Anatomic Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - John D. Christein
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - J. Pablo Arnoletti
- Division of General Surgery, Surgical Oncology, Department of Surgery, University of Alabama at Birmingham, Alabama, United States of America
| | - Marty J. Heslin
- Division of General Surgery, Surgical Oncology, Department of Surgery, University of Alabama at Birmingham, Alabama, United States of America
| | - Tracy L. Gamblin
- Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Joseph H. Richardson
- Division of General Surgery, Surgical Oncology, Department of Surgery, University of Alabama at Birmingham, Alabama, United States of America
| | - Mary-Ann Bjornsti
- Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Karina J. Yoon
- Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
- * E-mail:
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48
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Malaney P, Nicosia SV, Davé V. One mouse, one patient paradigm: New avatars of personalized cancer therapy. Cancer Lett 2013; 344:1-12. [PMID: 24157811 DOI: 10.1016/j.canlet.2013.10.010] [Citation(s) in RCA: 216] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2013] [Revised: 10/09/2013] [Accepted: 10/14/2013] [Indexed: 12/26/2022]
Abstract
Over the last few decades, study of cancer in mouse models has gained popularity. Sophisticated genetic manipulation technologies and commercialization of these murine systems have made it possible to generate mice to study human disease. Given the large socio-economic burden of cancer, both on academic research and the health care industry, there is a need for in vivo animal cancer models that can provide a rationale that is translatable to the clinic. Such a bench-to-bedside transition will facilitate a long term robust strategy that is economically feasible and clinically effective to manage cancer. The major hurdles in considering mouse models as a translational platform are the lack of tumor heterogeneity and genetic diversity, which are a hallmark of human cancers. The present review, while critical of these pitfalls, discusses two newly emerging concepts of personalized mouse models called "Mouse Avatars" and Co-clinical Trials. Development of "Mouse Avatars" entails implantation of patient tumor samples in mice for subsequent use in drug efficacy studies. These avatars allow for each patient to have their own tumor growing in an in vivo system, thereby allowing the identification of a personalized therapeutic regimen, eliminating the cost and toxicity associated with non-targeted chemotherapeutic measures. In Co-clinical Trials, genetically engineered mouse models (GEMMs) are used to guide therapy in an ongoing human patient trial. Murine and patient trials are conducted concurrently, and information obtained from the murine system is applied towards future clinical management of the patient's tumor. The concurrent trials allow for a real-time integration of the murine and human tumor data. In combination with several molecular profiling techniques, the "Mouse Avatar" and Co-clinical Trial concepts have the potential to revolutionize the drug development and health care process. The present review outlines the current status, challenges and the future potential of these two new in vivo approaches in the field of personalized oncology.
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Affiliation(s)
- Prerna Malaney
- Morsani College of Medicine, Department of Pathology and Cell Biology, Tampa, FL 33612, USA
| | - Santo V Nicosia
- Morsani College of Medicine, Department of Pathology and Cell Biology, Tampa, FL 33612, USA
| | - Vrushank Davé
- Morsani College of Medicine, Department of Pathology and Cell Biology, Tampa, FL 33612, USA; Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
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Lonardo E, Cioffi M, Sancho P, Sanchez-Ripoll Y, Trabulo SM, Dorado J, Balic A, Hidalgo M, Heeschen C. Metformin targets the metabolic achilles heel of human pancreatic cancer stem cells. PLoS One 2013; 8:e76518. [PMID: 24204632 PMCID: PMC3799760 DOI: 10.1371/journal.pone.0076518] [Citation(s) in RCA: 138] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2013] [Accepted: 09/01/2013] [Indexed: 12/15/2022] Open
Abstract
Pancreatic ductal adenocarcinomas contain a subset of exclusively tumorigenic cancer stem cells (CSCs), which are capable of repopulating the entire heterogeneous cancer cell populations and are highly resistant to standard chemotherapy. Here we demonstrate that metformin selectively ablated pancreatic CSCs as evidenced by diminished expression of pluripotency-associated genes and CSC-associated surface markers. Subsequently, the ability of metformin-treated CSCs to clonally expand in vitro was irreversibly abrogated by inducing apoptosis. In contrast, non-CSCs preferentially responded by cell cycle arrest, but were not eliminated by metformin treatment. Mechanistically, metformin increased reactive oxygen species production in CSC and reduced their mitochondrial transmembrane potential. The subsequent induction of lethal energy crisis in CSCs was independent of AMPK/mTOR. Finally, in primary cancer tissue xenograft models metformin effectively reduced tumor burden and prevented disease progression; if combined with a stroma-targeting smoothened inhibitor for enhanced tissue penetration, while gemcitabine actually appeared dispensable.
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Affiliation(s)
- Enza Lonardo
- Stem Cells & Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Michele Cioffi
- Stem Cells & Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Patricia Sancho
- Stem Cells & Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Yolanda Sanchez-Ripoll
- Stem Cells & Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Sara Maria Trabulo
- Stem Cells & Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Jorge Dorado
- Stem Cells & Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Anamaria Balic
- Stem Cells & Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Manuel Hidalgo
- Gastrointestinal Cancer Clinical Research Unit, Clinical Research Programme (CNIO), Spanish National Cancer Research Centre, Madrid, Spain
| | - Christopher Heeschen
- Stem Cells & Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
- * E-mail:
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Venkannagari S, Fiskus W, Peth K, Atadja P, Hidalgo M, Maitra A, Bhalla KN. Superior efficacy of co-treatment with dual PI3K/mTOR inhibitor NVP-BEZ235 and pan-histone deacetylase inhibitor against human pancreatic cancer. Oncotarget 2013; 3:1416-27. [PMID: 23232026 PMCID: PMC3717802 DOI: 10.18632/oncotarget.724] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Genetic alterations activating K-RAS and PI3K/AKT signaling are also known to induce the activity of mTOR kinase through TORC1 and TORC2 complexes in human pancreatic ductal adenocarcinoma (PDAC). Here, we determined the effects of the dual PI3K and mTOR inhibitor, NVP-BEZ235 (BEZ235), and the pan-histone deacetylase inhibitor panobinostat (PS) against human PDAC cells. Treatment with BEZ235 or PS inhibited cell cycle progression with induction of the cell cycle inhibitory proteins, p21 waf1 and p27 kip1. BEZ235 and PS also dose dependently induced loss of cell viability of the cultured PDAC cells, associated with depletion of phosphorylated (p) AKT, as well as of the TORC1 substrates 4EBP1 and p70S6 kinase. While inhibiting p-AKT, treatment with PS induced the levels of the pro-apoptotic proteins BIM and BAK. Co-treatment with BEZ235 and PS synergistically induced apoptosis of the cultured PDAC cells. This was accompanied by marked attenuation of the levels of p-AKT and Bcl-xL but induction of BIM. Although in vivo treatment with BEZ235 or PS reduced tumor growth, co-treatment with BEZ235 and PS was significantly more effective in controlling the xenograft growth of Panc1 PDAC cells in the nude mice. Furthermore, co-treatment with BEZ235 and PS more effectively blocked tumor growth of primary PDAC heterotransplants (possessing K-RAS mutation and AKT2 amplification) subcutaneously implanted in the nude mice than each agent alone. These findings demonstrate superior activity and support further in vivo evaluation of combined treatment with BEZ235 and PS against PDAC that possess heightened activity of RAS-RAF-ERK1/2 and PI3K-AKT-mTOR pathways.
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