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Jain A, Das R, Giri M, Mane P, Shard A. Carbohydrate kinase inhibition: a promising strategy in cancer treatment. Drug Discov Today 2025; 30:104308. [PMID: 39912130 DOI: 10.1016/j.drudis.2025.104308] [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: 12/09/2024] [Revised: 01/21/2025] [Accepted: 01/30/2025] [Indexed: 02/07/2025]
Abstract
Carbohydrate kinases (CKs) are pivotal in various biological processes, including energy consumption, cell signaling, and biosynthesis. They are a group of enzymes that facilitate the phosphorylation of carbohydrates, playing a crucial role in cellular metabolism. These enzymes facilitate the transfer of a phosphate group from a high-energy donor like ATP to a specified location on a carbohydrate substrate. Dysregulated kinase activity drives tumor growth and progression. Inhibitors targeting these enzymes have been developed and used in cancer therapy. The CK family encompasses three major types: hexokinases, ribokinases, and phosphatidylinositol kinases, with inhibitors of paramount importance in cancer treatment. This review explores the role of CKs in cancer and its inhibitors, providing insights into improving existing inhibitors and designing new ones.
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Affiliation(s)
- Archit Jain
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research-Ahmedabad, Gandhinagar, Gujarat 382355, India
| | - Rudradip Das
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research-Ahmedabad, Gandhinagar, Gujarat 382355, India
| | - Muskan Giri
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research-Ahmedabad, Gandhinagar, Gujarat 382355, India
| | - Pranita Mane
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research-Ahmedabad, Gandhinagar, Gujarat 382355, India
| | - Amit Shard
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research-Ahmedabad, Gandhinagar, Gujarat 382355, India.
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Varshini MS, Krishnamurthy PT, Reddy RA, Wadhwani A, Chandrashekar VM. Insights into the Emerging Therapeutic Targets of Triple-negative Breast Cancer. Curr Cancer Drug Targets 2025; 25:3-25. [PMID: 38385495 DOI: 10.2174/0115680096280750240123054936] [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: 09/23/2023] [Revised: 12/24/2023] [Accepted: 01/09/2024] [Indexed: 02/23/2024]
Abstract
Triple-negative Breast Cancer (TNBC), the most aggressive breast cancer subtype, is characterized by the non-appearance of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Clinically, TNBC is marked by its low survival rate, poor therapeutic outcomes, high aggressiveness, and lack of targeted therapies. Over the past few decades, many clinical trials have been ongoing for targeted therapies in TNBC. Although some classes, such as Poly (ADP Ribose) Polymerase (PARP) inhibitors and immunotherapies, have shown positive therapeutic outcomes, however, clinical effects are not much satisfiable. Moreover, the development of drug resistance is the major pattern observed in many targeted monotherapies. The heterogeneity of TNBC might be the cause for limited clinical benefits. Hence,, there is a need for the potential identification of new therapeutic targets to address the above limitations. In this context, some novel targets that can address the above-mentioned concerns are emerging in the era of TNBC therapy, which include Hypoxia Inducible Factor (HIF-1α), Matrix Metalloproteinase 9 (MMP-9), Tumour Necrosis Factor-α (TNF-α), β-Adrenergic Receptor (β-AR), Voltage Gated Sodium Channels (VGSCs), and Cell Cycle Regulators. Currently, we summarize the ongoing clinical trials and discuss the novel therapeutic targets in the management of TNBC.
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Affiliation(s)
- Magham Sai Varshini
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, 643001, TN, India
| | | | - Ramakamma Aishwarya Reddy
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, 643001, TN, India
| | - Ashish Wadhwani
- Department of Pharmaceutical Biotechnology, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, 643001, TN, India
- Faculty of Health Sciences, School of Pharmacy, JSS Academy of Higher Education and Research, Mauritius, Vacoas, 73304, Mauritius
| | - V M Chandrashekar
- Department of Pharmacology, HSK College of Pharmacy, Bagalkot, 587101, Karnataka, India
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Shi A, Yun F, Shi L, Liu X, Jia Y. Research progress on the mechanism of common inflammatory pathways in the pathogenesis and development of lymphoma. Ann Med 2024; 56:2329130. [PMID: 38489405 PMCID: PMC10946270 DOI: 10.1080/07853890.2024.2329130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 02/25/2024] [Indexed: 03/17/2024] Open
Abstract
In recent years, the incidence and mortality rates of lymphoma have gradually increased worldwide. Tumorigenesis and drug resistance are closely related to intracellular inflammatory pathways in lymphoma. Therefore, understanding the biological role of inflammatory pathways and their abnormal activation in relation to the development of lymphoma and their selective modulation may open new avenues for targeted therapy of lymphoma. The biological functions of inflammatory pathways are extensive, and they are central hubs for regulating inflammatory responses, immune responses, and the tumour immune microenvironment. However, limited studies have investigated the role of inflammatory pathways in lymphoma development. This review summarizes the relationship between abnormal activation of common inflammatory pathways and lymphoma development to identify precise and efficient targeted therapeutic options for patients with advanced, drug-resistant lymphoma.
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Affiliation(s)
- Aorong Shi
- Department of Pathology, Basic Medical Sciences College, Inner Mongolia Medical University, Hohhot, China
| | - Fen Yun
- Department of Pathology, Basic Medical Sciences College, Inner Mongolia Medical University, Hohhot, China
- Department of Pathology, The First Affiliated Hospital of Inner Mongolia Medical University, Huhhot, China
| | - Lin Shi
- Department of Pathology, Basic Medical Sciences College, Inner Mongolia Medical University, Hohhot, China
- Department of Pathology, The First Affiliated Hospital of Inner Mongolia Medical University, Huhhot, China
| | - Xia Liu
- Department of Pathology, Basic Medical Sciences College, Inner Mongolia Medical University, Hohhot, China
- Department of Pathology, The First Affiliated Hospital of Inner Mongolia Medical University, Huhhot, China
| | - Yongfeng Jia
- Department of Pathology, Basic Medical Sciences College, Inner Mongolia Medical University, Hohhot, China
- Department of Pathology, The First Affiliated Hospital of Inner Mongolia Medical University, Huhhot, China
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Deng Z, Qing Q, Huang B. A bibliometric analysis of the application of the PI3K-AKT-mTOR signaling pathway in cancer. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:7255-7272. [PMID: 38709265 DOI: 10.1007/s00210-024-03112-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 04/18/2024] [Indexed: 05/07/2024]
Abstract
PI3K-AKT-mTOR plays as important role in the growth, metabolism, proliferation, and migration of cancer cells, and in apoptosis, autophagy, inflammation, and angiogenesis in cancer. In this study, the aim was to comprehensively review the current research landscape regarding the PI3K-AKT-mTOR pathway in cancer, using bibliometrics to analyze research hotspots, and provide ideas for future research directions. Literature published on the topic between January 2006 and May 2023 was retrieved from the Web of Science core database, and key information and a visualization map were analyzed using CiteSpace and VOSviewer. A total of 5800 articles from 95 countries/regions were collected, including from China and the USA. The number of publications on the topic increased year on year. The major research institution was the University of Texas MD Anderson Cancer Center. Oncotarget and Clinical Cancer Research were the most prevalent journals in the field. Of 26,621 authors, R Kurzrock published the most articles, and J Engelman was cited most frequently. "A549 cell," "first line treatment," "first in human phase I," and "inhibitor" were the keywords of emerging research hotspots. Inhibitors of the PI3K-AKT-mTOR pathway and their use in clinical therapeutic strategies for cancer were the main topics in the field, and future research should also focus on PI3K-AKT-mTOR pathway inhibitors. This study is the first to comprehensively summarize trends and development s in research into the PI3K-AKT-mTOR pathway in cancer. The information that was obtained clarified recent research frontiers and directions, providing references for scholars of cancer management.
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Affiliation(s)
- Zhengzheng Deng
- School of Public Health, University of South China, Hengyang, 421001, Hunan Province, China
| | - Qiancheng Qing
- School of Public Health, University of South China, Hengyang, 421001, Hunan Province, China
| | - Bo Huang
- School of Public Health, University of South China, Hengyang, 421001, Hunan Province, China.
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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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Liu Y, Sun Q, Wei X. Strategies and techniques for preclinical therapeutic targeting of PI3K in oncology: where do we stand in 2024? Expert Opin Ther Targets 2024; 28:221-232. [PMID: 38646899 DOI: 10.1080/14728222.2024.2342522] [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: 09/14/2023] [Accepted: 04/06/2024] [Indexed: 04/23/2024]
Abstract
INTRODUCTION The PI3K/AKT/mTOR signaling pathway is an important signaling pathway in eukaryotic cells that is activated in a variety of cancers and is also associated with treatment resistance. This signaling pathway is an important target for anticancer therapy and holds great promise for research. At the same time PI3K inhibitors have a general problem that they have unavoidable toxic side effects. AREAS COVERED This review provides an explanation of the role of PI3K in the development and progression of cancer, including several important mutations, and a table listing the cancers caused by these mutations. We discuss the current landscape of PI3K inhibitors in preclinical and clinical trials, address the mechanisms of resistance to PI3K inhibition along with their associated toxic effects, and highlight significant advancements in preclinical research of this field. Furthermore, based on our study and comprehension of PI3K, we provide a recapitulation of the key lessons learned from the research process and propose potential measures for improvement that could prove valuable. EXPERT OPINION The PI3K pathway is a biological pathway of great potential value. However, the reduction of its toxic side effects and combination therapies need to be further investigated.
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Affiliation(s)
- Yanyan Liu
- Laboratory of Aging Research and Cancer Drug Target, Department of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Sichuan, People's Republic of China
| | - Qiu Sun
- Laboratory of Aging Research and Cancer Drug Target, Department of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Sichuan, People's Republic of China
- West China Medical Publishers, West China Hospital, Sichuan University, Chengdu, China
| | - Xiawei Wei
- Laboratory of Aging Research and Cancer Drug Target, Department of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Sichuan, People's Republic of China
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Hu J, Fu S, Zhan Z, Zhang J. Advancements in dual-target inhibitors of PI3K for tumor therapy: Clinical progress, development strategies, prospects. Eur J Med Chem 2024; 265:116109. [PMID: 38183777 DOI: 10.1016/j.ejmech.2023.116109] [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: 12/05/2023] [Revised: 12/24/2023] [Accepted: 12/28/2023] [Indexed: 01/08/2024]
Abstract
Phosphoinositide 3-kinases (PI3Ks) modify lipids by the phosphorylation of inositol phospholipids at the 3'-OH position, thereby participating in signal transduction and exerting effects on various physiological processes such as cell growth, metabolism, and organism development. PI3K activation also drives cancer cell growth, survival, and metabolism, with genetic dysregulation of this pathway observed in diverse human cancers. Therefore, this target is considered a promising potential therapeutic target for various types of cancer. Currently, several selective PI3K inhibitors and one dual-target PI3K inhibitor have been approved and launched on the market. However, the majority of these inhibitors have faced revocation or voluntary withdrawal of indications due to concerns regarding their adverse effects. This article provides a comprehensive review of the structure and biological functions, and clinical status of PI3K inhibitors, with a specific emphasis on the development strategies and structure-activity relationships of dual-target PI3K inhibitors. The findings offer valuable insights and future directions for the development of highly promising dual-target drugs targeting PI3K.
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Affiliation(s)
- Jiarui Hu
- Department of Neurology, Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Siyu Fu
- Department of Neurology, Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Zixuan Zhan
- Department of Neurology, Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Jifa Zhang
- Department of Neurology, Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
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Williams NO, Quiroga D, Johnson C, Brufsky A, Chambers M, Bhattacharya S, Patterson M, Sardesai SD, Stover D, Lustberg M, Noonan AM, Cherian M, Bystry DM, Hill KL, Chen M, Phelps MA, Grever M, Stephens JA, Ramaswamy B, Carson WE, Wesolowski R. Phase Ib study of HSP90 inhibitor, onalespib (AT13387), in combination with paclitaxel in patients with advanced triple-negative breast cancer. Ther Adv Med Oncol 2023; 15:17588359231217976. [PMID: 38152697 PMCID: PMC10752118 DOI: 10.1177/17588359231217976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Accepted: 11/15/2023] [Indexed: 12/29/2023] Open
Abstract
Background Heat shock protein 90 (HSP90) is a molecular chaperone required for stabilization of client proteins over-activated in triple-negative breast cancer (TNBC). Over-expression of HSP90 client proteins has been implicated in paclitaxel resistance. Onalespib (AT13387) is a potent inhibitor of HSP90 that could improve paclitaxel efficacy when administered in combination. Design This phase Ib trial administered onalespib with paclitaxel in patients with advanced TNBC to assess safety and establish a recommended phase II dose (RP2D). Objectives The primary objectives were determining the dose-limiting toxicities and maximum tolerated dose of combination therapy. Secondary objectives included pharmacokinetic (PK) analysis and determination of overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS). Methods Patients with advanced TNBC were treated with standard dose intravenous paclitaxel in combination with intravenous onalespib at doses ranging from 120 to 260 mg/m2 administered on days 1, 8, and 15 of a 28-day cycle using a standard 3 + 3 design. A total of 15 patients were enrolled to dose expansion cohort at RP2D to confirm safety profile. Results Thirty-one patients were enrolled in the study, of which over 90% had received prior taxane therapy. Paclitaxel was given for metastatic disease in 23% of patients. Adverse events (AEs) included anemia (grade 3: 20%), lymphopenia (grade 3: 17%), and neutropenia (grade 3: 33%, grade 4: 4%). The most frequent grade ⩾3 non-hematologic AE was diarrhea (7%). The established RP2D was 260 mg/m2 onalespib when given with paclitaxel at 80 mg/m2. PK analysis revealed a modest drug interaction profile for onalespib in the combination regimen. ORR was 20%. Three patients achieved complete responses, all of whom had received prior taxane therapy. Median DOR was 5.6 months; median PFS was 2.9 months. Conclusion Combination treatment with onalespib and paclitaxel had an acceptable toxicity profile and RP2D was determined to be 260 mg/m2 of onalespib. Combination therapy showed antitumor activity in patients with advanced TNBC. Trial registration Onalespib and paclitaxel in treating patients with advanced TNBC https://clinicaltrials.gov/ct2/show/NCT02474173.
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Affiliation(s)
- Nicole O. Williams
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Dionisia Quiroga
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Courtney Johnson
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Adam Brufsky
- University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA
| | - Mara Chambers
- University of Kentucky Markey Cancer Center, Lexington, KY, USA
| | | | - Maria Patterson
- Stefanie Spielman Comprehensive Breast Center, The Ohio State University, Columbus, OH, USA
| | - Sagar D. Sardesai
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Daniel Stover
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Maryam Lustberg
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Anne M. Noonan
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Mathew Cherian
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Darlene M. Bystry
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Kasey L. Hill
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Min Chen
- The Ohio State University College of Pharmacy, Columbus, OH, USA
| | - Mitch A. Phelps
- The Ohio State University – Arthur G. James Comprehensive Cancer Center, Columbus, OH, USA
- The Ohio State University College of Pharmacy, Columbus, OH, USA
| | - Michael Grever
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Julie A. Stephens
- Center for Biostatistics, Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH, USA
| | | | - William E. Carson
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Robert Wesolowski
- The Ohio State University Comprehensive Cancer Center, 1800 Cannon Drive, 1310D Lincoln Tower, Columbus, OH 43210, USA
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Zhu S, Wu Y, Song B, Yi M, Yan Y, Mei Q, Wu K. Recent advances in targeted strategies for triple-negative breast cancer. J Hematol Oncol 2023; 16:100. [PMID: 37641116 PMCID: PMC10464091 DOI: 10.1186/s13045-023-01497-3] [Citation(s) in RCA: 103] [Impact Index Per Article: 51.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 08/21/2023] [Indexed: 08/31/2023] Open
Abstract
Triple-negative breast cancer (TNBC), a highly aggressive subtype of breast cancer, negatively expresses estrogen receptor, progesterone receptor, and the human epidermal growth factor receptor 2 (HER2). Although chemotherapy is the main form of treatment for patients with TNBC, the effectiveness of chemotherapy for TNBC is still limited. The search for more effective therapies is urgent. Multiple targeted therapeutic strategies have emerged according to the specific molecules and signaling pathways expressed in TNBC. These include PI3K/AKT/mTOR inhibitors, epidermal growth factor receptor inhibitors, Notch inhibitors, poly ADP-ribose polymerase inhibitors, and antibody-drug conjugates. Moreover, immune checkpoint inhibitors, for example, pembrolizumab, atezolizumab, and durvalumab, are widely explored in the clinic. We summarize recent advances in targeted therapy and immunotherapy in TNBC, with the aim of serving as a reference for the development of individualized treatment of patients with TNBC in the future.
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Affiliation(s)
- Shuangli Zhu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yuze Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Bin Song
- Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China
| | - Ming Yi
- Department of Breast Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310000, China
| | - Yuheng Yan
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Qi Mei
- Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China.
- Cancer Center, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Kongming Wu
- Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China.
- Cancer Center, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Pan Z, Zhao Y, Wang X, Xie X, Liu M, Zhang K, Wang L, Bai D, Foster LJ, Shu R, He G. Targeting bromodomain-containing proteins: research advances of drug discovery. MOLECULAR BIOMEDICINE 2023; 4:13. [PMID: 37142850 PMCID: PMC10159834 DOI: 10.1186/s43556-023-00127-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 04/02/2023] [Indexed: 05/06/2023] Open
Abstract
Bromodomain (BD) is an evolutionarily conserved protein module found in 46 different BD-containing proteins (BCPs). BD acts as a specific reader for acetylated lysine residues (KAc) and serves an essential role in transcriptional regulation, chromatin remodeling, DNA damage repair, and cell proliferation. On the other hand, BCPs have been shown to be involved in the pathogenesis of a variety of diseases, including cancers, inflammation, cardiovascular diseases, and viral infections. Over the past decade, researchers have brought new therapeutic strategies to relevant diseases by inhibiting the activity or downregulating the expression of BCPs to interfere with the transcription of pathogenic genes. An increasing number of potent inhibitors and degraders of BCPs have been developed, some of which are already in clinical trials. In this paper, we provide a comprehensive review of recent advances in the study of drugs that inhibit or down-regulate BCPs, focusing on the development history, molecular structure, biological activity, interaction with BCPs and therapeutic potentials of these drugs. In addition, we discuss current challenges, issues to be addressed and future research directions for the development of BCPs inhibitors. Lessons learned from the successful or unsuccessful development experiences of these inhibitors or degraders will facilitate the further development of efficient, selective and less toxic inhibitors of BCPs and eventually achieve drug application in the clinic.
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Affiliation(s)
- Zhaoping Pan
- Department of Dermatology & Venerology and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
- Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology (CIII), Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yuxi Zhao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Disease, Department of Orthodontics and Pediatrics, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Xiaoyun Wang
- Department of Dermatology & Venerology and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
- Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology (CIII), Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xin Xie
- College of Medical Technology and School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada
| | - Mingxia Liu
- Department of Dermatology & Venerology and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Kaiyao Zhang
- Department of Dermatology & Venerology and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Lian Wang
- Department of Dermatology & Venerology and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Ding Bai
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Disease, Department of Orthodontics and Pediatrics, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Leonard J Foster
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada
| | - Rui Shu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Disease, Department of Orthodontics and Pediatrics, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
| | - Gu He
- Department of Dermatology & Venerology and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
- Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology (CIII), Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Chen M, Lan H, Yao S, Jin K, Chen Y. Metabolic Interventions in Tumor Immunity: Focus on Dual Pathway Inhibitors. Cancers (Basel) 2023; 15:cancers15072043. [PMID: 37046703 PMCID: PMC10093048 DOI: 10.3390/cancers15072043] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 03/23/2023] [Accepted: 03/27/2023] [Indexed: 04/14/2023] Open
Abstract
The metabolism of tumors and immune cells in the tumor microenvironment (TME) can affect the fate of cancer and immune responses. Metabolic reprogramming can occur following the activation of metabolic-related signaling pathways, such as phosphoinositide 3-kinases (PI3Ks) and the mammalian target of rapamycin (mTOR). Moreover, various tumor-derived immunosuppressive metabolites following metabolic reprogramming also affect antitumor immune responses. Evidence shows that intervention in the metabolic pathways of tumors or immune cells can be an attractive and novel treatment option for cancer. For instance, administrating inhibitors of various signaling pathways, such as phosphoinositide 3-kinases (PI3Ks), can improve T cell-mediated antitumor immune responses. However, dual pathway inhibitors can significantly suppress tumor growth more than they inhibit each pathway separately. This review discusses the latest metabolic interventions by dual pathway inhibitors as well as the advantages and disadvantages of this therapeutic approach.
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Affiliation(s)
- Min Chen
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China
| | - Huanrong Lan
- Department of Surgical Oncology, Affiliated Hangzhou Cancer Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China
| | - Shiya Yao
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua 321000, China
| | - Ketao Jin
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua 321000, China
| | - Yun Chen
- Department of Colorectal Surgery, Xinchang People's Hospital, Affiliated Xinchang Hospital, Wenzhou Medical University, Xinchang 312500, China
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12
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Candido MF, Medeiros M, Veronez LC, Bastos D, Oliveira KL, Pezuk JA, Valera ET, Brassesco MS. Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario. Pharmaceutics 2023; 15:pharmaceutics15020664. [PMID: 36839989 PMCID: PMC9966033 DOI: 10.3390/pharmaceutics15020664] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 02/09/2023] [Accepted: 02/10/2023] [Indexed: 02/18/2023] Open
Abstract
Childhood cancer is considered rare, corresponding to ~3% of all malignant neoplasms in the human population. The World Health Organization (WHO) reports a universal occurrence of more than 15 cases per 100,000 inhabitants around the globe, and despite improvements in diagnosis, treatment and supportive care, one child dies of cancer every 3 min. Consequently, more efficient, selective and affordable therapeutics are still needed in order to improve outcomes and avoid long-term sequelae. Alterations in kinases' functionality is a trademark of cancer and the concept of exploiting them as drug targets has burgeoned in academia and in the pharmaceutical industry of the 21st century. Consequently, an increasing plethora of inhibitors has emerged. In the present study, the expression patterns of a selected group of kinases (including tyrosine receptors, members of the PI3K/AKT/mTOR and MAPK pathways, coordinators of cell cycle progression, and chromosome segregation) and their correlation with clinical outcomes in pediatric solid tumors were accessed through the R2: Genomics Analysis and Visualization Platform and by a thorough search of published literature. To further illustrate the importance of kinase dysregulation in the pathophysiology of pediatric cancer, we analyzed the vulnerability of different cancer cell lines against their inhibition through the Cancer Dependency Map portal, and performed a search for kinase-targeted compounds with approval and clinical applicability through the CanSAR knowledgebase. Finally, we provide a detailed literature review of a considerable set of small molecules that mitigate kinase activity under experimental testing and clinical trials for the treatment of pediatric tumors, while discuss critical challenges that must be overcome before translation into clinical options, including the absence of compounds designed specifically for childhood tumors which often show differential mutational burdens, intrinsic and acquired resistance, lack of selectivity and adverse effects on a growing organism.
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Affiliation(s)
- Marina Ferreira Candido
- Department of Cell Biology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil
| | - Mariana Medeiros
- Regional Blood Center, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil
| | - Luciana Chain Veronez
- Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil
| | - David Bastos
- Department of Biology, Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-901, SP, Brazil
| | - Karla Laissa Oliveira
- Department of Biology, Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-901, SP, Brazil
| | - Julia Alejandra Pezuk
- Departament of Biotechnology and Innovation, Anhanguera University of São Paulo, UNIAN/SP, São Paulo 04119-001, SP, Brazil
| | - Elvis Terci Valera
- Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil
| | - María Sol Brassesco
- Departament of Biotechnology and Innovation, Anhanguera University of São Paulo, UNIAN/SP, São Paulo 04119-001, SP, Brazil
- Correspondence: ; Tel.: +55-16-3315-9144; Fax: +55-16-3315-4886
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13
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Yang Z, Liu Y, Cheng Q, Chen T. Targeting super enhancers for liver disease: a review. PeerJ 2023; 11:e14780. [PMID: 36726725 PMCID: PMC9885865 DOI: 10.7717/peerj.14780] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 01/03/2023] [Indexed: 01/28/2023] Open
Abstract
Background Super enhancers (SEs) refer to the ultralong regions of a gene accompanied by multiple transcription factors and cofactors and strongly drive the expression of cell-type-related genes. Recent studies have demonstrated that SEs play crucial roles in regulating gene expression related to cell cycle progression and transcription. Aberrant activation of SEs is closely related to the occurrence and development of liver disease. Liver disease, especially liver failure and hepatocellular carcinoma (HCC), constitutes a major class of diseases that seriously endanger human health. Currently, therapeutic strategies targeting SEs can dramatically prevent disease progression and improve the prognosis of animal models. The associated new approaches to the treatment of related liver disease are relatively new and need systematic elaboration. Objectives In this review, we elaborate on the features of SEs and discuss their function in liver disease. Additionally, we review their application prospects in clinical practice in the future. The article would be of interest to hepatologists, molecular biologists, clinicians, and all those concerned with targeted therapy and prognosis of liver disease. Methodology We searched three bibliographic databases (Web of Science Core Collection, Embase, PubMed) from 01/1981 to 06/2022 for peer-reviewed scientific publications focused on (1) gene treatment of liver disease; (2) current status of SE research; and (3) targeting SEs for liver disease. We included English language original studies only. Results The number of published studies considering the role of enhancers in liver disease is considerable. Since SEs were just defined in 2013, the corresponding data on SEs are scarce: approximately 50 papers found in bibliographic databases on the correlation between enhancers (or SEs) and liver disease. Remarkably, half of these papers were published in the past three years, indicating the growing interest of the scientific community in this issue. Studies have shown that treatments targeting components of SEs can improve outcomes in liver disease in animal and clinical trials. Conclusions The treatment of liver disease is facing a bottleneck, and new treatments are needed. Therapeutic regimens targeting SEs have an important role in the treatment of liver disease. However, given the off-target effect of gene therapy and the lack of clinical trials, the available experimental data are still fragmented and controversial.
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14
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Skorda A, Bay ML, Hautaniemi S, Lahtinen A, Kallunki T. Kinase Inhibitors in the Treatment of Ovarian Cancer: Current State and Future Promises. Cancers (Basel) 2022; 14:6257. [PMID: 36551745 PMCID: PMC9777107 DOI: 10.3390/cancers14246257] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/10/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022] Open
Abstract
Ovarian cancer is the deadliest gynecological cancer, the high-grade serous ovarian carcinoma (HGSC) being its most common and most aggressive form. Despite the latest therapeutical advancements following the introduction of vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors and poly-ADP-ribose-polymerase (PARP) inhibitors to supplement the standard platinum- and taxane-based chemotherapy, the expected overall survival of HGSC patients has not improved significantly from the five-year rate of 42%. This calls for the development and testing of more efficient treatment options. Many oncogenic kinase-signaling pathways are dysregulated in HGSC. Since small-molecule kinase inhibitors have revolutionized the treatment of many solid cancers due to the generality of the increased activation of protein kinases in carcinomas, it is reasonable to evaluate their potential against HGSC. Here, we present the latest concluded and on-going clinical trials on kinase inhibitors in HGSC, as well as the recent work concerning ovarian cancer patient organoids and xenograft models. We discuss the potential of kinase inhibitors as personalized treatments, which would require comprehensive assessment of the biological mechanisms underlying tumor spread and chemoresistance in individual patients, and their connection to tumor genome and transcriptome to establish identifiable subgroups of patients who are most likely to benefit from a given therapy.
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Affiliation(s)
- Aikaterini Skorda
- Cancer Invasion and Resistance Group, Danish Cancer Society Research Center, Strandboulevarden 49, DK-2100 Copenhagen, Denmark
| | - Marie Lund Bay
- Cancer Invasion and Resistance Group, Danish Cancer Society Research Center, Strandboulevarden 49, DK-2100 Copenhagen, Denmark
| | - Sampsa Hautaniemi
- Research Program in Systems Oncology, Research Programs Unit, Faculty of Medicine, University of Helsinki, FI-00014 Helsinki, Finland
| | - Alexandra Lahtinen
- Research Program in Systems Oncology, Research Programs Unit, Faculty of Medicine, University of Helsinki, FI-00014 Helsinki, Finland
| | - Tuula Kallunki
- Cancer Invasion and Resistance Group, Danish Cancer Society Research Center, Strandboulevarden 49, DK-2100 Copenhagen, Denmark
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
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15
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Patrad E, Khalighfard S, Amiriani T, Khori V, Alizadeh AM. Molecular mechanisms underlying the action of carcinogens in gastric cancer with a glimpse into targeted therapy. Cell Oncol 2022; 45:1073-1117. [PMID: 36149600 DOI: 10.1007/s13402-022-00715-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/03/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Gastric cancer imposes a substantial global health burden despite its overall incidence decrease. A broad spectrum of inherited, environmental and infectious factors contributes to the development of gastric cancer. A profound understanding of the molecular underpinnings of gastric cancer has lagged compared to several other tumors with similar incidence and morbidity rates, owing to our limited knowledge of the role of carcinogens in this malignancy. The International Agency for Research on Cancer (IARC) has classified gastric carcinogenic agents into four groups based on scientific evidence from human and experimental animal studies. This review aims to explore the potential comprehensive molecular and biological impacts of carcinogens on gastric cancer development and their interactions and interferences with various cellular signaling pathways. CONCLUSIONS In this review, we highlight recent clinical trial data reported in the literature dealing with different ways to target various carcinogens in gastric cancer. Moreover, we touch upon other multidisciplinary therapeutic approaches such as surgery, adjuvant and neoadjuvant chemotherapy. Rational clinical trials focusing on identifying suitable patient populations are imperative to the success of single-agent therapeutics. Novel insights regarding signaling pathways that regulate gastric cancer can potentially improve treatment responses to targeted therapy alone or in combination with other/conventional treatments. Preventive strategies such as control of H. pylori infection through eradication or immunization as well as dietary habit and lifestyle changes may reduce the incidence of this multifactorial disease, especially in high prevalence areas. Further in-depth understanding of the molecular mechanisms involved in the role of carcinogenic agents in gastric cancer development may offer valuable information and update state-of-the-art resources for physicians and researchers to explore novel ways to combat this disease, from bench to bedside. A schematic outlining of the interaction between gastric carcinogenic agents and intracellular pathways in gastric cancer H. pylori stimulates multiple intracellular pathways, including PI3K/AKT, NF-κB, Wnt, Shh, Ras/Raf, c-MET, and JAK/STAT, leading to epithelial cell proliferation and differentiation, apoptosis, survival, motility, and inflammatory cytokine release. EBV can stimulate intracellular pathways such as the PI3K/Akt, RAS/RAF, JAK/STAT, Notch, TGF-β, and NF-κB, leading to cell survival and motility, proliferation, invasion, metastasis, and the transcription of anti-apoptotic genes and pro-inflammatory cytokines. Nicotine and alcohol can lead to angiogenesis, metastasis, survival, proliferation, pro-inflammatory, migration, and chemotactic by stimulating various intracellular signaling pathways such as PI3K/AKT, NF-κB, Ras/Raf, ROS, and JAK/STAT. Processed meat contains numerous carcinogenic compounds that affect multiple intracellular pathways such as sGC/cGMP, p38 MAPK, ERK, and PI3K/AKT, leading to anti-apoptosis, angiogenesis, metastasis, inflammatory responses, proliferation, and invasion. Lead compounds may interact with multiple signaling pathways such as PI3K/AKT, NF-κB, Ras/Raf, DNA methylation-dependent, and epigenetic-dependent, leading to tumorigenesis, carcinogenesis, malignancy, angiogenesis, DNA hypermethylation, cell survival, and cell proliferation. Stimulating signaling pathways such as PI3K/Akt, RAS/RAF, JAK/STAT, WNT, TGF-β, EGF, FGFR2, and E-cadherin through UV ionizing radiation leads to cell survival, proliferation, and immortalization in gastric cancer. The consequence of PI3K/AKT, NF-κB, Ras/Raf, ROS, JAK/STAT, and WNT signaling stimulation by the carcinogenic component of Pickled vegetables and salted fish is the Warburg effect, tumorigenesis, angiogenesis, proliferation, inflammatory response, and migration.
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Affiliation(s)
- Elham Patrad
- Cancer Research Center, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Solmaz Khalighfard
- Cancer Research Center, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Taghi Amiriani
- Ischemic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Vahid Khori
- Ischemic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Ali Mohammad Alizadeh
- Cancer Research Center, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran.
- Breast Disease Research Center, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran.
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16
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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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17
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Rinne N, Christie EL, Ardasheva A, Kwok CH, Demchenko N, Low C, Tralau-Stewart C, Fotopoulou C, Cunnea P. Targeting the PI3K/AKT/mTOR pathway in epithelial ovarian cancer, therapeutic treatment options for platinum-resistant ovarian cancer. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2022; 4:573-595. [PMID: 35582310 PMCID: PMC9019160 DOI: 10.20517/cdr.2021.05] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 03/05/2021] [Accepted: 03/16/2021] [Indexed: 12/24/2022]
Abstract
The survival rates for women with ovarian cancer have shown scant improvement in recent years, with a 5-year survival rate of less than 40% for women diagnosed with advanced ovarian cancer. High-grade serous ovarian cancer (HGSOC) is the most lethal subtype where the majority of women develop recurrent disease and chemotherapy resistance, despite over 70%-80% of patients initially responding to platinum-based chemotherapy. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway regulates many vital processes such as cell growth, survival and metabolism. However, this pathway is frequently dysregulated in cancers including different subtypes of ovarian cancer, through amplification or somatic mutations of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), amplification of AKT isoforms, or deletion or inactivation of PTEN. Further evidence indicates a role for the PI3K/AKT/mTOR pathway in the development of chemotherapy resistance in ovarian cancer. Thus, targeting key nodes of the PI3K/AKT/mTOR pathway is a potential therapeutic prospect. In this review, we outline dysregulation of PI3K signaling in ovarian cancer, with a particular emphasis on HGSOC and platinum-resistant disease. We review pre-clinical evidence for inhibitors of the main components of the PI3K pathway and highlight past, current and upcoming trials in ovarian cancers for different inhibitors of the pathway. Whilst no inhibitors of the PI3K/AKT/mTOR pathway have thus far advanced to the clinic for the treatment of ovarian cancer, several promising compounds which have the potential to restore platinum sensitivity and improve clinical outcomes for patients are under evaluation and in various phases of clinical trials.
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Affiliation(s)
- Natasha Rinne
- Department of Surgery & Cancer, Imperial College London, Hammersmith campus, London W12 0NN, UK
| | | | - Anastasia Ardasheva
- Department of Surgery & Cancer, Imperial College London, Hammersmith campus, London W12 0NN, UK
| | - Chun Hei Kwok
- Department of Surgery & Cancer, Imperial College London, Hammersmith campus, London W12 0NN, UK
| | - Nikita Demchenko
- Department of Surgery & Cancer, Imperial College London, Hammersmith campus, London W12 0NN, UK
| | - Caroline Low
- Department of Metabolism Digestion & Reproduction, Imperial College London, London W12 0NN, UK
| | - Catherine Tralau-Stewart
- Takeda Academic Innovation, Center for External Innovation, Takeda California, San Diego, CA 92121, USA
| | - Christina Fotopoulou
- Department of Surgery & Cancer, Imperial College London, Hammersmith campus, London W12 0NN, UK
| | - Paula Cunnea
- Department of Surgery & Cancer, Imperial College London, Hammersmith campus, London W12 0NN, UK
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18
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Rasti AR, Guimaraes-Young A, Datko F, Borges VF, Aisner DL, Shagisultanova E. PIK3CA Mutations Drive Therapeutic Resistance in Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer. JCO Precis Oncol 2022; 6:e2100370. [PMID: 35357905 PMCID: PMC8984255 DOI: 10.1200/po.21.00370] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 11/17/2021] [Accepted: 02/15/2022] [Indexed: 12/21/2022] Open
Abstract
The phosphatidylinositol 3-kinase (PI3K) pathway is an intracellular pathway activated in response to progrowth signaling, such as human epidermal growth factor receptor 2 (HER2) and other kinases. Abnormal activation of PI3K has long been recognized as one of the main oncogenic drivers in breast cancer, including HER2-positive (HER2+) subtype. Somatic activating mutations in the gene encoding PI3K alpha catalytic subunit (PIK3CA) are present in approximately 30% of early-stage HER2+ tumors and drive therapeutic resistance to multiple HER2-targeted agents. Here, we review currently available agents targeting PI3K, discuss their potential role in HER2+ breast cancer, and provide an overview of ongoing trials of PI3K inhibitors in HER2+ disease. Additionally, we review the landscape of PIK3CA mutational testing and highlight the gaps in knowledge that could present potential barriers in the effective application of PI3K inhibitors for treatment of HER2+ breast cancer.
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Affiliation(s)
| | - Amy Guimaraes-Young
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Farrah Datko
- University of Colorado Health Cancer Center, Harmony Campus, Fort Collins, CO
| | - Virginia F. Borges
- Young Women Breast Cancer Translational Program, University of Colorado Cancer Center, Aurora, CO
| | - Dara L. Aisner
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Elena Shagisultanova
- Young Women Breast Cancer Translational Program, University of Colorado Cancer Center, Aurora, CO
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19
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Popescu VB, Kanhaiya K, Năstac DI, Czeizler E, Petre I. Network controllability solutions for computational drug repurposing using genetic algorithms. Sci Rep 2022; 12:1437. [PMID: 35082323 PMCID: PMC8791995 DOI: 10.1038/s41598-022-05335-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 12/29/2021] [Indexed: 12/22/2022] Open
Abstract
Control theory has seen recently impactful applications in network science, especially in connections with applications in network medicine. A key topic of research is that of finding minimal external interventions that offer control over the dynamics of a given network, a problem known as network controllability. We propose in this article a new solution for this problem based on genetic algorithms. We tailor our solution for applications in computational drug repurposing, seeking to maximize its use of FDA-approved drug targets in a given disease-specific protein-protein interaction network. We demonstrate our algorithm on several cancer networks and on several random networks with their edges distributed according to the Erdős-Rényi, the Scale-Free, and the Small World properties. Overall, we show that our new algorithm is more efficient in identifying relevant drug targets in a disease network, advancing the computational solutions needed for new therapeutic and drug repurposing approaches.
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Affiliation(s)
| | | | - Dumitru Iulian Năstac
- POLITEHNICA University of Bucharest, Faculty of Electronics, Telecommunications and Information Technology, 061071, Bucharest, Romania
| | - Eugen Czeizler
- Computer Science, Åbo Akademi University, 20500, Turku, Finland
- National Institute for Research and Development in Biological Sciences, 060031, Bucharest, Romania
| | - Ion Petre
- Department of Mathematics and Statistics, University of Turku, 20014, Turku, Finland.
- National Institute for Research and Development in Biological Sciences, 060031, Bucharest, Romania.
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20
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Sun HY, Du ST, Li YY, Deng GT, Zeng FR. Bromodomain and extra-terminal inhibitors emerge as potential therapeutic avenues for gastrointestinal cancers. World J Gastrointest Oncol 2022; 14:75-89. [PMID: 35116104 PMCID: PMC8790409 DOI: 10.4251/wjgo.v14.i1.75] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 08/11/2021] [Accepted: 11/30/2021] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal (GI) cancers, including colorectal cancer, pancreatic cancer, liver cancer and gastric cancer, are severe social burdens due to high incidence and mortality rates. Bromodomain and extra-terminal (BET) proteins are epigenetic readers consisting of four conserved members (BRD2, BRD3, BRD4 and BRDT). BET family perform pivotal roles in tumorigenesis through transcriptional regulation, thereby emerging as potential therapeutic targets. BET inhibitors, disrupting the interaction between BET proteins and acetylated lysines, have been reported to suppress tumor initiation and progression in most of GI cancers. In this review, we will demonstrate how BET proteins participate in the GI cancers progression and highlight the therapeutic potential of targeting BET proteins for GI cancers treatment.
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Affiliation(s)
- Hui-Yan Sun
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Department of Oncology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Song-Tao Du
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Department of Colorectal Surgical Oncology, Harbin Medical University Cancer Hospital, Harbin 150081, Heilongjiang Province, China
| | - Ya-Yun Li
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Guang-Tong Deng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Fu-Rong Zeng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Department of Oncology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
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21
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He Y, Sun MM, Zhang GG, Yang J, Chen KS, Xu WW, Li B. Targeting PI3K/Akt signal transduction for cancer therapy. Signal Transduct Target Ther 2021; 6:425. [PMID: 34916492 PMCID: PMC8677728 DOI: 10.1038/s41392-021-00828-5] [Citation(s) in RCA: 760] [Impact Index Per Article: 190.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 11/02/2021] [Accepted: 11/10/2021] [Indexed: 02/06/2023] Open
Abstract
The phosphatidylinositol 3-kinase (PI3K)/Akt pathway plays a crucial role in various cellular processes and is aberrantly activated in cancers, contributing to the occurrence and progression of tumors. Examining the upstream and downstream nodes of this pathway could allow full elucidation of its function. Based on accumulating evidence, strategies targeting major components of the pathway might provide new insights for cancer drug discovery. Researchers have explored the use of some inhibitors targeting this pathway to block survival pathways. However, because oncogenic PI3K pathway activation occurs through various mechanisms, the clinical efficacies of these inhibitors are limited. Moreover, pathway activation is accompanied by the development of therapeutic resistance. Therefore, strategies involving pathway inhibitors and other cancer treatments in combination might solve the therapeutic dilemma. In this review, we discuss the roles of the PI3K/Akt pathway in various cancer phenotypes, review the current statuses of different PI3K/Akt inhibitors, and introduce combination therapies consisting of signaling inhibitors and conventional cancer therapies. The information presented herein suggests that cascading inhibitors of the PI3K/Akt signaling pathway, either alone or in combination with other therapies, are the most effective treatment strategy for cancer.
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Affiliation(s)
- Yan He
- MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Miao Miao Sun
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Tumor Pathology, Zhengzhou, China
| | - Guo Geng Zhang
- MOE Key Laboratory of Tumor Molecular Biology and Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Jing Yang
- MOE Key Laboratory of Tumor Molecular Biology and Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Kui Sheng Chen
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Tumor Pathology, Zhengzhou, China.
| | - Wen Wen Xu
- MOE Key Laboratory of Tumor Molecular Biology and Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China.
| | - Bin Li
- MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China.
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22
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Valikhani M, Rahimian E, Ahmadi SE, Chegeni R, Safa M. Involvement of classic and alternative non-homologous end joining pathways in hematologic malignancies: targeting strategies for treatment. Exp Hematol Oncol 2021; 10:51. [PMID: 34732266 PMCID: PMC8564991 DOI: 10.1186/s40164-021-00242-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 10/13/2021] [Indexed: 12/31/2022] Open
Abstract
Chromosomal translocations are the main etiological factor of hematologic malignancies. These translocations are generally the consequence of aberrant DNA double-strand break (DSB) repair. DSBs arise either exogenously or endogenously in cells and are repaired by major pathways, including non-homologous end-joining (NHEJ), homologous recombination (HR), and other minor pathways such as alternative end-joining (A-EJ). Therefore, defective NHEJ, HR, or A-EJ pathways force hematopoietic cells toward tumorigenesis. As some components of these repair pathways are overactivated in various tumor entities, targeting these pathways in cancer cells can sensitize them, especially resistant clones, to radiation or chemotherapy agents. However, targeted therapy-based studies are currently underway in this area, and furtherly there are some biological pitfalls, clinical issues, and limitations related to these targeted therapies, which need to be considered. This review aimed to investigate the alteration of DNA repair elements of C-NHEJ and A-EJ in hematologic malignancies and evaluate the potential targeted therapies against these pathways.
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Affiliation(s)
- Mohsen Valikhani
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, School of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran
| | - Elahe Rahimian
- Department of Medical Translational Oncology, National Center for Tumor Diseases (NCT) Dresden, Dresden, Germany
| | - Seyed Esmaeil Ahmadi
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, School of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran
| | - Rouzbeh Chegeni
- Medical Laboratory Sciences, Program, College of Health and Human Sciences, Northern Illinois University, DeKalb, IL, USA
| | - Majid Safa
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, School of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran.
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23
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Razani E, Pourbagheri-Sigaroodi A, Safaroghli-Azar A, Zoghi A, Shanaki-Bavarsad M, Bashash D. The PI3K/Akt signaling axis in Alzheimer's disease: a valuable target to stimulate or suppress? Cell Stress Chaperones 2021; 26:871-887. [PMID: 34386944 PMCID: PMC8578535 DOI: 10.1007/s12192-021-01231-3] [Citation(s) in RCA: 119] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 07/23/2021] [Accepted: 08/09/2021] [Indexed: 12/12/2022] Open
Abstract
Among the long list of age-related complications, Alzheimer's disease (AD) has the most dreadful impact on the quality of life due to its devastating effects on memory and cognitive abilities. Although a plausible correlation between the phosphatidylinositol 3-kinase (PI3K) signaling and different processes involved in neurodegeneration has been evidenced, few articles reviewed the task. The current review aims to unravel the mechanisms by which the PI3K pathway plays pro-survival roles in normal conditions, and also to discuss the original data obtained from international research laboratories on this topic. Responses to questions on how alterations of the PI3K/Akt signaling pathway affect Tau phosphorylation and the amyloid cascade are given. In addition, we provide a general overview of the association between oxidative stress, neuroinflammation, alterations of insulin signaling, and altered autophagy with aberrant activation of this axis in the AD brain. The last section provides a special focus on the therapeutic possibility of the PI3K/Akt/mTOR modulators, either categorized as chemicals or herbals, in AD. In conclusion, determining the correct timing for the administration of the drugs seems to be one of the most important factors in the success of these agents. Also, the role of the PI3K/Akt signaling axis in the progression or repression of AD widely depends on the context of the cells; generally speaking, while PI3K/Akt activation in neurons and neural stem cells is favorable, its activation in microglia cells may be harmful.
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Affiliation(s)
- Elham Razani
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Atieh Pourbagheri-Sigaroodi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ava Safaroghli-Azar
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Anahita Zoghi
- Department of Neurology, School of Medicine, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahsa Shanaki-Bavarsad
- Institute of Neuroscience, Universitat Autònoma de Barcelona, 08193, Bellaterra, Barcelona, Spain
- Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, 08193, Bellaterra, Barcelona, Spain
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Abstract
Around three out of one hundred thousand people are diagnosed with glioblastoma multiforme, simply called glioblastoma, which is the most common primary brain tumor in adults. With a dismal prognosis of a little over a year, receiving a glioblastoma diagnosis is oftentimes fatal. A major advancement in its treatment was made almost two decades ago when the alkylating chemotherapeutic agent temozolomide (TMZ) was combined with radiotherapy (RT). Little progress has been made since then. Therapies that focus on the modulation of autophagy, a key process that regulates cellular homeostasis, have been developed to curb the progression of glioblastoma. The dual role of autophagy (cell survival or cell death) in glioblastoma has led to the development of autophagy inhibitors and promoters that either work as monotherapies or as part of a combination therapy to induce cell death, cellular senescence, and counteract the ability of glioblastoma stem cells (GSCs) for initiating tumor recurrence. The myriad of cellular pathways that act upon the modulation of autophagy have created contention between two groups: those who use autophagy inhibition versus those who use promotion of autophagy to control glioblastoma growth. We discuss rationale for using current major therapeutics, their molecular mechanisms for modulation of autophagy in glioblastoma and GSCs, their potentials for making strides in combating glioblastoma progression, and their possible shortcomings. These shortcomings may fuel the innovation of novel delivery systems and therapies involving TMZ in conjunction with another agent to pave the way towards a new gold standard of glioblastoma treatment.
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Affiliation(s)
- Amanda J Manea
- Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, 6439 Garners Ferry Road, Columbia, SC, 29209, USA
| | - Swapan K Ray
- Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, 6439 Garners Ferry Road, Columbia, SC, 29209, USA.
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25
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Feng L, Wang G, Chen Y, He G, Liu B, Liu J, Chiang CM, Ouyang L. Dual-target inhibitors of bromodomain and extra-terminal proteins in cancer: A review from medicinal chemistry perspectives. Med Res Rev 2021; 42:710-743. [PMID: 34633088 DOI: 10.1002/med.21859] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 07/14/2021] [Accepted: 09/26/2021] [Indexed: 02/05/2023]
Abstract
Bromodomain-containing protein 4 (BRD4), as the most studied member of the bromodomain and extra-terminal (BET) family, is a chromatin reader protein interpreting epigenetic codes through binding to acetylated histones and non-histone proteins, thereby regulating diverse cellular processes including cell cycle, cell differentiation, and cell proliferation. As a promising drug target, BRD4 function is closely related to cancer, inflammation, cardiovascular disease, and liver fibrosis. Currently, clinical resistance to BET inhibitors has limited their applications but synergistic antitumor effects have been observed when used in combination with other tumor inhibitors targeting additional cellular components such as PLK1, HDAC, CDK, and PARP1. Therefore, designing dual-target inhibitors of BET bromodomains is a rational strategy in cancer treatment to increase potency and reduce drug resistance. This review summarizes the protein structures and biological functions of BRD4 and discusses recent advances of dual BET inhibitors from a medicinal chemistry perspective. We also discuss the current design and discovery strategies for dual BET inhibitors, providing insight into potential discovery of additional dual-target BET inhibitors.
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Affiliation(s)
- Lu Feng
- State Key Laboratory of Biotherapy and Cancer Center, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China
| | - Guan Wang
- State Key Laboratory of Biotherapy and Cancer Center, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China
| | - Yi Chen
- State Key Laboratory of Biotherapy and Cancer Center and Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Gu He
- State Key Laboratory of Biotherapy and Cancer Center, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China
| | - Bo Liu
- State Key Laboratory of Biotherapy and Cancer Center, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China
| | - Jie Liu
- State Key Laboratory of Biotherapy and Cancer Center, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China
| | - Cheng-Ming Chiang
- Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.,Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.,Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Liang Ouyang
- State Key Laboratory of Biotherapy and Cancer Center, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China
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26
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Zhang X, Liu Y. Targeting the PI3K/AKT/mTOR Signaling Pathway in Primary Central Nervous System Lymphoma: Current Status and Future Prospects. CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS 2021; 19:165-173. [PMID: 32416683 DOI: 10.2174/1871527319666200517112252] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 04/10/2020] [Accepted: 04/11/2020] [Indexed: 12/22/2022]
Abstract
Primary Central Nervous System Lymphoma (PCNSL) is a rare invasive extranodal non- Hodgkin lymphoma, a vast majority of which is Diffuse Large B-Cell Lymphoma (DLBCL). Although high-dose methotrexate-based immunochemotherapy achieves a high remission rate, the risk of relapse and related death remains a crucial obstruction to long-term survival. Novel agents for the treatment of lymphatic malignancies have significantly broadened the horizons of therapeutic options for PCNSL. The PI3K/AKT/mTOR signaling pathway is one of the most important pathways for Bcell malignancy growth and survival. Novel therapies that target key components of this pathway have shown antitumor effects in many B-cell malignancies, including DLBCL. This review will discuss the aberrant status of the PI3K/AKT/mTOR signaling pathways in PCNSL and the application prospects of inhibitors in hopes of providing alternative clinical therapeutic strategies and improving prognosis.
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Affiliation(s)
- Xiaowei Zhang
- Department of Hematology, Beijing Tiantan Hospital, Capital Medical University, Nan Si Huan Xi Lu 119, Fengtai District, Beijing 100070, China
| | - Yuanbo Liu
- Department of Hematology, Beijing Tiantan Hospital, Capital Medical University, Nan Si Huan Xi Lu 119, Fengtai District, Beijing 100070, China
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27
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van der Ploeg P, Uittenboogaard A, Thijs AMJ, Westgeest HM, Boere IA, Lambrechts S, van de Stolpe A, Bekkers RLM, Piek JMJ. The effectiveness of monotherapy with PI3K/AKT/mTOR pathway inhibitors in ovarian cancer: A meta-analysis. Gynecol Oncol 2021; 163:433-444. [PMID: 34253390 DOI: 10.1016/j.ygyno.2021.07.008] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 07/01/2021] [Accepted: 07/05/2021] [Indexed: 12/31/2022]
Abstract
OBJECTIVE To determine the clinical benefit of monotherapy with PI3K/AKT/mTOR inhibitors in patients diagnosed with advanced or recurrent ovarian cancer and to investigate the predictive value of current PI3K/AKT/mTOR biomarkers on therapy response. METHODS A systematic search was conducted in PubMed, Embase and the Cochrane Library for articles reporting on treatment with PI3K/AKT/mTOR inhibitors in ovarian cancer. The primary endpoint was defined as the clinical benefit rate (CBR), including the proportion of patients with complete (CR) and partial response (PR) and stable disease (SD). Secondary endpoints included the overall response rate (ORR, including CR and PR) and drug-related grade 3 and 4 adverse events. RESULTS We included 233 patients from 19 studies and observed a pooled CBR of 32% (95% CI 20-44%) and ORR of 3% (95% CI 0-6%) in advanced or recurrent ovarian cancer patients treated with PI3K/AKT/mTOR inhibitors. Subgroup analysis tended to favor the studies who selected patients based on current PI3K/AKT/mTOR biomarker criteria (e.g. genomic alterations or loss of PTEN protein expression), but the difference in CBR was not statistically significant from studies with unselected populations (respectively, CBR of 42% (95% CI 23-62%) and 27% (95% CI 14-42%), P = 0.217). To better reflect true patient benefit, we excluded SD <6 months as a beneficial outcome which resulted in a pooled CBR of 7% (95% CI 2-13%). The overall proportion of patients with drug-related grade 3 and 4 adverse events was 36%. CONCLUSIONS The efficacy of monotherapy with PI3K/AKT/mTOR inhibitors in advanced recurrent ovarian cancer patients is limited to a small subgroup and selection of patients with the use of current biomarkers did not improved the CBR significantly. Given the toxicity profile, we suggest that current treatment with PI3K/AKT/mTOR inhibitors should not be initiated unless in clinical trials. Furthermore, improved biomarkers to measure functional PI3K/AKT/mTOR pathway activity are needed to optimize patient selection.
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Affiliation(s)
- Phyllis van der Ploeg
- Department of Obstetrics and Gynecology and Catharina Cancer Institute, Catharina Hospital, Eindhoven, the Netherlands; GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands.
| | - Aniek Uittenboogaard
- Department of Obstetrics and Gynecology and Catharina Cancer Institute, Catharina Hospital, Eindhoven, the Netherlands
| | - Anna M J Thijs
- Department of Medical Oncology, Catharina Hospital, Eindhoven, the Netherlands
| | | | - Ingrid A Boere
- Department of Medical Oncology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands
| | - Sandrina Lambrechts
- Department of Obstetrics and Gynecology, Maastricht University Medical Center+, Maastricht, the Netherlands
| | | | - Ruud L M Bekkers
- Department of Obstetrics and Gynecology and Catharina Cancer Institute, Catharina Hospital, Eindhoven, the Netherlands; GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands
| | - Jurgen M J Piek
- Department of Obstetrics and Gynecology and Catharina Cancer Institute, Catharina Hospital, Eindhoven, the Netherlands
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28
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Luo XY, Wu KM, He XX. Advances in drug development for hepatocellular carcinoma: clinical trials and potential therapeutic targets. J Exp Clin Cancer Res 2021; 40:172. [PMID: 34006331 PMCID: PMC8130401 DOI: 10.1186/s13046-021-01968-w] [Citation(s) in RCA: 134] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 04/27/2021] [Indexed: 02/06/2023] Open
Abstract
Although hepatocellular carcinoma (HCC) is one of the deadliest health burdens worldwide, few drugs are available for its clinical treatment. However, in recent years, major breakthroughs have been made in the development of new drugs due to intensive fundamental research and numerous clinical trials in HCC. Traditional systemic therapy schemes and emerging immunotherapy strategies have both advanced. Between 2017 and 2020, the United States Food and Drug Administration (FDA) approved a variety of drugs for the treatment of HCC, including multikinase inhibitors (regorafenib, lenvatinib, cabozantinib, and ramucirumab), immune checkpoint inhibitors (nivolumab and pembrolizumab), and bevacizumab combined with atezolizumab. Currently, there are more than 1000 ongoing clinical trials involving HCC, which represents a vibrant atmosphere in the HCC drug research and development field. Additionally, traditional Chinese medicine approaches are being gradually optimized. This review summarizes FDA-approved agents for HCC, elucidates promising agents evaluated in clinical phase I/II/III trials and identifies emerging targets for HCC treatment. In addition, we introduce the development of HCC drugs in China. Finally, we discuss potential problems in HCC drug therapy and possible future solutions and indicate future directions for the development of drugs for HCC treatment.
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Affiliation(s)
- Xiang-Yuan Luo
- Institute of Liver and Gastrointestinal Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Kong-Ming Wu
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xing-Xing He
- Institute of Liver and Gastrointestinal Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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29
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Sabbah DA, Hajjo R, Bardaweel SK, Zhong HA. Phosphatidylinositol 3-kinase (PI3K) inhibitors: a recent update on inhibitor design and clinical trials (2016-2020). Expert Opin Ther Pat 2021; 31:877-892. [PMID: 33970742 DOI: 10.1080/13543776.2021.1924150] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Introduction: The phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway plays a central role in regulating cell growth and proliferation and thus has been considered as effective anticancer drug targets. Many PI3K inhibitors have been developed and progressed to various stages of clinical trials, and some have been approved as anticancer treatment. In this review, we discuss the drug design and clinical development of PI3K inhibitors over the past 4 years. We review the selectivity and potency of 47 PI3K inhibitors. Structural determinants for increasing selectivity toward PI3K subtype-selectivity or mutant selectivity are discussed. Future research direction and current clinical development in combination therapy of inhibitors involved in PI3Ks are also discussed.Area covered: This review covers clinical trial reports and patent literature on PI3K inhibitors and their selectivity published between 2016 and 2020.Expert opinion: To PI3Kα mutants (E542K, E545K, and H1047R), it is highly desirable to design and develop mutant-specific PI3K inhibitors. It is also necessary to develop subtype-selective PI3Kα inhibitors to minimize toxicity. To reduce drug resistance and to improve efficacy, future studies should include combination therapy of PI3K inhibitors with existing anticancer drugs from different pathways.
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Affiliation(s)
- Dima A Sabbah
- Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman, Jordan
| | - Rima Hajjo
- Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman, Jordan
| | - Sanaa K Bardaweel
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Jordan, Amman, Jordan
| | - Haizhen A Zhong
- DSC 362, Department of Chemistry, The University of Nebraska at Omaha, Omaha, Nebraska, USA
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30
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Nepali K, Liou JP. Recent developments in epigenetic cancer therapeutics: clinical advancement and emerging trends. J Biomed Sci 2021; 28:27. [PMID: 33840388 PMCID: PMC8040241 DOI: 10.1186/s12929-021-00721-x] [Citation(s) in RCA: 113] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 03/29/2021] [Indexed: 12/13/2022] Open
Abstract
Epigenetic drug discovery field has evidenced significant advancement in the recent times. A plethora of small molecule inhibitors have progressed to clinical stage investigations and are being explored exhaustively to ascertain conclusive benefits in diverse malignancies. Literature precedents indicates that substantial amount of efforts were directed towards the use of epigenetic tools in monotherapy as well as in combination regimens at the clinical level, however, the preclinical/preliminary explorations were inclined towards the identification of prudent approaches that can leverage the anticancer potential of small molecule epigenetic inhibitors as single agents only. This review article presents an update of FDA approved epigenetic drugs along with the epigenetic inhibitors undergoing clinical stage investigations in different cancer types. A detailed discussion of the pragmatic strategies that are expected to steer the progress of the epigenetic therapy through the implementation of emerging approaches such as PROTACS and CRISPR/Cas9 along with logical ways for scaffold fabrication to selectively approach the enzyme isoforms in pursuit of garnering amplified antitumor effects has been covered. In addition, the compilation also presents the rational strategies for the construction of multi-targeting scaffold assemblages employing previously identified pharmacophores as potential alternatives to the combination therapy.
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Affiliation(s)
- Kunal Nepali
- School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan
| | - Jing-Ping Liou
- School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.
- Biomedical Commercialization Center, Taipei Medical University, Taipei, 11031, Taiwan.
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31
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Augmented Antitumor Activity for Novel Dual PI3K/BDR4 Inhibitors, SF2523 and SF1126 in Ewing Sarcoma. J Pediatr Hematol Oncol 2021; 43:e304-e311. [PMID: 33480647 DOI: 10.1097/mph.0000000000002054] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 12/03/2020] [Indexed: 01/15/2023]
Abstract
Ewing sarcoma (ES) is the second most common pediatric bone cancer. Despite recent advances in the treatment, patients with metastatic tumors have dismal prognosis and hence novel therapies are urgently needed to combat this cancer. A recent study has shown that phosphoinositide-3 kinase (PI3K) inhibitors can synergistically increase sensitivity to bromodomain and extraterminal domain inhibitors in ES cells and therefore combined inhibition of PI3K and bromodomain and extraterminal domain bromodomain proteins might provide benefit in this cancer. Herein, we have investigated the efficacy of dual PI3K/BRD4 inhibitors, SF2523 and SF1126, for their antitumor activity in ES cell lines. The effect of SF1126 and SF2523 on cell viability and PI3K signaling was assessed on a panel of human ES cell lines. To evaluate the antitumor activity of SF1126, A673 cells were injected intrafemorally into RAG-2-/- mice and treated with 50 mg/kg SF1126 6 days per week, for 30 days. Both SF1126 and SF2523 decreased cell survival and inhibited phosphorylation of AKT in human ES cell lines. In vivo, SF1126 showed a significant reduction in tumor volume. These results suggest that dual PI3K/BRD4 inhibitor, SF1126, has antitumor activity in ES models.
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32
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Mishra R, Patel H, Alanazi S, Kilroy MK, Garrett JT. PI3K Inhibitors in Cancer: Clinical Implications and Adverse Effects. Int J Mol Sci 2021; 22:3464. [PMID: 33801659 PMCID: PMC8037248 DOI: 10.3390/ijms22073464] [Citation(s) in RCA: 173] [Impact Index Per Article: 43.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 03/19/2021] [Accepted: 03/23/2021] [Indexed: 02/07/2023] Open
Abstract
The phospatidylinositol-3 kinase (PI3K) pathway is a crucial intracellular signaling pathway which is mutated or amplified in a wide variety of cancers including breast, gastric, ovarian, colorectal, prostate, glioblastoma and endometrial cancers. PI3K signaling plays an important role in cancer cell survival, angiogenesis and metastasis, making it a promising therapeutic target. There are several ongoing and completed clinical trials involving PI3K inhibitors (pan, isoform-specific and dual PI3K/mTOR) with the goal to find efficient PI3K inhibitors that could overcome resistance to current therapies. This review focuses on the current landscape of various PI3K inhibitors either as monotherapy or in combination therapies and the treatment outcomes involved in various phases of clinical trials in different cancer types. There is a discussion of the drug-related toxicities, challenges associated with these PI3K inhibitors and the adverse events leading to treatment failure. In addition, novel PI3K drugs that have potential to be translated in the clinic are highlighted.
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Affiliation(s)
| | | | | | | | - Joan T. Garrett
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Cincinnati, Cincinnati, OH 45267-0514, USA; (R.M.); (H.P.); (S.A.); (M.K.K.)
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Cummings M, Freer C, Orsi NM. Targeting the tumour microenvironment in platinum-resistant ovarian cancer. Semin Cancer Biol 2021; 77:3-28. [PMID: 33607246 DOI: 10.1016/j.semcancer.2021.02.007] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 01/09/2021] [Accepted: 02/10/2021] [Indexed: 02/07/2023]
Abstract
Ovarian cancer typically presents at an advanced stage, and although the majority of cases initially respond well to platinum-based therapies, chemoresistance almost always occurs leading to a poor long-term prognosis. While various cellular autonomous mechanisms contribute to intrinsic or acquired platinum resistance, the tumour microenvironment (TME) plays a central role in resistance to therapy and disease progression by providing cancer stem cell niches, promoting tumour cell metabolic reprogramming, reducing chemotherapy drug perfusion and promoting an immunosuppressive environment. As such, the TME is an attractive therapeutic target which has been the focus of intense research in recent years. This review provides an overview of the unique ovarian cancer TME and its role in disease progression and therapy resistance, highlighting some of the latest preclinical and clinical data on TME-targeted therapies. In particular, it focuses on strategies targeting cancer-associated fibroblasts, tumour-associated macrophages, cancer stem cells and cancer cell metabolic vulnerabilities.
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Affiliation(s)
- M Cummings
- Leeds Institute of Medical Research at St James's, St James's University Hospital, Beckett Street, Leeds, LS9 7TF, United Kingdom
| | - C Freer
- Leeds Institute of Medical Research at St James's, St James's University Hospital, Beckett Street, Leeds, LS9 7TF, United Kingdom
| | - N M Orsi
- Leeds Institute of Medical Research at St James's, St James's University Hospital, Beckett Street, Leeds, LS9 7TF, United Kingdom; St James's Institute of Oncology, Bexley Wing, Beckett Street, Leeds, LS9 7TF, United Kingdom.
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Pan Y, Chen Z, Qi F, Liu J. Identification of drug compounds for keloids and hypertrophic scars: drug discovery based on text mining and DeepPurpose. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:347. [PMID: 33708974 PMCID: PMC7944324 DOI: 10.21037/atm-21-218] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Background Keloids (KL) and hypertrophic scars (HS) are forms of abnormal cutaneous scarring characterized by excessive deposition of extracellular matrix and fibroblast proliferation. Currently, the efficacy of drug therapies for KL and HS is limited. The present study aimed to investigate new drug therapies for KL and HS by using computational methods. Methods Text mining and GeneCodis were used to mine genes closely related to KL and HS. Protein-protein interaction analysis was performed using Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and Cytoscape. The selection of drugs targeting the genes closely related to KL and HS was carried out using Pharmaprojects. Drug-target interaction prediction was performed using DeepPurpose, through which candidate drugs with the highest predicted binding affinity were finally obtained. Results Our analysis using text mining identified 69 KL- and HS-related genes. Gene enrichment analysis generated 25 genes, representing 7 pathways and 130 targeting drugs. DeepPurpose recommended 14 drugs as the final drug list, including 2 phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitors, 10 prostaglandin-endoperoxide synthase 2 (PTGS2) inhibitors and 2 vascular endothelial growth factor A (VEGFA) antagonists. Conclusions Drug discovery using in silico text mining and DeepPurpose may be a powerful and effective way to identify drugs targeting the genes related to KL and HS.
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Affiliation(s)
- Yuyan Pan
- Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhiwei Chen
- Big Data and Artificial Intelligence Center, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Fazhi Qi
- Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jiaqi Liu
- Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.,Artificial Intelligence Center for Plastic Surgery and Cutaneous Soft Tissue Cancers, Zhongshan Hospital, Fudan University, Shanghai, China
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35
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Gong J, Chuang J, Cho M, Toomey K, Hendifar A, Li D. Molecular Targets, Pathways, and Therapeutic Implications for Hepatocellular Carcinoma. Int J Mol Sci 2020; 21:ijms21155232. [PMID: 32718047 PMCID: PMC7432744 DOI: 10.3390/ijms21155232] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 07/19/2020] [Accepted: 07/21/2020] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) represents one of the leading causes of cancer mortality worldwide. While significant advances have been made for the treatment of advanced hepatocellular carcinoma in the past few years, the prognosis remains poor and effective biomarkers to guide selection of therapies remain noticeably absent. However, several targeted therapies have been approved in the past few years that have improved the outlook for this disease. In this review, we will highlight the recent therapies approved for the treatment of advanced HCC and discuss promising therapeutic options, targets, and pathways for drug development and consideration for future clinical trials.
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Affiliation(s)
- Jun Gong
- Department of Gastrointestinal Malignancies, Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA 90048, USA;
| | - Jeremy Chuang
- Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA;
| | - May Cho
- Department of Internal Medicine, UC Davis Comprehensive Cancer Center, Sacramento, CA 95817, USA; (M.C.); (K.T.)
| | - Kyra Toomey
- Department of Internal Medicine, UC Davis Comprehensive Cancer Center, Sacramento, CA 95817, USA; (M.C.); (K.T.)
| | - Andrew Hendifar
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA;
| | - Daneng Li
- Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA;
- Correspondence:
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Zhang M, Jang H, Nussinov R. PI3K inhibitors: review and new strategies. Chem Sci 2020; 11:5855-5865. [PMID: 32953006 PMCID: PMC7472334 DOI: 10.1039/d0sc01676d] [Citation(s) in RCA: 112] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Accepted: 05/18/2020] [Indexed: 12/16/2022] Open
Abstract
The search is on for effective specific inhibitors for PI3Kα mutants. PI3Kα, a critical lipid kinase, has two subunits, catalytic and inhibitory. PIK3CA, the gene that encodes the p110α catalytic subunit is a highly mutated protein in cancer. Dysregulation of PI3Kα signalling is commonly associated with tumorigenesis and drug resistance. Despite its vast importance, only recently the FDA approved the first drug (alpelisib by Novartis) for breast cancer. A second (GDC0077), classified as PI3Kα isoform-specific, is undergoing clinical trials. Not surprisingly, these ATP-competitive drugs commonly elicit severe concentration-dependent side effects. Here we briefly review PI3Kα mutations, focus on PI3K drug repertoire and propose new, to-date unexplored PI3Kα therapeutic strategies. These include (1) an allosteric and orthosteric inhibitor combination and (2) taking advantage of allosteric rescue mutations to guide drug discovery.
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Affiliation(s)
- Mingzhen Zhang
- Computational Structural Biology Section , Frederick National Laboratory for Cancer Research , National Cancer Institute at Frederick , Frederick , MD 21702 , USA . ; Tel: +1-301-846-5579
| | - Hyunbum Jang
- Computational Structural Biology Section , Frederick National Laboratory for Cancer Research , National Cancer Institute at Frederick , Frederick , MD 21702 , USA . ; Tel: +1-301-846-5579
| | - Ruth Nussinov
- Computational Structural Biology Section , Frederick National Laboratory for Cancer Research , National Cancer Institute at Frederick , Frederick , MD 21702 , USA . ; Tel: +1-301-846-5579
- Department of Human Molecular Genetics and Biochemistry , Sackler School of Medicine , Tel Aviv University , Tel Aviv 69978 , Israel
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Chen H, Gotimer K, De Souza C, Tepper CG, Karnezis AN, Leiserowitz GS, Chien J, Smith LH. Short-term organoid culture for drug sensitivity testing of high-grade serous carcinoma. Gynecol Oncol 2020; 157:783-792. [PMID: 32253045 PMCID: PMC7819712 DOI: 10.1016/j.ygyno.2020.03.026] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2020] [Accepted: 03/21/2020] [Indexed: 01/06/2023]
Abstract
OBJECTIVE Cancer patient-derived organoids (PDOs) grow as three dimensional (3D) structures in the presence of extracellular matrix and have been found to represent the original tumor's genetic complexity. In addition, PDOs can be grown and subjected to drug sensitivity testing in a shorter time course and with lesser expense than patient-derived xenograft models. Many patients with recurrent ovarian cancer develop malignant effusions that become refractory to chemotherapy. Since these same patients often present for palliative aspiration of ascites or pleural effusions, there is a potential opportunity to obtain tumor specimens in the form of multicellular spheroids (MCS) present in malignant effusion fluids. Our objective was to develop a short duration culture of MCS from ovarian cancer malignant effusions in conditions selected to support organoid growth and use them as a platform for empirical drug sensitivity testing. METHODS In this study, malignant effusion specimens were collected from patients with high-grade serous ovarian carcinoma (HGSOC). MCS were recovered and subjected to culture conditions designed to support organoid growth. In a subset of specimens, RNA-sequencing was performed at two time points during the short-term culture to determine changes in transcriptome in response to culture conditions. Organoid induction was also characterized in these specimens using Ki67 staining and histologic analysis. Drug sensitivity testing was performed on all specimens. RESULTS Our model describes organoids formed within days of primary culture, which can recapitulate the histological features of malignant ascites fluid and can be expanded for at least 6 days. RNA-seq analysis of four patient specimens showed that within 6 days of culture, there was significant up-regulation of genes related to cellular proliferation, epithelial-mesenchymal transition, and KRAS signaling pathways. Drug sensitivity testing identified several agents with therapeutic potential. CONCLUSIONS Short duration organoid culture of MCS from HGSOC malignant effusions can be used as a platform for empiric drug sensitivity testing. These ex vivo models may be helpful in screening new or existing therapeutic agents prior to individualized treatment options.
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Affiliation(s)
- Hui Chen
- Department of Obstetrics and Gynecology, University of California Davis Health, Sacramento, CA 95817, United States of America
| | - Kristin Gotimer
- Department of Obstetrics and Gynecology, University of California Davis Health, Sacramento, CA 95817, United States of America
| | - Cristabelle De Souza
- Department of Biochemistry and Molecular Medicine, University of California Davis Health, Sacramento, CA 95817, United States of America
| | - Clifford G Tepper
- Department of Biochemistry and Molecular Medicine, University of California Davis Health, Sacramento, CA 95817, United States of America
| | - Anthony N Karnezis
- Department of Pathology and Laboratory Medicine, University of California Davis Health, Sacramento, CA 95817, United States of America
| | - Gary S Leiserowitz
- Department of Obstetrics and Gynecology, University of California Davis Health, Sacramento, CA 95817, United States of America
| | - Jeremy Chien
- Department of Obstetrics and Gynecology, University of California Davis Health, Sacramento, CA 95817, United States of America; Department of Biochemistry and Molecular Medicine, University of California Davis Health, Sacramento, CA 95817, United States of America.
| | - Lloyd H Smith
- Department of Obstetrics and Gynecology, University of California Davis Health, Sacramento, CA 95817, United States of America.
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Lee MJ, Jin N, Grandis JR, Johnson DE. Alterations and molecular targeting of the GSK-3 regulator, PI3K, in head and neck cancer. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2020; 1867:118679. [PMID: 32061630 PMCID: PMC7671657 DOI: 10.1016/j.bbamcr.2020.118679] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 02/06/2020] [Accepted: 02/09/2020] [Indexed: 12/17/2022]
Abstract
Head and neck squamous cell carcinoma (HNSCC) is a highly morbid, genetically unstable disease derived from the mucoepithelium of the upper aerodigestive tract. Recent characterization of this disease has implicated the PI3K-Akt-mTOR pathway as one of the most frequently dysregulated pathways. As such, there are several classes of PI3K inhibitors currently undergoing clinical trials. In this article, we review the PI3K pathway, mutations of this pathway in HNSCC, drugs that target PI3K, the impact of these agents on the PI3K and GSK-3 signaling axes, ongoing clinical trials evaluating PI3K inhibitors, and the challenges of using these drugs in the clinic. This article is part of a Special Issue entitled: GSK-3 and related kinases in cancer, neurological and other disorders edited by James McCubrey, Agnieszka Gizak and Dariusz Rakus.
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Affiliation(s)
- Michelle J Lee
- School of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Nan Jin
- Department of Otolaryngology, University of California, San Francisco, USA
| | - Jennifer R Grandis
- Department of Otolaryngology, University of California, San Francisco, USA
| | - Daniel E Johnson
- Department of Otolaryngology, University of California, San Francisco, USA.
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Huang TT, Lampert EJ, Coots C, Lee JM. Targeting the PI3K pathway and DNA damage response as a therapeutic strategy in ovarian cancer. Cancer Treat Rev 2020; 86:102021. [PMID: 32311593 DOI: 10.1016/j.ctrv.2020.102021] [Citation(s) in RCA: 107] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 03/30/2020] [Accepted: 03/31/2020] [Indexed: 12/24/2022]
Abstract
Ovarian cancer is the most lethal gynecological malignancy worldwide although exponential progress has been made in its treatment over the last decade. New agents and novel combination treatments are on the horizon. Among many new drugs, a series of PI3K/AKT/mTOR pathway (referred to as the PI3K pathway) inhibitors are under development or already in clinical testing. The PI3K pathway is frequently upregulated in ovarian cancer and activated PI3K signaling contributes to increased cell survival and chemoresistance. However, no significant clinical success has been achieved with the PI3K pathway inhibitor(s) to date, reflecting the complex biology and also highlighting the need for combination treatment strategies. DNA damage repair pathways have been active therapeutic targets in ovarian cancer. Emerging data suggest the PI3K pathway is also involved in DNA replication and genome stability, making DNA damage response (DDR) inhibitors as an attractive combination treatment for PI3K pathway blockades. This review describes an expanded role for the PI3K pathway in the context of DDR and cell cycle regulation. We also present the novel treatment strategies combining PI3K pathway inhibitors with DDR blockades to improve the efficacy of these inhibitors for ovarian cancer.
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Affiliation(s)
- Tzu-Ting Huang
- Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
| | - Erika J Lampert
- Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Cynthia Coots
- Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Jung-Min Lee
- Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
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40
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Wu Q, Wu W, Jacevic V, Franca TCC, Wang X, Kuca K. Selective inhibitors for JNK signalling: a potential targeted therapy in cancer. J Enzyme Inhib Med Chem 2020; 35:574-583. [PMID: 31994958 PMCID: PMC7034130 DOI: 10.1080/14756366.2020.1720013] [Citation(s) in RCA: 113] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
c-Jun N-terminal kinase (JNK) signalling regulates both cancer cell apoptosis and survival. Emerging evidence show that JNK promoted tumour progression is involved in various cancers, that include human pancreatic-, lung-, and breast cancer. The pro-survival JNK oncoprotein functions in a cell context- and cell type-specific manner to affect signal pathways that modulate tumour initiation, proliferation, and migration. JNK is therefore considered a potential oncogenic target for cancer therapy. Currently, designing effective and specific JNK inhibitors is an active area in the cancer treatment. Some ATP-competitive inhibitors of JNK, such as SP600125 and AS601245, are widely used in vitro; however, this type of inhibitor lacks specificity as they indiscriminately inhibit phosphorylation of all JNK substrates. Moreover, JNK has at least three isoforms with different functions in cancer development and identifying specific selective inhibitors is crucial for the development of targeted therapy in cancer. Some selective inhibitors of JNK are identified; however, their clinical studies in cancer are relatively less conducted. In this review, we first summarised the function of JNK signalling in cancer progression; there is a focus on the discussion of the novel selective JNK inhibitors as potential targeting therapy in cancer. Finally, we have offered a future perspective of the selective JNK inhibitors in the context of cancer therapies. We hope this review will help to further understand the role of JNK in cancer progression and provide insight into the design of novel selective JNK inhibitors in cancer treatment.
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Affiliation(s)
- Qinghua Wu
- College of Life Science, Yangtze University, Jingzhou, China.,College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China.,Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, Czech Republic
| | - Wenda Wu
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China.,Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, Czech Republic
| | - Vesna Jacevic
- Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, Czech Republic.,National Poison Control Centre, Military Medical Academy, Belgrade, Serbia.,Medical Faculty of the Military Medical Academy, University of Defence, Belgrade, Serbia
| | - Tanos C C Franca
- Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, Czech Republic.,Laboratory of Molecular Modeling Applied to the Chemical and Biological Defense, Military Institute of Engineering, Rio de Janeiro, Brazil
| | - Xu Wang
- National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, China
| | - Kamil Kuca
- Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, Czech Republic
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41
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Tarantelli C, Lupia A, Stathis A, Bertoni F. Is There a Role for Dual PI3K/mTOR Inhibitors for Patients Affected with Lymphoma? Int J Mol Sci 2020; 21:E1060. [PMID: 32033478 PMCID: PMC7037719 DOI: 10.3390/ijms21031060] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 01/31/2020] [Accepted: 02/03/2020] [Indexed: 12/12/2022] Open
Abstract
The activation of the PI3K/AKT/mTOR pathway is a main driver of cell growth, proliferation, survival, and chemoresistance of cancer cells, and, for this reason, represents an attractive target for developing targeted anti-cancer drugs. There are plenty of preclinical data sustaining the anti-tumor activity of dual PI3K/mTOR inhibitors as single agents and in combination in lymphomas. Clinical responses, including complete remissions (especially in follicular lymphoma patients), are also observed in the very few clinical studies performed in patients that are affected by relapsed/refractory lymphomas or chronic lymphocytic leukemia. In this review, we summarize the literature on dual PI3K/mTOR inhibitors focusing on the lymphoma setting, presenting both the three compounds still in clinical development and those with a clinical program stopped or put on hold.
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Affiliation(s)
- Chiara Tarantelli
- Institute of Oncology Research, Faculty of Biomedical Sciences, USI, 6500 Bellinzona, Switzerland;
| | - Antonio Lupia
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy;
| | - Anastasios Stathis
- Oncology Institute of Southern Switzerland, 6500 Bellinzona, Switzerland;
- Faculty of Biomedical Sciences, USI, 6900 Lugano, Switzerland
| | - Francesco Bertoni
- Institute of Oncology Research, Faculty of Biomedical Sciences, USI, 6500 Bellinzona, Switzerland;
- Oncology Institute of Southern Switzerland, 6500 Bellinzona, Switzerland;
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Arafeh R, Samuels Y. PIK3CA in cancer: The past 30 years. Semin Cancer Biol 2019; 59:36-49. [DOI: 10.1016/j.semcancer.2019.02.002] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Revised: 01/08/2019] [Accepted: 02/07/2019] [Indexed: 02/07/2023]
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Han J, Tang Y, Zhong M, Wu W. Antitumor effects and mechanisms of 1,25(OH)2D3 in the Pfeiffer diffuse large B lymphoma cell line. Mol Med Rep 2019; 20:5064-5074. [PMID: 31638226 PMCID: PMC6854594 DOI: 10.3892/mmr.2019.10756] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Accepted: 08/06/2019] [Indexed: 12/12/2022] Open
Abstract
Diffuse large B cell lymphoma (DLBCL) represents the most common subtype of non-Hodgkin lymphoma in China. 1,25-Dihydroxyvitamin D3 [1,25(OH)2D3] has been shown to possess significant antitumor potential and is degraded by 25-hydroxyvitamin D-24-hydroxylase (CYP24A1). In the present study, the role of CYP24A1 and autophagy, and their underlying mechanisms in the anticancer effects of 1,25(OH)2D3 in DLBCL cells, were investigated. It was found that the levels of CYP24A1 in DLBCL lymph node tissues were higher than in hyperplasia lymphadenitis tissue. Moreover, the expression of CYP24A1 was positively associated with the Ann Arbor stage and the International Prognostic Index in patients with DLBCL, and negatively associated with the clinical response to treatment. Patients >60 years of age were found to have a higher level of CYP24A1. 1,25(OH)2D3 inhibited the proliferation of the Pfeiffer DLBCL cell line and increased the G1 phase population of Pfeiffer cells. Rapamycin (RAPA) in combination with 1,25(OH)2D3 increased the G1 phase distribution of Pfeiffer cells. Furthermore, RAPA blocked the increase of CYP24A1 and vitamin D receptor (VDR) expression induced by 1,25(OH)2D3. 1,25(OH)2D3 induced the formation of autophagosomes, increased the expression of autophagy related protein light chain (LC)3II/LC3I and reduced the expression of the ubiquitin binding protein P62. In addition, 1,25(OH)2D3 decreased the phosphorylation of AKT and mammalian target of RAPA (mTOR), and downstream targets eukaryotic translation imitation factor 4E-binding protein 1 and ribosomal protein S6 kinase β-1 in Pfeiffer cells. The results from the present study suggested that CYP24A1 may be a novel prognostic indicator for DLBCL. 1,25(OH)2D3 inhibited proliferation and induced autophagy of Pfeiffer cells. In addition, 1,25(OH)2D3 increased the G1 phase population of Pfeiffer cells. These effects may be mediated by inhibition of the AKT/mTOR/PI3K signaling pathway. RAPA increased the cell cycle arrest induced by 1,25(OH)2D3 by blocking the upregulated expression of CYP24A1 and VDR.
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Affiliation(s)
- Jing Han
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Yonghong Tang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Meizuo Zhong
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Wenlin Wu
- Department of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong 510000, P.R. China
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Abstract
Less than a decade ago, it was shown that bromodomains, acetyl lysine 'reader' modules found in proteins with varied functions, were highly tractable small-molecule targets. This is an unusual property for protein-protein or protein-peptide interaction domains, and it prompted a wave of chemical probe discovery to understand the biological potential of new agents that targeted bromodomains. The original examples, inhibitors of the bromodomain and extra-terminal (BET) class of bromodomains, showed enticing anti-inflammatory and anticancer activities, and several compounds have since advanced to human clinical trials. Here, we review the current state of BET inhibitor biology in relation to clinical development, and we discuss the next wave of bromodomain inhibitors with clinical potential in oncology and non-oncology indications. The lessons learned from BET inhibitor programmes should affect efforts to develop drugs that target non-BET bromodomains and other epigenetic readers.
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45
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Patidar K, Panwar U, Vuree S, Sweta J, Sandhu MK, Nayarisseri A, Singh SK. An In silico Approach to Identify High Affinity Small Molecule
Targeting m-TOR Inhibitors for the Clinical Treatment of
Breast Cancer. Asian Pac J Cancer Prev 2019; 20:1229-1241. [PMID: 31030499 PMCID: PMC6948900 DOI: 10.31557/apjcp.2019.20.4.1229] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Breast cancer is the most frequent malignancy among women. It is a heterogeneous disease with different subtypes defined by its hormone receptor. A hormone receptor is mainly concerned with the progression of the PI3K/AKT/mTOR pathway which is often dysregulated in breast cancer. This is a major signaling pathway that controls the activities such as cell growth, cell division, and cell proliferation. The present study aims to suppress mTOR protein by its various inhibitors and to select one with the highest binding affinity to the receptor protein. Out of 40 inhibitors of mTOR against breast cancer, SF1126 was identified to have the best docking score of -8.705, using Schrodinger Suite which was further subjected for high throughput screening to obtain best similar compound using Lipinski’s filters. The compound obtained after virtual screening, ID: ZINC85569445 is seen to have the highest affinity with the target protein mTOR. The same result based on the binding free energy analysis using MM-GBSA showed that the compound ZINC85569445 to have the the highest binding free energy. The next study of interaction between the ligand and receptor protein with the pharmacophore mapping showed the best conjugates, and the ZINC85569445 can be further studied for future benefits of treatment of breast cancer.
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Affiliation(s)
- Khushboo Patidar
- In silico Research Laboratory, Eminent Biosciences, Indore, Madhya Pradesh, India. ,
| | - Umesh Panwar
- Computer Aided Drug Designing and Molecular Modeling Lab, Department of Bioinformatics, Alagappa University, Karaikudi,Tamil Nadu, India
| | - Sugunakar Vuree
- Department of Biotechnology, Lovely Faculty of Technology and Sciences, Division of Research and Development, Lovely Professional University, Phagwara, Punjab, India
| | - Jajoriya Sweta
- In silico Research Laboratory, Eminent Biosciences, Indore, Madhya Pradesh, India. ,
| | - Manpreet Kaur Sandhu
- In silico Research Laboratory, Eminent Biosciences, Indore, Madhya Pradesh, India. ,
| | - Anuraj Nayarisseri
- In silico Research Laboratory, Eminent Biosciences, Indore, Madhya Pradesh, India. , ,Computer Aided Drug Designing and Molecular Modeling Lab, Department of Bioinformatics, Alagappa University, Karaikudi,Tamil Nadu, India.,Bioinformatics Research Laboratory, LeGene Biosciences Pvt Ltd., Indore, India
| | - Sanjeev Kumar Singh
- Computer Aided Drug Designing and Molecular Modeling Lab, Department of Bioinformatics, Alagappa University, Karaikudi,Tamil Nadu, India
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Conway JRW, Herrmann D, Evans TRJ, Morton JP, Timpson P. Combating pancreatic cancer with PI3K pathway inhibitors in the era of personalised medicine. Gut 2019; 68:742-758. [PMID: 30396902 PMCID: PMC6580874 DOI: 10.1136/gutjnl-2018-316822] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 10/02/2018] [Accepted: 10/04/2018] [Indexed: 12/16/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is among the most deadly solid tumours. This is due to a generally late-stage diagnosis of a primarily treatment-refractory disease. Several large-scale sequencing and mass spectrometry approaches have identified key drivers of this disease and in doing so highlighted the vast heterogeneity of lower frequency mutations that make clinical trials of targeted agents in unselected patients increasingly futile. There is a clear need for improved biomarkers to guide effective targeted therapies, with biomarker-driven clinical trials for personalised medicine becoming increasingly common in several cancers. Interestingly, many of the aberrant signalling pathways in PDAC rely on downstream signal transduction through the mitogen-activated protein kinase and phosphoinositide 3-kinase (PI3K) pathways, which has led to the development of several approaches to target these key regulators, primarily as combination therapies. The following review discusses the trend of PDAC therapy towards molecular subtyping for biomarker-driven personalised therapies, highlighting the key pathways under investigation and their relationship to the PI3K pathway.
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Affiliation(s)
- James RW Conway
- Garvan Institute of Medical Research & The Kinghorn Cancer Centre, Cancer Division, Sydney, New South Wales, Australia
| | - David Herrmann
- Garvan Institute of Medical Research & The Kinghorn Cancer Centre, Cancer Division, Sydney, New South Wales, Australia
- St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
| | - TR Jeffry Evans
- Cancer Department, Cancer Research UK Beatson Institute, Glasgow, UK
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Jennifer P Morton
- Cancer Department, Cancer Research UK Beatson Institute, Glasgow, UK
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Paul Timpson
- Garvan Institute of Medical Research & The Kinghorn Cancer Centre, Cancer Division, Sydney, New South Wales, Australia
- St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
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Thierauf J, Ramamurthy N, Jo VY, Robinson H, Frazier RP, Gonzalez J, Pacula M, Dominguez Meneses E, Nose V, Nardi V, Dias-Santagata D, Le LP, Lin DT, Faquin WC, Wirth LJ, Hess J, Iafrate AJ, Lennerz JK. Clinically Integrated Molecular Diagnostics in Adenoid Cystic Carcinoma. Oncologist 2019; 24:1356-1367. [PMID: 30926674 PMCID: PMC6795155 DOI: 10.1634/theoncologist.2018-0515] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 02/27/2019] [Indexed: 01/29/2023] Open
Abstract
Adenoid cystic carcinoma is a rare but aggressive type of salivary gland malignancy. This article addresses the need for more effective, biomarker‐informed therapies in rare cancers, focusing on clinical utility and financial sustainability of integrated next‐generation sequencing in routine practice. Background. Adenoid cystic carcinoma (ACC) is an aggressive salivary gland malignancy without effective systemic therapies. Delineation of molecular profiles in ACC has led to an increased number of biomarker‐stratified clinical trials; however, the clinical utility and U.S.‐centric financial sustainability of integrated next‐generation sequencing (NGS) in routine practice has, to our knowledge, not been assessed. Materials and Methods. In our practice, NGS genotyping was implemented at the discretion of the primary clinician. We combined NGS‐based mutation and fusion detection, with MYB break‐apart fluorescent in situ hybridization (FISH) and MYB immunohistochemistry. Utility was defined as the fraction of patients with tumors harboring alterations that are potentially amenable to targeted therapies. Financial sustainability was assessed using the fraction of global reimbursement. Results. Among 181 consecutive ACC cases (2011–2018), prospective genotyping was performed in 11% (n = 20/181; n = 8 nonresectable). Testing identified 5/20 (25%) NOTCH1 aberrations, 6/20 (30%) MYB‐NFIB fusions (all confirmed by FISH), and 2/20 (10%) MYBL1‐NFIB fusions. Overall, these three alterations (MYB/MYBL1/NOTCH1) made up 65% of patients, and this subset had a more aggressive course with significantly shorter progression‐free survival. In 75% (n = 6/8) of nonresectable patients, we detected potentially actionable alterations. Financial analysis of the global charges, including NGS codes, indicated 63% reimbursement, which is in line with national (U.S.‐based) and international levels of reimbursement. Conclusion. Prospective routine clinical genotyping in ACC can identify clinically relevant subsets of patients and is approaching financial sustainability. Demonstrating clinical utility and financial sustainability in an orphan disease (ACC) requires a multiyear and multidimensional program. Implications for Practice. Delineation of molecular profiles in adenoid cystic carcinoma (ACC) has been accomplished in the research setting; however, the ability to identify relevant patient subsets in clinical practice has not been assessed. This work presents an approach to perform integrated molecular genotyping of patients with ACC with nonresectable, recurrent, or systemic disease. It was determined that 75% of nonresectable patients harbor potentially actionable alterations and that 63% of charges are reimbursed. This report outlines that orphan diseases such as ACC require a multiyear, multidimensional program to demonstrate utility in clinical practice.
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Affiliation(s)
- Julia Thierauf
- Department of Pathology, Center for Integrated Diagnostics, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA
- Department of Otorhinolaryngology, Head and Neck Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Nisha Ramamurthy
- Department of Pathology, Center for Integrated Diagnostics, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA
| | - Vickie Y Jo
- Department of Pathology, Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts, USA
| | - Hayley Robinson
- Department of Pathology, Center for Integrated Diagnostics, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA
| | - Ryan P Frazier
- Department of Pathology, Center for Integrated Diagnostics, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA
| | - Jonathan Gonzalez
- Department of Pathology, Center for Integrated Diagnostics, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA
| | - Maciej Pacula
- Department of Pathology, Computational Pathology, Boston, Massachusetts, USA
| | | | - Vania Nose
- Department of Pathology, Head and Neck Pathology, Boston, Massachusetts, USA
- Department of Pathology, Surgical Pathology, Boston, Massachusetts, USA
| | - Valentina Nardi
- Department of Pathology, Center for Integrated Diagnostics, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA
| | - Dora Dias-Santagata
- Department of Pathology, Center for Integrated Diagnostics, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA
| | - Long P Le
- Department of Pathology, Center for Integrated Diagnostics, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA
- Department of Pathology, Computational Pathology, Boston, Massachusetts, USA
| | - Derrick T Lin
- Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA
| | - William C Faquin
- Department of Pathology, Surgical Pathology, Boston, Massachusetts, USA
- Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA
| | - Lori J Wirth
- Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA
- Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA
| | - Jochen Hess
- Department of Otorhinolaryngology, Head and Neck Surgery, Heidelberg University Hospital, Heidelberg, Germany
- Research Group Molecular Mechanisms of Head and Neck Tumors, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - A John Iafrate
- Department of Pathology, Center for Integrated Diagnostics, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA
| | - Jochen K Lennerz
- Department of Pathology, Center for Integrated Diagnostics, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA
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Minten EV, Yu DS. DNA Repair: Translation to the Clinic. Clin Oncol (R Coll Radiol) 2019; 31:303-310. [PMID: 30876709 DOI: 10.1016/j.clon.2019.02.007] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Revised: 02/18/2019] [Accepted: 02/20/2019] [Indexed: 12/18/2022]
Abstract
It has been well established that an accumulation of mutations in DNA, whether caused by external sources (e.g. ultraviolet light, radioactivity) or internal sources (e.g. metabolic by-products, such as reactive oxygen species), has the potential to cause a cell to undergo carcinogenesis and increase the risk for the development of cancer. Therefore, it is critically important for a cell to have the capacity to properly respond to and repair DNA damage as it occurs. The DNA damage response (DDR) describes a collection of DNA repair pathways that aid in the protection of genomic integrity by detecting myriad types of DNA damage and initiating the correct DNA repair pathway. In many instances, a deficiency in the DDR, whether inherited or spontaneously assumed, can increase the risk of carcinogenesis and ultimately tumorigenesis through the accumulation of mutations that fail to be properly repaired. Interestingly, although disruption of the DDR can lead to the initial genomic instability that can ultimately cause carcinogenesis, the DDR has also proven to be an invaluable target for anticancer drugs and therapies. Making matters more complicated, the DDR is also involved in the resistance to first-line cancer therapy. In this review, we will consider therapies already in use in the clinic and ongoing research into other avenues of treatment that target DNA repair pathways in cancer.
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Affiliation(s)
- E V Minten
- Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA, USA
| | - D S Yu
- Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA, USA.
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Hou G, Zhao Q, Zhang M, Fan T, Liu M, Shi X, Ren Y, Wang Y, Zhou J, Lu Z. Down-regulation of Rictor enhances cell sensitivity to PI3K inhibitor LY294002 by blocking mTORC2-medicated phosphorylation of Akt/PRAS40 in esophageal squamous cell carcinoma. Biomed Pharmacother 2018; 106:1348-1356. [DOI: 10.1016/j.biopha.2018.07.075] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Revised: 07/11/2018] [Accepted: 07/14/2018] [Indexed: 12/17/2022] Open
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Cross Talk Networks of Mammalian Target of Rapamycin Signaling With the Ubiquitin Proteasome System and Their Clinical Implications in Multiple Myeloma. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2018; 343:219-297. [PMID: 30712673 DOI: 10.1016/bs.ircmb.2018.06.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Multiple myeloma (MM) is the second most common hematological malignancy and results from the clonal amplification of plasma cells. Despite recent advances in treatment, MM remains incurable with a median survival time of only 5-6years, thus necessitating further insights into MM biology and exploitation of novel therapeutic approaches. Both the ubiquitin proteasome system (UPS) and the PI3K/Akt/mTOR signaling pathways have been implicated in the pathogenesis, and treatment of MM and different lines of evidence suggest a close cross talk between these central cell-regulatory signaling networks. In this review, we outline the interplay between the UPS and mTOR pathways and discuss their implications for the pathophysiology and therapy of MM.
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