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Chitoran E, Rotaru V, Stefan DC, Gullo G, Simion L. Blocking Tumoral Angiogenesis VEGF/VEGFR Pathway: Bevacizumab-20 Years of Therapeutic Success and Controversy. Cancers (Basel) 2025; 17:1126. [PMID: 40227654 PMCID: PMC11988089 DOI: 10.3390/cancers17071126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Revised: 03/22/2025] [Accepted: 03/26/2025] [Indexed: 04/15/2025] Open
Abstract
The "angiogenesis switch"-defined as the active process by which solid tumors develop their own circulation-plays an important role in both tumoral growth and propagation. As the malignant tumor grows and reaches a critical size, the metabolic needs as a function of an ever-increasing distance to the nearest emergent blood vessel, can no longer be covered by the microenvironment of the peritumoral tissue. Although a relatively discrete process, the "angiogenic switch" acts as a limiting stage of tumoral development present from the avascular hyperplasia phase to the vascularized neoplastic phase, providing support for tumor expansion and metastasis. Over time, research has focused on blocking the angiogenetic pathways (such as VEGF/VEGFR signaling axis) leading to the development of targeted therapeutic agents such as Bevacizumab. Objectives: We conducted a review of the molecular principles of tumoral angiogenesis and we tried to follow the history of Bevacizumab from its first approval for human usage 20 years ago to current days, focusing on the impact this agent had in solid tumor therapy. A comprehensive review of clinical trials pertaining to Bevacizumab (from the era of the preclinic trials leading to approval for human usage, to the more recent randomized trial focusing on combination targeted therapy) further details the role of this drug. We aimed to establish if this ancient drug continues to have a place in modern oncology. Conclusions: Bevacizumab, one of the first drugs targeting tumoral microenvironment, remains one of the most important oncologic agents blocking the VEGF/VEGFR angiogenic pathway. otherwise, history of 20 years marked by numerous controversies (ranging from methodological errors of clinical trials to withdrawal of approval for human usage in breast cancer patients, from discussions about severe side effects to resistance to therapy and limited efficacity), Bevacizumab continues to provide an optimal therapeutic option for many solid tumors that previously had little to no means of treatment, improving otherwise bleak outcomes. Even in the era of personalized precision oncology, Bevacizumab continues to be a key element in many therapeutic regimens both as monotherapy and in combination with newer targeted agents.
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Affiliation(s)
- Elena Chitoran
- Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- General Surgery and Surgical Oncology Department I, Bucharest Institute of Oncology “Prof. Dr. Al. Trestioreanu”, 022328 Bucharest, Romania
| | - Vlad Rotaru
- Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- General Surgery and Surgical Oncology Department I, Bucharest Institute of Oncology “Prof. Dr. Al. Trestioreanu”, 022328 Bucharest, Romania
| | - Daniela-Cristina Stefan
- Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Giuseppe Gullo
- Department of Obstetrics and Gynecology, Villa Sofia Cervello Hospital, University of Palermo, 90146 Palermo, Italy
| | - Laurentiu Simion
- Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- General Surgery and Surgical Oncology Department I, Bucharest Institute of Oncology “Prof. Dr. Al. Trestioreanu”, 022328 Bucharest, Romania
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Xu J, Wang X, Jia Z, Sun G. Effectiveness and safety of angiogenesis inhibitors combined with PD-1/PD-L1 blockades in the first-line treatment of patients with advanced hepatocellular carcinoma: A single-center retrospective study. Medicine (Baltimore) 2025; 104:e41814. [PMID: 40101095 PMCID: PMC11922473 DOI: 10.1097/md.0000000000041814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Accepted: 02/21/2025] [Indexed: 03/20/2025] Open
Abstract
The combination of immune checkpoint inhibitors targeting anti-programmed cell death-1 (anti-PD-1) or anti-programmed death ligand-1 (anti-PD-L1) with antiangiogenic agents has emerged as a revolutionary therapy for advanced hepatocellular carcinoma (aHCC). Key antiangiogenic medications encompass monoclonal antibodies targeting vascular endothelial growth factor (anti-VEGF mAbs) and multiple kinase inhibitors (MKIs). The aim of this study is to assess the difference of efficacy and safety between 2 combination therapies. This study retrospectively examined the outcomes of 57 patients with aHCC who underwent first-line treatment with a combination of immune checkpoint inhibitors and antiangiogenic therapy at the First Affiliated Hospital of Anhui Medical University, from September 2018 to July 2023. The analysis, conducted using SPSS software, focused on patient outcomes such as tumor response (assessed according to modified Response Evaluation Criteria in Solid Tumors criteria), objective response rate, disease control rate, progression-free survival, overall survival, and safety. Comparisons among different groups were also made. The anti-PD-1/anti-PD-L1-anti-VEGF mAbs group showed a trend of higher partial response rate (37.50% vs 22.45%), objective response rate (37.50% vs 24.49%), disease control rate (62.50% vs 59.18%), and seemed to achieve longer median progression-free survival (14.93 vs 14.90 months) and median overall survival (15.80 vs 11.10 months) without higher grade 3 or higher adverse events comparing to anti-PD-1/anti-PD-L1-MKIs group. Subgroup analysis showed that the anti-PD-1-lenvatinib group achieved longer median progression-free survival (23.97 months), while the anti-PD-1-regorafenib group achieved longer median overall survival (37.97 months). The anti-PD-1/anti-PD-L1 combined with anti-VEGF mAbs was effective and tolerable compared to anti-PD-1/anti-PD-L1-MKIs in aHCC. The addition of lenvatinib or regorafenib may provide promising incremental benefit for patients with aHCC.
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Affiliation(s)
- Jing Xu
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
| | - Xin Wang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
| | - Zhenya Jia
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
| | - Guoping Sun
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
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Qiao H, Guo H, Liang Z, Kang L, Zhang W. Primary hepatocellular carcinosarcoma: A case series and literature review. Clin Res Hepatol Gastroenterol 2025; 49:102520. [PMID: 39756650 DOI: 10.1016/j.clinre.2024.102520] [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: 07/18/2024] [Revised: 12/25/2024] [Accepted: 12/29/2024] [Indexed: 01/07/2025]
Abstract
INTRODUCTION Hepatocellular carcinosarcoma (HCS) is a rare and aggressive liver tumor with limited clinical evidence due to its infrequency. This case series aimed to enrich the existing knowledge on the diagnosis and clinical management of HCS. METHODS Four patients with HCS were evaluated, focusing on their symptoms, diagnoses, treatments, and outcomes. The imaging characteristics and tumorigenesis of HCS were also investigated, highlighting the role of p53 mutations. RESULTS This case series found that timely surgery and localized chemotherapy are crucial in managing HCS. Despite the promising results of targeted therapy, its limitations were observed in some patients. The onset and progression of HCS were found to be significantly correlated with the presence of p53 mutations. CONCLUSIONS This case series underscores the need for further research to improve the diagnosis and treatment of HCS and emphasizes the importance of timely surgery and localized chemotherapy in mitigating tumor side effects and potentially prolonging survival.
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Affiliation(s)
- Haodong Qiao
- Department of Hepatobiliary Surgery, General Hospital, Shijiazhuang, Hebei, PR China; Department of Graduate School, Hebei Medical University, Shijiazhuang, PR China
| | - Huaibin Guo
- Department of Hepatobiliary Surgery, General Hospital, Shijiazhuang, Hebei, PR China.
| | - Ze Liang
- Department of Hepatobiliary Surgery, General Hospital, Shijiazhuang, Hebei, PR China
| | - Lin Kang
- Department of Hepatobiliary Surgery, General Hospital, Shijiazhuang, Hebei, PR China
| | - Wanxing Zhang
- Department of Hepatobiliary Surgery, General Hospital, Shijiazhuang, Hebei, PR China
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Chen YH, Lee YM, Ou DL, Hsu CL, Hsu C, Chen CN, Ko JY, Tan CT. Regorafenib enhances M1/M2 macrophage polarization by inhibiting the secretion of plasminogen activator inhibitor-1 in head and neck squamous cell carcinoma. Life Sci 2024; 358:123147. [PMID: 39419267 DOI: 10.1016/j.lfs.2024.123147] [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: 04/29/2024] [Revised: 06/28/2024] [Accepted: 10/11/2024] [Indexed: 10/19/2024]
Abstract
AIMS Regorafenib, an oral multikinase inhibitor, is approved for the treatment of various metastatic/advanced cancers. Although clinical trials have reported the efficacy of regorafenib in multiple cancer types, its immunomodulatory activity in head and neck squamous cell carcinoma (HNSCC) remains unclear. MAIN METHODS This study investigated the effects of regorafenib on tumorigenesis by using two mouse models of HNSCC. The distribution of immune cells in tumor tissues was assessed through flow cytometry, RNA sequencing, and multiplex immunofluorescence staining. KEY FINDINGS Regorafenib exhibited significant antitumor activity in our HNSCC mouse models. Tumor-infiltrating lymphocyte isolation and RNA sequencing revealed that regorafenib can activate immune functions. Moreover, regorafenib-treated tumor-conditioned medium regulated macrophage proliferation ex vivo. Our data suggests that regorafenib modulates immune function by regulating both tumor and immune cells. Specifically, regorafenib induced the polarization of macrophages toward the proinflammatory M1 phenotype by suppressing the production of plasminogen activator inhibitor 1 (PAI-1), a macrophage regulator. In addition, regorafenib suppressed the secretion of PAI-1 from ex vivo human HNSCC organoids. SIGNIFICANCE Regorafenib enhances M1/M2 macrophage polarization and suppresses PAI-1 secretion from cancer cells, leading to a shift from M2 to M1 macrophages in the HNSCC tumor microenvironment.
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Affiliation(s)
- Yu-Hsin Chen
- Department of Otolaryngology, National Taiwan University Hospital, Taipei 10051, Taiwan; Stem Cell Core Laboratory, Center of Genomic Medicine, National Taiwan University, Taipei 10051, Taiwan; Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei 10051, Taiwan
| | - Yi-Mei Lee
- Department of Otolaryngology, National Taiwan University Hospital, Taipei 10051, Taiwan; Stem Cell Core Laboratory, Center of Genomic Medicine, National Taiwan University, Taipei 10051, Taiwan
| | - Da-Liang Ou
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei 10051, Taiwan; YongLin Institute of Health, National Taiwan University, Taipei 10051, Taiwan
| | - Chia-Lang Hsu
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei 10051, Taiwan; Department of Medical Research, National Taiwan University Hospital, Taipei 10051, Taiwan
| | - Chiun Hsu
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei 10051, Taiwan; Department of Oncology, National Taiwan University Cancer Center, Taipei 10672, Taiwan; Department of Oncology, National Taiwan University Hospital, Taipei 10051, Taiwan
| | - Chun-Nan Chen
- Department of Otolaryngology, National Taiwan University Hospital, Taipei 10051, Taiwan
| | - Jenq-Yuh Ko
- Department of Otolaryngology, National Taiwan University Hospital, Taipei 10051, Taiwan
| | - Ching-Ting Tan
- Department of Otolaryngology, National Taiwan University Hospital, Taipei 10051, Taiwan; Stem Cell Core Laboratory, Center of Genomic Medicine, National Taiwan University, Taipei 10051, Taiwan; Department of Otolaryngology, National Taiwan University College of Medicine, Taipei 10051, Taiwan; Department of Otolaryngology, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu 302058, Taiwan.
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Wang Z, Zhang Y, Liu J, Chen X. Bioequivalence and Pharmacokinetic Evaluation of Regorafenib Tablets in Healthy Chinese Volunteers. Clin Pharmacol Drug Dev 2024; 13:1317-1323. [PMID: 39439380 DOI: 10.1002/cpdd.1474] [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: 07/02/2024] [Accepted: 09/03/2024] [Indexed: 10/25/2024]
Abstract
This was a single-center, randomized, open-label, 2-formulation, and 2-cycle crossover trial conducted in 48 healthy Chinese volunteers, under fasting and fed conditions. The participants received oral doses of the test formulation (regorafenib) and reference formulation (40 mg) during each study period. Blood samples were collected before and up to 144 hours after the formulations were administered to determine changes in the pharmacokinetic parameters and adverse reactions, which were then used to evaluate bioequivalence and safety. The geometric mean ratios of maximum blood concentration, area under the plasma concentration-time curve from time 0 to the last quantifiable concentration, and area under the plasma concentration-time curve from time 0 to infinity for regorafenib were as follows: 94.7%, 91.4%, and 91.7%, respectively, under fasting conditions; and 94.6%, 97.7%, and 98.8%, respectively, under fed conditions. The 90% confidence intervals for the geometric mean ratios were within the 80%-125% equivalence interval for both the fasting and fed tests. Ingesting high-fat and high-calorie foods increases exposure to regorafenib, leading to slower rates of absorption. The safety profiles of the 2 preparations were similar.
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Affiliation(s)
- Zhaoyu Wang
- Clinical Pharmacokinetics Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yun Zhang
- Clinical Pharmacokinetics Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Jingjing Liu
- Clinical Pharmacokinetics Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Xijing Chen
- Clinical Pharmacokinetics Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
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Deng Q, Huang Y, Zeng J, Li X, Zheng X, Guo L, Shi J, Bai L. Recent advancements in the small-molecule drugs for hepatocellular carcinoma (HCC): Structure-activity relationships, pharmacological activities, and the clinical trials. Biomed Pharmacother 2024; 179:117343. [PMID: 39180795 DOI: 10.1016/j.biopha.2024.117343] [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: 06/12/2024] [Revised: 08/14/2024] [Accepted: 08/21/2024] [Indexed: 08/27/2024] Open
Abstract
BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world and the sixth leading cause of cancer death worldwide, and it is urgent to find safe and effective drugs for treatment. As an important therapeutic method, small-molecule drugs are continually being updated to achieve improved therapeutic effects. The purpose of this study was to investigate the structural effects of various FDA-listed small-molecule drugs sorafenib, cabozantinib, lenvatinib, and regorafenib on the corresponding HCC targets and possible structural optimization methods, and to explore the mechanism for identifying potential therapeutic drugs that offer better efficacy and fewer side effects. METHODS The structure-activity relationship, pharmacological actions, and clinical applications of small-molecule drugs were reviewed by referencing MEDLINE, Web of Science, CNKI, and other databases, summarizing and integrating the relevant content. RESULTS The results showed that small-molecule drugs can inhibit HCC primarily by forming hydrogen bonds with Glu885, Asp1046, and Cys919 on the HCC target. HCC can be targeted by inhibiting the activation of multiple pathways, blocking the conduction of downstream signaling, and reducing the formation of tumor blood vessels. In general, small-molecule drugs primarily target four key receptors in HCC: VEGFR, PDGFR, EGFR, and FGFR, to achieve effective treatment. CONCLUSIONS By revealing their structure-activity relationships, pharmacological actions, and clinical trials, small-molecule drugs can offer broad prospects for the development of new medications.
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Affiliation(s)
- Qichuan Deng
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yu Huang
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, Sichuan, China
| | - Jing Zeng
- School of Food and Bioengineering, Xihua University, Chengdu, Sichuan 610039, China
| | - Xinyu Li
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Xianyi Zheng
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Li Guo
- The State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.
| | - Jianyou Shi
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
| | - Lan Bai
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China; The State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.
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Payo-Serafín T, Méndez-Blanco C, Fernández-Palanca P, Martínez-Geijo J, Reviejo M, Ortiz-de-Urbina JJ, González-Gallego J, Marin JJG, Mauriz JL, San-Miguel B. Risk versus Benefit of Tyrosine Kinase Inhibitors for Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Clin Pharmacol Ther 2024; 116:328-345. [PMID: 38803056 DOI: 10.1002/cpt.3312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 05/06/2024] [Indexed: 05/29/2024]
Abstract
Although the treatment landscape has rapidly evolved over the last years, hepatocellular carcinoma (HCC) is one of the most lethal cancers. With recent advances, both immunotherapy and tyrosine kinase inhibitors (TKIs)-based chemotherapy constitute the standard treatment for advanced HCC. A systematic search of randomized clinical trials employing TKIs was performed in 17 databases, obtaining 25 studies evaluating the prognosis, tumor response, and presence of adverse events (AEs) related to TKIs in HCC. Overall effect sizes were estimated for the hazard ratios (HR) and odds ratios (OR) with 95% confidence interval (CI), either extracted or calculated with the Parmar method, employing STATA 16. Heterogeneity was assessed by Chi-square-based Q-test and inconsistency (I2) statistic; source of heterogeneity by meta-regression and subgroup analysis; and publication bias by funnel plot asymmetry and Egger's test. The research protocol was registered in PROSPERO (CRD42023397263). Meta-analysis revealed a correlation between survival and tumor response parameters and TKI treatment vs. placebo, despite detecting high heterogeneity. Combined TKI treatment showed a significantly better objective response rate (ORR) with no heterogeneity, whereas publication bias was only detected with time to progression (TTP). Few gastrointestinal and neurological disorders were associated with TKI treatment vs. placebo or with combined treatment. However, a higher number of serious AEs were related to TKI treatment vs. sorafenib alone. Results show positive clinical benefits from TKI treatment, supporting the approval and maintenance of TKI-based therapy for advanced HCC, while establishing appropriate strategies to maximize efficacy and minimize toxicity.
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Affiliation(s)
- Tania Payo-Serafín
- Institute of Biomedicine (IBIOMED), Universidad de León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Carolina Méndez-Blanco
- Institute of Biomedicine (IBIOMED), Universidad de León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Paula Fernández-Palanca
- Institute of Biomedicine (IBIOMED), Universidad de León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Jennifer Martínez-Geijo
- Institute of Biomedicine (IBIOMED), Universidad de León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - María Reviejo
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Experimental Hepatology and Drug Targeting (HEVEPHARM), IBSAL, University of Salamanca, Salamanca, Spain
| | - Juan José Ortiz-de-Urbina
- Institute of Biomedicine (IBIOMED), Universidad de León, León, Spain
- Pharmacy Service, Complejo Asistencial Universitario de León (CAULE), Hospital of León, León, Spain
| | - Javier González-Gallego
- Institute of Biomedicine (IBIOMED), Universidad de León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Jose J G Marin
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Experimental Hepatology and Drug Targeting (HEVEPHARM), IBSAL, University of Salamanca, Salamanca, Spain
| | - José L Mauriz
- Institute of Biomedicine (IBIOMED), Universidad de León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Beatriz San-Miguel
- Institute of Biomedicine (IBIOMED), Universidad de León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
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Yu J, Bai Y, Cui Z, Cheng C, Ladekarl M, Cheng KC, Chan KS, Yarmohammadi H, Mauriz JL, Zhang Y. Efficacy and safety of regorafenib as a first-line agent alone or in combination with an immune checkpoint inhibitor for advanced hepatocellular carcinoma: a retrospective cohort study. J Gastrointest Oncol 2024; 15:1072-1081. [PMID: 38989425 PMCID: PMC11231837 DOI: 10.21037/jgo-24-315] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 06/24/2024] [Indexed: 07/12/2024] Open
Abstract
BACKGROUND The RESORCE-III trial demonstrated that advanced hepatocellular carcinoma (HCC) patients who progressed on sorafenib and had second-line therapy with regorafenib improved overall survival compared with placebo. Later, immunotherapy with immune checkpoint inhibitors (ICIs) combined with antiangiogenetic antibodies has evolved as the preferred first-line treatment for fit patients. We aimed to explore the efficacy and safety of regorafenib as a first-line agent alone or in combination with ICIs in patients with advanced HCC. METHODS We identified 50 patients with advanced HCC treated with regorafenib as a first-line agent. Two patients were lost to follow-up and excluded. Baseline factors, dosing, concomitant use of ICIs, toxicity and outcome of treatment were recorded from electronic medical records. RESULTS Twenty-six patients received regorafenib as monotherapy and twenty-two received regorafenib + ICI in combination. In the total cohort, the median progression-free survival (mPFS) was 7.7 months and the median overall survival (mOS) was 16.7 months (P=0.02). Objective response rate (ORR) and disease control rate (DCR) assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 were 21% and 73%. In the regorafenib monotherapy group, mPFS was 5.9 months, and mOS was 13.9 months; in the combination group, mPFS was 7.8 months, and mOS was 23.6 months. ORR and DCR were 15% and 65% in the monotherapy group, and 27% and 82% in the combined treatment group, respectively. CONCLUSIONS Regorafenib used in combination with ICIs had a mild safety profile and resulted in improved response and an almost doubling of mOS compared to monotherapy, warranting further prospective evaluation in a randomized study.
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Affiliation(s)
- Jianfa Yu
- Department of Hepatobiliary and Pancreatic Surgery, Tianjin First Central Hospital, Tianjin, China
| | - Yi Bai
- Department of Hepatobiliary and Pancreatic Surgery, Tianjin First Central Hospital, Tianjin, China
| | - Zilin Cui
- Department of Hepatobiliary and Pancreatic Surgery, Tianjin First Central Hospital, Tianjin, China
| | | | - Morten Ladekarl
- Department of Oncology, Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Kai-Chi Cheng
- Department of Surgery, Kwong Wah Hospital, Hong Kong, China
| | - Kai Siang Chan
- Department of General Surgery, Tan Tock Seng Hospital, Singapore, Singapore
| | - Hooman Yarmohammadi
- Division of Interventional Radiology, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - José L. Mauriz
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
- Biomedical Research Networking Centre of Liver and Digestive Diseases (CIBERehd), Carlos III Health Institute, Madrid, Spain
| | - Yamin Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Tianjin First Central Hospital, Tianjin, China
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Lee HJ, Choi HJ, Jeong YJ, Na YH, Hong JT, Han JM, Hoe HS, Lim KH. Developing theragnostics for Alzheimer's disease: Insights from cancer treatment. Int J Biol Macromol 2024; 269:131925. [PMID: 38685540 DOI: 10.1016/j.ijbiomac.2024.131925] [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: 01/01/2024] [Revised: 04/24/2024] [Accepted: 04/25/2024] [Indexed: 05/02/2024]
Abstract
The prevalence of Alzheimer's disease (AD) and its associated economic and societal burdens are on the rise, but there are no curative treatments for AD. Interestingly, this neurodegenerative disease shares several biological and pathophysiological features with cancer, including cell-cycle dysregulation, angiogenesis, mitochondrial dysfunction, protein misfolding, and DNA damage. However, the genetic factors contributing to the overlap in biological processes between cancer and AD have not been actively studied. In this review, we discuss the shared biological features of cancer and AD, the molecular targets of anticancer drugs, and therapeutic approaches. First, we outline the common biological features of cancer and AD. Second, we describe several anticancer drugs, their molecular targets, and their effects on AD pathology. Finally, we discuss how protein-protein interactions (PPIs), receptor inhibition, immunotherapy, and gene therapy can be exploited for the cure and management of both cancer and AD. Collectively, this review provides insights for the development of AD theragnostics based on cancer drugs and molecular targets.
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Affiliation(s)
- Hyun-Ju Lee
- Korea Brain Research Institute (KBRI), 61, Cheomdan-ro, Dong-gu, Daegu 41062, Republic of Korea
| | - Hee-Jeong Choi
- Korea Brain Research Institute (KBRI), 61, Cheomdan-ro, Dong-gu, Daegu 41062, Republic of Korea
| | - Yoo Joo Jeong
- Korea Brain Research Institute (KBRI), 61, Cheomdan-ro, Dong-gu, Daegu 41062, Republic of Korea; Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science & Technology (DGIST), 333, Techno jungang-daero, Hyeonpung-eup, Dalseong-gun, Daegu 42988, Republic of Korea
| | - Yoon-Hee Na
- College of Pharmacy, Chungbuk National University, Cheongju-si 28160, Republic of Korea
| | - Jin Tae Hong
- College of Pharmacy, Chungbuk National University, Cheongju-si 28160, Republic of Korea
| | - Ji Min Han
- College of Pharmacy, Chungbuk National University, Cheongju-si 28160, Republic of Korea.
| | - Hyang-Sook Hoe
- Korea Brain Research Institute (KBRI), 61, Cheomdan-ro, Dong-gu, Daegu 41062, Republic of Korea; Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science & Technology (DGIST), 333, Techno jungang-daero, Hyeonpung-eup, Dalseong-gun, Daegu 42988, Republic of Korea.
| | - Key-Hwan Lim
- College of Pharmacy, Chungbuk National University, Cheongju-si 28160, Republic of Korea.
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10
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Cortez N, Villegas C, Burgos V, Ortiz L, Cabrera-Pardo JR, Paz C. Therapeutic Potential of Chlorogenic Acid in Chemoresistance and Chemoprotection in Cancer Treatment. Int J Mol Sci 2024; 25:5189. [PMID: 38791228 PMCID: PMC11121551 DOI: 10.3390/ijms25105189] [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: 03/13/2024] [Revised: 04/23/2024] [Accepted: 04/29/2024] [Indexed: 05/26/2024] Open
Abstract
Chemotherapeutic drugs are indispensable in cancer treatment, but their effectiveness is often lessened because of non-selective toxicity to healthy tissues, which triggers inflammatory pathways that are harmful to vital organs. In addition, tumors' resistance to drugs causes failures in treatment. Chlorogenic acid (5-caffeoylquinic acid, CGA), found in plants and vegetables, is promising in anticancer mechanisms. In vitro and animal studies have indicated that CGA can overcome resistance to conventional chemotherapeutics and alleviate chemotherapy-induced toxicity by scavenging free radicals effectively. This review is a summary of current information about CGA, including its natural sources, biosynthesis, metabolism, toxicology, role in combatting chemoresistance, and protective effects against chemotherapy-induced toxicity. It also emphasizes the potential of CGA as a pharmacological adjuvant in cancer treatment with drugs such as 5-fluorouracil, cisplatin, oxaliplatin, doxorubicin, regorafenib, and radiotherapy. By analyzing more than 140 papers from PubMed, Google Scholar, and SciFinder, we hope to find the therapeutic potential of CGA in improving cancer therapy.
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Affiliation(s)
- Nicole Cortez
- Laboratory of Natural Products & Drug Discovery, Center CEBIM, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco 4780000, Chile; (N.C.); (C.V.)
| | - Cecilia Villegas
- Laboratory of Natural Products & Drug Discovery, Center CEBIM, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco 4780000, Chile; (N.C.); (C.V.)
| | - Viviana Burgos
- Departamento de Ciencias Biológicas y Químicas, Facultad de Recursos Naturales, Universidad Católica de Temuco, Rudecindo Ortega, Temuco 4780000, Chile;
| | - Leandro Ortiz
- Instituto de Ciencias Químicas, Facultad de Ciencias, Universidad Austral de Chile, Valdivia 5110566, Chile;
| | - Jaime R. Cabrera-Pardo
- Laboratorio de Química Aplicada y Sustentable, Departamento de Química, Facultad de Ciencias, Universidad de Tarapacá, Arica 1000000, Chile;
| | - Cristian Paz
- Laboratory of Natural Products & Drug Discovery, Center CEBIM, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco 4780000, Chile; (N.C.); (C.V.)
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11
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Doostmohammadi A, Jooya H, Ghorbanian K, Gohari S, Dadashpour M. Potentials and future perspectives of multi-target drugs in cancer treatment: the next generation anti-cancer agents. Cell Commun Signal 2024; 22:228. [PMID: 38622735 PMCID: PMC11020265 DOI: 10.1186/s12964-024-01607-9] [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: 12/27/2023] [Accepted: 04/05/2024] [Indexed: 04/17/2024] Open
Abstract
Cancer is a major public health problem worldwide with more than an estimated 19.3 million new cases in 2020. The occurrence rises dramatically with age, and the overall risk accumulation is combined with the tendency for cellular repair mechanisms to be less effective in older individuals. Conventional cancer treatments, such as radiotherapy, surgery, and chemotherapy, have been used for decades to combat cancer. However, the emergence of novel fields of cancer research has led to the exploration of innovative treatment approaches focused on immunotherapy, epigenetic therapy, targeted therapy, multi-omics, and also multi-target therapy. The hypothesis was based on that drugs designed to act against individual targets cannot usually battle multigenic diseases like cancer. Multi-target therapies, either in combination or sequential order, have been recommended to combat acquired and intrinsic resistance to anti-cancer treatments. Several studies focused on multi-targeting treatments due to their advantages include; overcoming clonal heterogeneity, lower risk of multi-drug resistance (MDR), decreased drug toxicity, and thereby lower side effects. In this study, we'll discuss about multi-target drugs, their benefits in improving cancer treatments, and recent advances in the field of multi-targeted drugs. Also, we will study the research that performed clinical trials using multi-target therapeutic agents for cancer treatment.
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Affiliation(s)
- Ali Doostmohammadi
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran
- Student Research Committee, Semnan University of Medical Sciences, Semnan, Iran
| | - Hossein Jooya
- Biochemistry Group, Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Kimia Ghorbanian
- Student Research Committee, Semnan University of Medical Sciences, Semnan, Iran
| | - Sargol Gohari
- Department of Biology, Central Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Mehdi Dadashpour
- Department of Medical Biotechnology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran.
- Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran.
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12
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Chatzikalil E, Stergiou IE, Papadakos SP, Konstantinidis I, Theocharis S. The Clinical Relevance of the EPH/Ephrin Signaling Pathway in Pediatric Solid and Hematologic Malignancies. Int J Mol Sci 2024; 25:3834. [PMID: 38612645 PMCID: PMC11011407 DOI: 10.3390/ijms25073834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 03/26/2024] [Accepted: 03/26/2024] [Indexed: 04/14/2024] Open
Abstract
Pediatric neoplasms represent a complex group of malignancies that pose unique challenges in terms of diagnosis, treatment, and understanding of the underlying molecular pathogenetic mechanisms. Erythropoietin-producing hepatocellular receptors (EPHs), the largest family of receptor tyrosine kinases and their membrane-tethered ligands, ephrins, orchestrate short-distance cell-cell signaling and are intricately involved in cell-pattern morphogenesis and various developmental processes. Unraveling the role of the EPH/ephrin signaling pathway in the pathophysiology of pediatric neoplasms and its clinical implications can contribute to deciphering the intricate landscape of these malignancies. The bidirectional nature of the EPH/ephrin axis is underscored by emerging evidence revealing its capacity to drive tumorigenesis, fostering cell-cell communication within the tumor microenvironment. In the context of carcinogenesis, the EPH/ephrin signaling pathway prompts a reevaluation of treatment strategies, particularly in pediatric oncology, where the modest progress in survival rates and enduring treatment toxicity necessitate novel approaches. Molecularly targeted agents have emerged as promising alternatives, prompting a shift in focus. Through a nuanced understanding of the pathway's intricacies, we aim to lay the groundwork for personalized diagnostic and therapeutic strategies, ultimately contributing to improved outcomes for young patients grappling with neoplastic challenges.
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Affiliation(s)
- Elena Chatzikalil
- Division of Pediatric Hematology-Oncology, First Department of Pediatrics, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Ioanna E. Stergiou
- Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Stavros P. Papadakos
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | | | - Stamatios Theocharis
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece;
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13
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Yang Z, Zhang X, Bai X, Xi X, Liu W, Zhong W. Anti-angiogenesis in colorectal cancer therapy. Cancer Sci 2024; 115:734-751. [PMID: 38233340 PMCID: PMC10921012 DOI: 10.1111/cas.16063] [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: 09/18/2023] [Revised: 11/16/2023] [Accepted: 12/16/2023] [Indexed: 01/19/2024] Open
Abstract
The morbidity of colorectal cancer (CRC) has risen to third place among malignant tumors worldwide. In addition, CRC is a common cancer in China whose incidence increases annually. Angiogenesis plays an important role in the development of tumors because it can bring the nutrients that cancer cells need and take away metabolic waste. Various mechanisms are involved in the formation of neovascularization, and vascular endothelial growth factor is a key mediator. Meanwhile, angiogenesis inhibitors and drug resistance (DR) are challenges to consider when formulating treatment strategies for patients with different conditions. Thus, this review will discuss the molecules, signaling pathways, microenvironment, treatment, and DR of angiogenesis in CRC.
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Affiliation(s)
- Zhenni Yang
- Department of Gastroenterology and HepatologyGeneral Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive DiseasesTianjinChina
- Department of Gastroenterology and HepatologyXing'an League People's HospitalXing'an LeagueChina
| | - Xuqian Zhang
- Department of Gastroenterology and HepatologyGeneral Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive DiseasesTianjinChina
- Department of Gastroenterology and HepatologyChina Aerospace Science and Industry CorporationBeijingChina
| | - Xiaozhe Bai
- Department of Gastroenterology and HepatologyXing'an League People's HospitalXing'an LeagueChina
| | - Xiaonan Xi
- State Key Laboratory of Medicinal Chemical Biology and College of PharmacyNankai UniversityTianjinChina
| | - Wentian Liu
- Department of Gastroenterology and HepatologyGeneral Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive DiseasesTianjinChina
| | - Weilong Zhong
- Department of Gastroenterology and HepatologyGeneral Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive DiseasesTianjinChina
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Nguyen HT, Van KT, Pham-The H, Braire J, Thi PH, Nguyen TA, Nguyen Thi QG, Dang Thi TA, Le-Nhat-Thuy G, Le Thi TA, Ngoc DV, Nguyen Van T. Synthesis, molecular docking analysis and in vitro evaluation of new heterocyclic hybrids of 4-aza-podophyllotoxin as potent cytotoxic agents. RSC Adv 2024; 14:1838-1853. [PMID: 38192320 PMCID: PMC10772362 DOI: 10.1039/d3ra07396c] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 12/27/2023] [Indexed: 01/10/2024] Open
Abstract
Two different synthetic approaches to novel heterocyclic hybrid compounds of 4-azapodophyllotoxin were investigated. The obtained products were characterized by infrared spectroscopy, nuclear magnetic resonance spectroscopy, and high-resolution mass spectrometry. MTT protocol was then performed to examine the cytotoxic activity of these products against KB, HepG2, A549, MCF7, and Hek-293 cell lines. The cytotoxic assessment indicated that all products displayed moderate to high cytotoxicity against all tested cancer cell lines. The most active compound 13k containing the 2-methoxypyridin-4-yl group exhibited selective cytotoxicity against KB, A549, and HepG2 cell lines with the IC50 values ranging from 0.23 to 0.27 μM, which were between 5- to 10-fold more potent than the positive control ellipticine. Compounds 13a (HetAr = thiophen-3-yl) and 13d (HetAr = 5-bromofuran-2-yl) displayed high cytotoxic selectivity for A549 and HepG2 cancer cell lines when compared to the other cancer cell lines and low toxicity to the normal Hek-293 cell line. Molecular docking study was conducted to evaluate the interaction of new synthesized compounds with the colchicine-binding-site of tubulin. Besides that, physicochemical and pharmacokinetic properties of the most active compounds 13h,k were predicted.
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Affiliation(s)
- Ha Thanh Nguyen
- Institute of Chemistry, Vietnam Academy of Science and Technology 18 Hoang Quoc Viet, Cau Giay Hanoi Vietnam
- Graduate University of Science and Technology, Vietnam Academy of Science and Technology 18 Hoang Quoc Viet, Cau Giay Hanoi Vietnam
| | - Ket Tran Van
- Graduate University of Science and Technology, Vietnam Academy of Science and Technology 18 Hoang Quoc Viet, Cau Giay Hanoi Vietnam
- Military Technical Academy 236 Hoang Quoc Viet, Bac Tu Liem Hanoi Vietnam
| | - Hai Pham-The
- University of Science and Technology of Hanoi, Vietnam Academy of Science and Technology 18 Hoang Quoc Viet, Cau Giay Hanoi Vietnam
| | - Julien Braire
- Université de Rennes 1 2 Av. du Professeur Léon Bernard 35042 Rennes France
| | - Phuong Hoang Thi
- Institute of Chemistry, Vietnam Academy of Science and Technology 18 Hoang Quoc Viet, Cau Giay Hanoi Vietnam
| | - Tuan Anh Nguyen
- Institute of Chemistry, Vietnam Academy of Science and Technology 18 Hoang Quoc Viet, Cau Giay Hanoi Vietnam
| | - Quynh Giang Nguyen Thi
- Institute of Chemistry, Vietnam Academy of Science and Technology 18 Hoang Quoc Viet, Cau Giay Hanoi Vietnam
| | - Tuyet Anh Dang Thi
- Institute of Chemistry, Vietnam Academy of Science and Technology 18 Hoang Quoc Viet, Cau Giay Hanoi Vietnam
- Graduate University of Science and Technology, Vietnam Academy of Science and Technology 18 Hoang Quoc Viet, Cau Giay Hanoi Vietnam
| | - Giang Le-Nhat-Thuy
- Institute of Chemistry, Vietnam Academy of Science and Technology 18 Hoang Quoc Viet, Cau Giay Hanoi Vietnam
- Graduate University of Science and Technology, Vietnam Academy of Science and Technology 18 Hoang Quoc Viet, Cau Giay Hanoi Vietnam
| | - Tu Anh Le Thi
- Institute of Chemistry, Vietnam Academy of Science and Technology 18 Hoang Quoc Viet, Cau Giay Hanoi Vietnam
| | - Doan Vu Ngoc
- Military Technical Academy 236 Hoang Quoc Viet, Bac Tu Liem Hanoi Vietnam
| | - Tuyen Nguyen Van
- Institute of Chemistry, Vietnam Academy of Science and Technology 18 Hoang Quoc Viet, Cau Giay Hanoi Vietnam
- Graduate University of Science and Technology, Vietnam Academy of Science and Technology 18 Hoang Quoc Viet, Cau Giay Hanoi Vietnam
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15
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Liu J, Li J, Zhu Y, Jing R, Ding S, Zhang J, Zhao L, Chen Y, Shen J. Advances in Drug Therapy for Gastrointestinal Stromal Tumour. Curr Med Chem 2024; 31:3057-3073. [PMID: 37151058 DOI: 10.2174/0929867330666230505163151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 02/05/2023] [Accepted: 03/03/2023] [Indexed: 05/09/2023]
Abstract
INTRODUCTION Gastrointestinal stromal tumour (GIST) is a common gastrointestinal sarcoma located in the stromal cells of the digestive tract, and molecular studies have revealed the pathogenesis of mutations in KIT and PDGFRA genes. Since imatinib opened the era of targeted therapy for GIST, tyrosine kinase inhibitors (TKIs) that can treat GIST have been developed successively. However, the lack of new drugs with satisfactory therapeutic standards has made addressing resistance a significant challenge for TKIs in the face of the resistance to first-line and second-line drugs. Therefore, we need to find as many drugs and new treatments that block mutated genes as possible. METHODS We conducted a comprehensive collection of literature using databases, integrated and analysed the selected literature based on keywords and the comprehensive nature of the articles, and finally wrote articles based on the content of the studies. RESULTS In this article, we first briefly explained the relationship between GIST and KIT/ PDGFRα and then introduced the related drug treatment. The research progress of TKIs was analyzed according to the resistance of the drugs. CONCLUSION This article describes the research progress of some TKIs and briefly introduces the currently approved TKIs and some drugs under investigation that may have better therapeutic effects, hoping to provide clues to the research of new drugs.
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Affiliation(s)
- Ju Liu
- College of Pharmacy, Liaoning University, Shenyang, Liaoning 110036, P.R. China
- API Engineering Technology Research Center of Liaoning Province, Shenyang, Liaoning 110036, P.R. China
- Small Molecular Targeted Drug R&D Engineering Research Center of Liaoning Province, Shenyang, Liaoning 110036, P.R. China
| | - Jiawei Li
- College of Pharmacy, Liaoning University, Shenyang, Liaoning 110036, P.R. China
| | - Yan Zhu
- College of Pharmacy, Liaoning University, Shenyang, Liaoning 110036, P.R. China
| | - Rui Jing
- College of Pharmacy, Liaoning University, Shenyang, Liaoning 110036, P.R. China
| | - Shi Ding
- College of Pharmacy, Liaoning University, Shenyang, Liaoning 110036, P.R. China
- API Engineering Technology Research Center of Liaoning Province, Shenyang, Liaoning 110036, P.R. China
- Small Molecular Targeted Drug R&D Engineering Research Center of Liaoning Province, Shenyang, Liaoning 110036, P. R. China
| | - Jifang Zhang
- College of Pharmacy, Liaoning University, Shenyang, Liaoning 110036, P.R. China
| | - Leyan Zhao
- College of Pharmacy, Liaoning University, Shenyang, Liaoning 110036, P.R. China
| | - Ye Chen
- College of Pharmacy, Liaoning University, Shenyang, Liaoning 110036, P.R. China
- API Engineering Technology Research Center of Liaoning Province, Shenyang, Liaoning 110036, P.R. China
- Small Molecular Targeted Drug R&D Engineering Research Center of Liaoning Province, Shenyang, Liaoning 110036, P.R. China
| | - Jiwei Shen
- College of Pharmacy, Liaoning University, Shenyang, Liaoning 110036, P.R. China
- API Engineering Technology Research Center of Liaoning Province, Shenyang, Liaoning 110036, P.R. China
- Small Molecular Targeted Drug R&D Engineering Research Center of Liaoning Province, Shenyang, Liaoning 110036, P.R. China
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16
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Kuan FC, Li JM, Huang YC, Chang SF, Shi CS. Therapeutic Potential of Regorafenib in Cisplatin-Resistant Bladder Cancer with High Epithelial-Mesenchymal Transition and Stemness Properties. Int J Mol Sci 2023; 24:17610. [PMID: 38139437 PMCID: PMC10743903 DOI: 10.3390/ijms242417610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 12/15/2023] [Accepted: 12/16/2023] [Indexed: 12/24/2023] Open
Abstract
Bladder cancer is becoming one of the most common malignancies across the world. Although treatment strategy has been continuously improved, which has led to cisplatin-based chemotherapy becoming the standard medication, cancer recurrence and metastasis still occur in a high proportion of patients because of drug resistance. The high efficacy of regorafenib, a broad-spectrum kinase inhibitor, has been evidenced in treating a variety of advanced cancers. Hence, this study investigated whether regorafenib could also effectively antagonize the survival of cisplatin-resistant bladder cancer and elucidate the underlying mechanism. Two types of cisplatin-resistant bladder cancer cells, T24R1 and T24R2, were isolated from T24 cisplatin-sensitive bladder cancer cells. These cells were characterized, and T24R1- and T24R2-xenografted tumor mice were created to examine the therapeutic efficacy of regorafenib. T24R1 and T24R2 cells exhibited higher expression levels of epithelial-mesenchymal transition (EMT) and stemness markers compared to the T24 cells, and regorafenib could simultaneously inhibit the viability and the expression of EMT/stemness markers of both T24R1 and T24R2 cells. Moreover, regorafenib could efficiently arrest the cell cycle, promote apoptosis, and block the transmigration/migration capabilities of both types of cells. Finally, regorafenib could significantly antagonize the growth of T24R1- and T24R2-xenografted tumors in mice. These results demonstrated the therapeutic efficacy of regorafenib in cisplatin-resistant bladder cancers. This study, thus, provides more insights into the mechanism of action of regorafenib and demonstrates its great potential in the future treatment of cisplatin-resistant advanced bladder cancer patients.
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Affiliation(s)
- Feng-Che Kuan
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan;
- Division of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital Chiayi Branch, Chiayi 61363, Taiwan
| | - Jhy-Ming Li
- Department of Animal Science, National Chiayi University, Chiayi 60004, Taiwan;
| | - Yun-Ching Huang
- Division of Urology, Department of Surgery, Chang Gung Memorial Hospital Chiayi Branch, Chiayi 61363, Taiwan;
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Shun-Fu Chang
- Department of Medical Research and Development, Chang Gung Memorial Hospital Chiayi Branch, Chiayi 61363, Taiwan
- Center for General Education, Chiayi Chang Gung University of Science and Technology, Chiayi 61363, Taiwan
| | - Chung-Sheng Shi
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan;
- Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital Chiayi Branch, Chiayi 61363, Taiwan
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Signorelli C, Chilelli MG, Giannarelli D, Basso M, Calegari MA, Anghelone A, Lucchetti J, Minelli A, Angotti L, Zurlo IV, Schirripa M, Morelli C, Dell’Aquila E, Cosimati A, Gemma D, Ribelli M, Emiliani A, Corsi DC, Arrivi G, Mazzuca F, Zoratto F, Morandi MG, Santamaria F, Saltarelli R, Ruggeri EM. Retrospective Correlation between First Drug Treatment Duration and Survival Outcomes in Sequential Treatment with Regorafenib and Trifluridine/Tipiracil in Refractory Metastatic Colorectal Cancer: A Real-World Subgroup Analysis. Cancers (Basel) 2023; 15:5758. [PMID: 38136304 PMCID: PMC10741389 DOI: 10.3390/cancers15245758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 12/03/2023] [Accepted: 12/06/2023] [Indexed: 12/24/2023] Open
Abstract
Background: Patients with refractory metastatic colorectal cancer (mCRC) rarely receive third-line or further treatment. In this context, regorafenib (R) and trifluridine/tipiracil (T) are two important novel therapeutic choices with statistically significant increases in overall survival (OS), progression-free survival (PFS), and disease control, with different toxicity profiles. This study is a subgroup analysis of our larger retrospective study, already published, whose objective was to assess the outcomes of patients when R and T were given sequentially. Patients and Methods: The study involved thirteen Italian cancer centers on a 10-year retrospective observation (2012-2022). In this subgroup analysis, we focused our attention on the correlation between the first drug treatment duration (<3 months, 3 to <6 months and ≥6 months) and survival outcomes in patients who had received the sequence regorafenib-to-trifluridine/tipiracil, or vice versa. Results: The initial study included 866 patients with mCRC who received sequential T/R, or R/T, or T or R alone. This analysis is focused on evaluating the impact of the duration of the first treatment in the sequence on clinical outcomes (OS, PFS) and includes 146 and 116 patients of the T/R and R/T sequences, respectively. Based on the duration of the first drug treatment, subgroups for the T/R sequence included 27 patients (18.4%) who received T for <3 months, 86 (58.9%) treated for 3 to <6 months, and 33 (22.6%) treated for ≥6 months; in the reverse sequence (R as the first drug), subgroups included 18 patients (15.5%) who received their first treatment for <3 months, 62 (53.4%) treated for 3 to <6 months, and 35 (31.0%) treated for ≥6 months. In patients who received their first drug treatment for a period of 3 to <6 months, the R/T sequence had a significantly longer median OS (13.7 vs. 10.8 months, p = 0.0069) and a longer median PFS (10.8 vs. 8.5 months, p = 0.0003) than the T/R group. There were no statistically significant differences between groups with first drug treatment durations of <3 months and ≥6 months. Conclusions: Our analysis seems to suggest that the administration of R for a period of 3 to <6 months before that of T can prolong both OS and PFS, as compared to the opposite sequence.
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Affiliation(s)
- Carlo Signorelli
- Medical Oncology Unit, Belcolle Hospital, ASL Viterbo, 01100 Viterbo, Italy
| | | | - Diana Giannarelli
- Biostatistics Unit, Scientific Directorate, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, 00168 Rome, Italy
| | - Michele Basso
- Unit of Medical Oncology, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, 00168 Rome, Italy
| | - Maria Alessandra Calegari
- Unit of Medical Oncology, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, 00168 Rome, Italy
| | - Annunziato Anghelone
- Unit of Medical Oncology, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, 00168 Rome, Italy
| | - Jessica Lucchetti
- Division of Medical Oncology, Policlinico Universitario Campus Bio-Medico, 00128 Rome, Italy
| | - Alessandro Minelli
- Division of Medical Oncology, Policlinico Universitario Campus Bio-Medico, 00128 Rome, Italy
| | - Lorenzo Angotti
- Division of Medical Oncology, Policlinico Universitario Campus Bio-Medico, 00128 Rome, Italy
| | | | - Marta Schirripa
- Medical Oncology Unit, Belcolle Hospital, ASL Viterbo, 01100 Viterbo, Italy
| | - Cristina Morelli
- Medical Oncology Unit, Department of Systems Medicine, Tor Vergata University Hospital, 00133 Rome, Italy
| | - Emanuela Dell’Aquila
- Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
| | - Antonella Cosimati
- Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
| | - Donatello Gemma
- Medical Oncology Unit, ASL Frosinone, 03039 Sora (FR), Italy
| | - Marta Ribelli
- Medical Oncology Unit, Isola Tiberina Hospital-Gemelli Isola, 00186 Rome, Italy
| | - Alessandra Emiliani
- Medical Oncology Unit, Isola Tiberina Hospital-Gemelli Isola, 00186 Rome, Italy
| | | | - Giulia Arrivi
- Department of Clinical and Molecular Medicine, Oncology Unit, Sant’ Andrea University Hospital, Sapienza University of Rome, 00189 Rome, Italy
| | - Federica Mazzuca
- Department of Clinical and Molecular Medicine, Oncology Unit, Sant’ Andrea University Hospital, Sapienza University of Rome, 00189 Rome, Italy
| | | | - Maria Grazia Morandi
- Medical Oncology Unit, San Camillo de Lellis Hospital, ASL Rieti, 02100 Rieti, Italy
| | - Fiorenza Santamaria
- UOC Oncology A, Policlinico Umberto I, 00185 Rome, Italy
- Experimental Medicine, Network Oncology and Precision Medicine, Department of Experimental Medicine, Sapienza University of Rome, 00189 Rome, Italy
| | - Rosa Saltarelli
- UOC Oncology, San Giovanni Evangelista Hospital, ASL RM5, 00019 Tivoli (RM), Italy
| | - Enzo Maria Ruggeri
- Medical Oncology Unit, Belcolle Hospital, ASL Viterbo, 01100 Viterbo, Italy
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Al-Wahaibi LH, Mohammed AF, Abdelrahman MH, Trembleau L, Youssif BGM. Design, Synthesis, and Biological Evaluation of Indole-2-carboxamides as Potential Multi-Target Antiproliferative Agents. Pharmaceuticals (Basel) 2023; 16:1039. [PMID: 37513950 PMCID: PMC10385579 DOI: 10.3390/ph16071039] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 07/15/2023] [Accepted: 07/18/2023] [Indexed: 07/30/2023] Open
Abstract
A small set of indole-based derivatives, IV and Va-I, was designed and synthesized. Compounds Va-i demonstrated promising antiproliferative activity, with GI50 values ranging from 26 nM to 86 nM compared to erlotinib's 33 nM. The most potent antiproliferative derivatives-Va, Ve, Vf, Vg, and Vh-were tested for EGFR inhibitory activity. Compound Va demonstrated the highest inhibitory activity against EGFR with an IC50 value of 71 ± 06 nM, which is higher than the reference erlotinib (IC50 = 80 ± 05 nM). Compounds Va, Ve, Vf, Vg, and Vh were further tested for BRAFV600E inhibitory activity. The tested compounds inhibited BRAFV600E with IC50 values ranging from 77 nM to 107 nM compared to erlotinib's IC50 value of 60 nM. The inhibitory activity of compounds Va, Ve, Vf, Vg, and Vh against VEGFR-2 was also determined. Finally, in silico docking experiments attempted to investigate the binding mode of compounds within the active sites of EGFR, BRAFV600E, and VEGFR-2.
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Affiliation(s)
- Lamya H Al-Wahaibi
- Department of Chemistry, College of Sciences, Princess Nourah bint Abdulrahman University, Riyadh 11564, Saudi Arabia
| | - Anber F Mohammed
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt
| | - Mostafa H Abdelrahman
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Assiut 71234, Egypt
| | - Laurent Trembleau
- School of Natural and Computing Sciences, University of Aberdeen, Meston Building, Aberdeen AB24 3UE, UK
| | - Bahaa G M Youssif
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt
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Signorelli C, Calegari MA, Basso M, Anghelone A, Lucchetti J, Minelli A, Angotti L, Zurlo IV, Schirripa M, Chilelli MG, Morelli C, Dell’Aquila E, Cosimati A, Gemma D, Ribelli M, Emiliani A, Corsi DC, Arrivi G, Mazzuca F, Zoratto F, Morandi MG, Santamaria F, Saltarelli R, Ruggeri EM. Treatment Settings and Outcomes with Regorafenib and Trifluridine/Tipiracil at Third-Line Treatment and beyond in Metastatic Colorectal Cancer: A Real-World Multicenter Retrospective Study. Curr Oncol 2023; 30:5456-5469. [PMID: 37366896 PMCID: PMC10296859 DOI: 10.3390/curroncol30060413] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Revised: 06/02/2023] [Accepted: 06/02/2023] [Indexed: 06/28/2023] Open
Abstract
BACKGROUND Patients with refractory mCRC rarely undergo third-line or subsequent treatment. This strategy could negatively impact their survival. In this setting, regorafenib (R) and trifluridine/tipiracil (T) are two key new treatment options with statistically significant improvements in overall survival (OS), progression-free survival (PFS), and disease control with different tolerance profiles. This study aimed to retrospectively evaluate the efficacy and safety profiles of these agents in real-world practice. MATERIALS AND METHODS In 2012-2022, 866 patients diagnosed with mCRC who received sequential R and T (T/R, n = 146; R/T, n = 116]) or T (n = 325]) or R (n = 279) only were retrospectively recruited from 13 Italian cancer institutes. RESULTS The median OS is significantly longer in the R/T group (15.9 months) than in the T/R group (13.9 months) (p = 0.0194). The R/T sequence had a statistically significant advantage in the mPFS, which was 8.8 months with T/R vs. 11.2 months with R/T (p = 0.0005). We did not find significant differences in outcomes between groups receiving T or R only. A total of 582 grade 3/4 toxicities were recorded. The frequency of grade 3/4 hand-foot skin reactions was higher in the R/T sequence compared to the reverse sequence (37.3% vs. 7.4%) (p = 0.01), while grade 3/4 neutropenia was slightly lower in the R/T group than in the T/R group (66.2% vs. 78.2%) (p = 0.13). Toxicities in the non-sequential groups were similar and in line with previous studies. CONCLUSIONS The R/T sequence resulted in a significantly longer OS and PFS and improved disease control compared with the reverse sequence. R and T given not sequentially have similar impacts on survival. More data are needed to define the best sequence and to explore the efficacy of sequential (T/R or R/T) treatment combined with molecular-targeted drugs.
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Affiliation(s)
- Carlo Signorelli
- Medical Oncology Unit, Belcolle Hospital, ASL Viterbo, 01100 Viterbo, Italy
| | - Maria Alessandra Calegari
- Unit of Medical Oncology, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, 00168 Rome, Italy
| | - Michele Basso
- Unit of Medical Oncology, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, 00168 Rome, Italy
| | - Annunziato Anghelone
- Unit of Medical Oncology, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, 00168 Rome, Italy
| | - Jessica Lucchetti
- Division of Medical Oncology, Policlinico Universitario Campus Bio-Medico, 00128 Rome, Italy
| | - Alessandro Minelli
- Division of Medical Oncology, Policlinico Universitario Campus Bio-Medico, 00128 Rome, Italy
| | - Lorenzo Angotti
- Division of Medical Oncology, Policlinico Universitario Campus Bio-Medico, 00128 Rome, Italy
| | | | - Marta Schirripa
- Medical Oncology Unit, Belcolle Hospital, ASL Viterbo, 01100 Viterbo, Italy
| | | | - Cristina Morelli
- Medical Oncology Unit, Department of Systems Medicine, Tor Vergata University Hospital, 00133 Rome, Italy
| | - Emanuela Dell’Aquila
- Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
| | - Antonella Cosimati
- Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
| | - Donatello Gemma
- Medical Oncology Unit, ASL Frosinone, 03039 Sora (FR), Italy
| | - Marta Ribelli
- Medical Oncology Unit, Ospedale San Giovanni Calibita Fatebenefratelli, Isola Tiberina, Gemelli Isola, 00186 Rome, Italy
| | - Alessandra Emiliani
- Medical Oncology Unit, Ospedale San Giovanni Calibita Fatebenefratelli, Isola Tiberina, Gemelli Isola, 00186 Rome, Italy
| | - Domenico Cristiano Corsi
- Medical Oncology Unit, Ospedale San Giovanni Calibita Fatebenefratelli, Isola Tiberina, Gemelli Isola, 00186 Rome, Italy
| | - Giulia Arrivi
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, Oncology Unit, Sant’ Andrea Hospital, 00189 Rome, Italy
| | - Federica Mazzuca
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, Oncology Unit, Sant’ Andrea Hospital, 00189 Rome, Italy
| | | | - Maria Grazia Morandi
- Medical Oncology Unit, San Camillo de Lellis Hospital, ASL Rieti, 02100 Rieti, Italy
| | - Fiorenza Santamaria
- Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy
- Medical Oncology A, Department of Radiological, Oncological and Pathological Sciences, Policlinico Umberto I, Sapienza University of Rome, 00185 Rome, Italy
| | - Rosa Saltarelli
- UOC Oncology, San Giovanni Evangelista Hospital, ASL RM5, 00019 Tivoli (RM), Italy
| | - Enzo Maria Ruggeri
- Medical Oncology Unit, Belcolle Hospital, ASL Viterbo, 01100 Viterbo, Italy
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Neto Í, Rocha J, Gaspar MM, Reis CP. Experimental Murine Models for Colorectal Cancer Research. Cancers (Basel) 2023; 15:2570. [PMID: 37174036 PMCID: PMC10177088 DOI: 10.3390/cancers15092570] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 04/25/2023] [Accepted: 04/26/2023] [Indexed: 05/15/2023] Open
Abstract
Colorectal cancer (CRC) is the third most prevalent malignancy worldwide and in both sexes. Numerous animal models for CRC have been established to study its biology, namely carcinogen-induced models (CIMs) and genetically engineered mouse models (GEMMs). CIMs are valuable for assessing colitis-related carcinogenesis and studying chemoprevention. On the other hand, CRC GEMMs have proven to be useful for evaluating the tumor microenvironment and systemic immune responses, which have contributed to the discovery of novel therapeutic approaches. Although metastatic disease can be induced by orthotopic injection of CRC cell lines, the resulting models are not representative of the full genetic diversity of the disease due to the limited number of cell lines suitable for this purpose. On the other hand, patient-derived xenografts (PDX) are the most reliable for preclinical drug development due to their ability to retain pathological and molecular characteristics. In this review, the authors discuss the various murine CRC models with a focus on their clinical relevance, benefits, and drawbacks. From all models discussed, murine CRC models will continue to be an important tool in advancing our understanding and treatment of this disease, but additional research is required to find a model that can correctly reflect the pathophysiology of CRC.
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Affiliation(s)
- Íris Neto
- Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal; (Í.N.); (J.R.)
| | - João Rocha
- Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal; (Í.N.); (J.R.)
| | - Maria Manuela Gaspar
- Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal; (Í.N.); (J.R.)
| | - Catarina P. Reis
- Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal; (Í.N.); (J.R.)
- Instituto de Biofísica e Engenharia Biomédica (IBEB), Faculdade de Ciências, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal
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21
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Fernández-Palanca P, Payo-Serafín T, Méndez-Blanco C, San-Miguel B, Tuñón MJ, González-Gallego J, Mauriz JL. Neuropilins as potential biomarkers in hepatocellular carcinoma: a systematic review of basic and clinical implications. Clin Mol Hepatol 2023; 29:293-319. [PMID: 36726054 PMCID: PMC10121286 DOI: 10.3350/cmh.2022.0425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 01/16/2023] [Accepted: 01/31/2023] [Indexed: 02/03/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common and deadly cancers worldwide and is characterized by complex molecular carcinogenesis. Neuropilins (NRPs) NRP1 and NRP2 are the receptors of multiple proteins involved in key signaling pathways associated with tumor progression. We aimed to systematically review all the available findings on their role in HCC. We searched the Scopus, Web of Science (WOS), PubMed, Cochrane and Embase databases for articles evaluating NRPs in preclinical or clinical HCC models. This study was registered in PROSPERO (CRD42022349774) and include 49 studies. Multiple cellular and molecular processes have been associated with one or both NRPs, indicating that they are potential diagnostic and prognostic biomarkers in HCC patients. Mainly NRP1 has been shown to promote tumor cell survival and progression by modulating several signaling pathways. NRPs mainly regulate angiogenesis, invasion and migration and have shown to induce invasion and metastasis. They also regulate the immune response and tumor microenvironment, showing a crucial interplay with the hypoxia response and microRNAs in HCC. Altogether, NRP1 and NRP2 are potential biomarkers and therapeutic targets, providing novel insight into the clinical landscape of HCC patients.
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Affiliation(s)
- Paula Fernández-Palanca
- Institute of Biomedicine (IBIOMED), Universidad de León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Tania Payo-Serafín
- Institute of Biomedicine (IBIOMED), Universidad de León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Carolina Méndez-Blanco
- Institute of Biomedicine (IBIOMED), Universidad de León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Beatriz San-Miguel
- Institute of Biomedicine (IBIOMED), Universidad de León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - María J. Tuñón
- Institute of Biomedicine (IBIOMED), Universidad de León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Javier González-Gallego
- Institute of Biomedicine (IBIOMED), Universidad de León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - José L. Mauriz
- Institute of Biomedicine (IBIOMED), Universidad de León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
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Ma SX, Li L, Cai H, Guo TK, Zhang LS. Therapeutic challenge for immunotherapy targeting cold colorectal cancer: A narrative review. World J Clin Oncol 2023; 14:81-88. [PMID: 36908678 PMCID: PMC9993140 DOI: 10.5306/wjco.v14.i2.81] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 12/13/2022] [Accepted: 02/07/2023] [Indexed: 02/21/2023] Open
Abstract
Cold colorectal tumors are not likely to trigger a robust immune response and tend to suppress the immune response. There may be three reasons. First, the complex tumor microenvironment of cold colorectal cancer (CRC) leads to tolerance and clearance of immunotherapy. Second, the modification and concealment of tumor-specific targets in cold CRC cause immune escape and immune response interruption. Finally, the difference in number and function of immune cell subsets in patients with cold CRC makes them respond poorly to immunotherapy. Therefore, we can only overcome the challenges in immunotherapy of cold CRC through in-depth research and understanding the changes and mechanisms in the above three aspects of cold CRC.
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Affiliation(s)
- Shi-Xun Ma
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou 73000, Gansu Province, China
| | - Li Li
- Scientific Research Division, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
| | - Hui Cai
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou 73000, Gansu Province, China
| | - Tian-Kang Guo
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou 73000, Gansu Province, China
| | - Lei-Sheng Zhang
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou 73000, Gansu Province, China
- Key Laboratory of Radiation Technology and Biophysics, Hefei Institute of Physical Science, Chinese Academy of Sciences, Hefei 230031, Anhui Province, China
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23
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Bandi SP, Datta D, Venuganti VVK. Hydrocaffeic acid-chitosan coating of gastric patch provides long-acting mucoadhesive delivery of model chemotherapeutic agent. Int J Pharm 2023; 631:122504. [PMID: 36529359 DOI: 10.1016/j.ijpharm.2022.122504] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 12/11/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022]
Abstract
The development of a long-acting orally administered dosage form is a challenge. Here, we report development of a multi-layered mucoadhesive gastric patch that could deliver entrapped chemotherapeutic agent for eight days after oral administration. The multi-layered patch was designed to contain core layer, mucoadhesive layer and backing layer. The core layer contained the model chemotherapeutic agent, regorafenib. The mucoadhesive layer made of chitosan-hydrocaffeic acid conjugate showed greatest mucoadhesion strength of 18.1 ± 0.78 kPa in freshly excised rat gastric mucosa. The backing layer made of hydrophobic polycaprolactone-polydimethylsiloxane composite showed the contact angle of 120 ± 4.7° after placement of water drop. The entrapped regorafenib predominantly released from the mucoadhesive-side of the patch into simulated gastric fluid and showed a zero-order release profile. The patches were found to be stable for desired characteristics for up to 3 months in long term storage conditions. The pharmacokinetic studies in rat model revealed constant plasma concentration of regorafenib sustained for 8 days after oral administration of gastric patch. The gastric tissue where the patch adhered for 8 days did not show any significant histological changes compared with the normal gastric tissue. The oral administration of single dose of regorafenib-loaded gastric patch in FaDu cell xenografted tumor bearing athymic nude mice has shown significant (P < 0.05) reduction in the tumor volume over 7 days compared to the control group. Taken together, the multi-layered mucoadhesive gastric patch can be developed as a long-acting oral drug delivery system.
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Affiliation(s)
- Sony Priyanka Bandi
- Department of Pharmacy, Birla Institute of Technology and Science (BITS) Pilani, Hyderabad Campus, Hyderabad 500078, Telangana State, India
| | - Deepanjan Datta
- Department of Pharmacy, Birla Institute of Technology and Science (BITS) Pilani, Hyderabad Campus, Hyderabad 500078, Telangana State, India
| | - Venkata Vamsi Krishna Venuganti
- Department of Pharmacy, Birla Institute of Technology and Science (BITS) Pilani, Hyderabad Campus, Hyderabad 500078, Telangana State, India.
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Shahidi S, Rostamizadeh K, Fathi M, Nedaei K, Ramazani A. Combination of Quercetin or/and siRNA-loaded DDAB-mPEG-PCL hybrid nanoparticles reverse resistance to Regorafenib in colon cancer cells. BMC Complement Med Ther 2022; 22:340. [PMID: 36575448 PMCID: PMC9793538 DOI: 10.1186/s12906-022-03787-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Accepted: 11/10/2022] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is the second leading cause of cancer death. Although Regorafenib showed survival benefits in patients with CRC, reports imply the recurrence of malignant phenotype resulting from chemotherapy. Evidence demonstrated that a5β1 integrin plays an important role in the Regorafenib treatment, which, may be led to resistance. In this study, the effects of /siRNA or/ and Quercetin loaded DDAB-mPEG-PCLnanoparticles could reverse this resistance phenotype in colon cancer cells in vitro. METHODS Regorafenib-resistant Ls-180 colon cancer cell line was developed by long-term exposure to Regorafenib. Quercetin and Regorafenib were separately encapsulated into mPEG-PCL micelles through the nano-precipitation method and characterized by DLS. Optimized doses of Quercetin and Regorafenib were used for combination therapy of resistant cells followed cytotoxicity study using MTT. Gene expression levels of the β1 subunit of integrin were determined by the real-time method of RT-PCR. RESULTS Developed Regorafenib resistant LS-180 showed to have Regorafenib IC50 of 38.96 ± 1.72 µM whereas IC50 in non-resistant cells were 8.51 ± 0.29 µM, which meaningful was lower statistically compared to that of a resistant one. The β1 mRNA level of whole α5β1 integrin was significantly higher in the resistant cells compared to those of non-resistant ones. Gene expression levels in each siRNA-loaded nanoparticle and Quercetin-loaded one were lower than that in mock experiments. Finally, when these two types of nanoparticles were used to treat resistant cells, gene expression decrease of integrin indicated a greater effect that could be capable of reverse resistancy. CONCLUSION Results of this study demonstrated another confirmation of involving integrins in cancer resistance following chemotherapy using Regorafenib. Also, it indicated how using siRNA targeting integrin could enhance the plant derivatives like Quercetin effects to reverse resistance in vitro.
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Affiliation(s)
- Shabnam Shahidi
- grid.469309.10000 0004 0612 8427Department of Clinical Biochemistry, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Kobra Rostamizadeh
- grid.469309.10000 0004 0612 8427Department of Pharmaceutical Biomaterial, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran ,grid.469309.10000 0004 0612 8427Zanjan Pharmaceutical Nanotechnology Research Center, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Mojtaba Fathi
- grid.469309.10000 0004 0612 8427Cancer Gene Therapy Research Center, Zanjan University of Medical Sciences, Zanjan, Iran ,grid.412606.70000 0004 0405 433XDepartment of Biochemistry and Genetics, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Keivan Nedaei
- grid.469309.10000 0004 0612 8427Department of Medical Biotechnology, Faculty of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Ali Ramazani
- grid.469309.10000 0004 0612 8427Cancer Gene Therapy Research Center, Zanjan University of Medical Sciences, Zanjan, Iran ,grid.469309.10000 0004 0612 8427Department of Pharmaceutical Biotechnology, Zanjan University of Medical Sciences, Zanjan, Iran
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25
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Haque E, Muhsen IN, Esmail A, Umoru G, Mylavarapu C, Ajewole VB, Abdelrahim M. Case report: Efficacy and safety of regorafenib plus fluorouracil combination therapy in the treatment of refractory metastatic colorectal cancer. Front Oncol 2022; 12:992455. [PMID: 36620581 PMCID: PMC9822717 DOI: 10.3389/fonc.2022.992455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 11/18/2022] [Indexed: 12/23/2022] Open
Abstract
Background More than half of patients with colorectal cancer (CRC) present with metastatic disease or develop recurrent disease on first-line and second-line options. Treatment beyond the second line remains an area of unmet need for patients with progressive or recurrent disease. Methods We retrospectively reviewed data of adult (>18 years old) patients with mCRC who received regorafenib + 5FU combination therapy at Houston Methodist Hospital with outcomes of interest including response rate, discontinuation due to side effects, and overall survival. Results Seven patients received regorafenib + 5FU combination therapy for mCRC after receiving at least two other lines of therapy (including at least one fluorouracil-based therapy). Four patients (57%) achieved disease control in 7-12 weeks after therapy initiation while three patients developed recurrent disease. In patients who achieved disease control, no new adverse events were reported among patients with this combination. Conclusion Regorafenib and Fluorouracil combination could be considered an option beyond the second line for patients with treatment-refractory metastatic colorectal cancer. Further studies, including a prospective trial, are needed to investigate the efficacy and safety of regorafenib plus 5FU therapy compared to other limited available therapies.
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Affiliation(s)
- Emaan Haque
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Ibrahim N. Muhsen
- Department of Medicine, Houston Methodist Hospital, Houston, TX, United States
| | - Abdullah Esmail
- Section of Gastrointestinal Oncology, Houston Methodist Neal Cancer Center, Houston, TX, United States,*Correspondence: Maen Abdelrahim, ; Abdullah Esmail,
| | - Godsfavour Umoru
- Department of Pharmacy, Houston Methodist Hospital, Houston, TX, United States,College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX, United States
| | - Charisma Mylavarapu
- Department of Medicine, Houston Methodist Hospital, Houston, TX, United States
| | - Veronica B. Ajewole
- Department of Pharmacy, Houston Methodist Hospital, Houston, TX, United States,College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX, United States
| | - Maen Abdelrahim
- Section of Gastrointestinal Oncology, Houston Methodist Neal Cancer Center, Houston, TX, United States,Cockrell Center for Advanced Therapeutic Phase I program, Houston Methodist Research Institute, Houston, TX, United States,Department of Medicine, Weill Cornell Medical College, New York, NY, United States,*Correspondence: Maen Abdelrahim, ; Abdullah Esmail,
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Regorafenib Induces Senescence and Epithelial-Mesenchymal Transition in Colorectal Cancer to Promote Drug Resistance. Cells 2022; 11:cells11223663. [PMID: 36429091 PMCID: PMC9688587 DOI: 10.3390/cells11223663] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 11/14/2022] [Accepted: 11/15/2022] [Indexed: 11/19/2022] Open
Abstract
Potential intrinsic resistance mechanisms to regorafenib were explored after short exposure (3 days) on five CRC cell lines (HCT-116, SW1116, LS-1034, SW480, Caco-2). The observation of senescence-like features led to the investigation of a drug-initiated phenotype switch. Following long-term exposure (12 months) of HCT-116 and SW480 cell lines to regorafenib, we developed resistant models to explore acquired resistance. SW480 cells demonstrated senescent-like properties, including a cell arrest in the late G2/prophase cell cycle stage and a statistically significant decrease in the expression of G1 Cyclin-Dependent Kinase inhibitors and key cell cycle regulators. A specific senescence-associated secretome was also observed. In contrast, HCT-116 treated cells presented early senescent features and developed acquired resistance triggering EMT and a more aggressive phenotype over time. The gained migration and invasion ability by long-exposed cells was associated with the increased expression level of key cellular and extracellular EMT-related factors. The PI3K/AKT pathway was a significant player in the acquired resistance of HCT-116 cells, possibly related to a PI3KCA mutation in this cell line. Our findings provide new insights into the phenotypic plasticity of CRC cells able, under treatment pressure, to acquire a stable TIS or to use an early senescence state to undergo EMT.
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Abstract
Undifferentiated small round cell sarcomas (SRCSs) of bone and soft tissue comprise a heterogeneous group of highly aggressive tumours associated with a poor prognosis, especially in metastatic disease. SRCS entities mainly occur in the third decade of life and can exhibit striking disparities regarding preferentially affected sex and tumour localization. SRCSs comprise new entities defined by specific genetic abnormalities, namely EWSR1-non-ETS fusions, CIC-rearrangements or BCOR genetic alterations, as well as EWSR1-ETS fusions in the prototypic SRCS Ewing sarcoma. These gene fusions mainly encode aberrant oncogenic transcription factors that massively rewire the transcriptome and epigenome of the as yet unknown cell or cells of origin. Additional mutations or copy number variants are rare at diagnosis and, depending on the tumour entity, may involve TP53, CDKN2A and others. Histologically, these lesions consist of small round cells expressing variable levels of CD99 and specific marker proteins, including cyclin B3, ETV4, WT1, NKX3-1 and aggrecan, depending on the entity. Besides locoregional treatment that should follow standard protocols for sarcoma management, (neo)adjuvant treatment is as yet ill-defined but generally follows that of Ewing sarcoma and is associated with adverse effects that might compromise quality of life. Emerging studies on the molecular mechanisms of SRCSs and the development of genetically engineered animal models hold promise for improvements in early detection, disease monitoring, treatment-related toxicity, overall survival and quality of life.
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Hameedat F, Pizarroso NA, Teixeira N, Pinto S, Sarmento B. Functionalized FcRn-targeted nanosystems for oral drug delivery: A new approach to colorectal cancer treatment. Eur J Pharm Sci 2022; 176:106259. [PMID: 35842140 DOI: 10.1016/j.ejps.2022.106259] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 07/01/2022] [Accepted: 07/11/2022] [Indexed: 01/17/2023]
Abstract
Colorectal cancer (CRC) is the second type of cancer with the highest lethality rate. The current chemotherapy to treat CRC causes systemic toxicity, unsatisfying response rate, and low tumor-specific selectivity, which is mainly administered by invasive routes. The chronic and aggressive nature of cancers may require long-term regimens. Thus, the oral route is preferred. However, the orally administered drugs still need to surpass the harsh environment of the gastrointestinal tract and the biological barriers. Nanotechnology is a promising strategy to overcome the oral route limitations. Targeted nanoparticle systems decorated with functional groups can enhance the delivery of anticancer agents to tumor sites. It is described in the literature that the neonatal Fc receptor (FcRn) is expressed in cancer tissue and overexpressed in CRC epithelial cells. However, the impact of FcRn-targeted nanosystems in the treatment of CRC has been poorly investigated. This review article discusses the current knowledge on the involvement of the FcRn in CRC, as well as to critically assess its relevance as a target for further localization of oral nanocarriers in CRC tumor cells. Finally, a brief overview of cancer therapeutics, strategies to design the nanoparticles of anticancer drugs and a review of decorated nanoparticles with FcRn moieties are explored.
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Affiliation(s)
- Fatima Hameedat
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, Porto 4200-393, Portugal; NANOMED EMJMD, Pharmacy School, Faculty of Health, University of Angers, France; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, Porto 4200-393, Portugal
| | - Nuria A Pizarroso
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, Porto 4200-393, Portugal
| | - Natália Teixeira
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, Porto 4200-393, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, Porto 4200-393, Portugal; Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Rua do Campo Alegre, Porto 4169-007, Portugal
| | - Soraia Pinto
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, Porto 4200-393, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, Porto 4200-393, Portugal; ICBAS - Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Rua Jorge Viterbo Ferreira, 228, Porto 4150-180, Portugal
| | - Bruno Sarmento
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, Porto 4200-393, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, Porto 4200-393, Portugal; CESPU - IUCS, Rua Central de Gandra 1317, Gandra 4585-116, Portugal.
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Modulation of autophagy: a Phase II study of vorinostat plus hydroxychloroquine versus regorafenib in chemotherapy-refractory metastatic colorectal cancer (mCRC). Br J Cancer 2022; 127:1153-1161. [PMID: 35739299 DOI: 10.1038/s41416-022-01892-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 05/15/2022] [Accepted: 06/09/2022] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND In metastatic colorectal cancer (mCRC), regorafenib (RGF), a multi-kinase inhibitor with angiogenic inhibition has modest effects on survival. We reported that autophagy modulation using hydroxychloroquine (HCQ), enhances the anticancer activity of the histone deacetylase inhibitor, vorinostat (VOR), in mCRC, is well tolerated, and has comparable activity to RGF. Thus, we conducted a prospective study of VOR/HCQ versus RGF in mCRC. METHODS This is a randomised, controlled trial of VOR 400 mg and HCQ 600 mg orally daily versus RGF 160 mg orally daily (3 weeks on/1 week off), every 4 weeks, in patients with mCRC. PRIMARY ENDPOINT median progression-free survival (mPFS). Secondary endpoints: median overall survival (mOS); adverse events; pharmacodynamic analyses. RESULTS From 2/2015-10/2017, 42 patients were randomised to VOR/HCQ and RGF. Median age was 58.4 years. mPFS on VOR/HCQ was 1.9 months versus 4.35 months with RGF (P = 0.032). There was no difference in mOS (P = 0.9). Treatment was tolerated in both arms. In both arms, there was improved anti-tumour immunity. CONCLUSIONS VOR/HCQ had an inferior PFS when compared to RGF, although there was an increase in anti-tumour immunity in mCRC. VOR/HCQ has a favourable safety profile, and immune or tumour biomarkers may be used to identify clinical benefit of autophagy modulation in mCRC. CLINICAL TRIAL REGISTRATION NCT02316340.
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Ren SH, Cui ZL, Lang MR, Li Q, Zhang W, Fang F, Wu Q, Cui YL, Li HK, Chen P, Zhang Y, Song T. Efficacy and safety of sequential therapy with sorafenib and regorafenib for advanced hepatocellular carcinoma: a two-center study in China. J Gastrointest Oncol 2022; 13:1266-1277. [PMID: 35837206 PMCID: PMC9274072 DOI: 10.21037/jgo-22-397] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 06/09/2022] [Indexed: 10/21/2023] Open
Abstract
BACKGROUND Regorafenib is a standard 2nd-line treatment for patients with advanced hepatocellular carcinoma (HCC), but the efficacy and safety of sequential therapy with sorafenib and regorafenib among advanced HCC patients in China is not clear. METHODS This was a retrospective, two-center, cohort study of advanced HCC patients who received sequential therapy of sorafenib and regorafenib from October 2018 to April 2020 at 2 Chinese institutions. The patients were converted directly to regorafenib after failing to respond to sorafenib monotherapy. The patients underwent evaluations every 4-6 weeks to determine the efficacy and safety of the treatment according to physiological, laboratory, and radiological results. A radiological evaluation using computed tomography or magnetic resonance imaging scans was conducted. The outcomes included overall survival (OS) and progression-free survival (PFS). RESULTS A total of 43 patients received regorafenib as a 2nd-line treatment after sorafenib progression. Of these patients, 26 (60.5%) and 17 (39.5%) were diagnosed with Barcelona Clinic Liver Cancer (BCLC) stages B and C, respectively. The median PFS was 11.0 [95% confidence interval (CI): 5.8-16.2] months, and the median OS was 17.0 (95% CI: 12.8-21.2) months. Conversely, the most common toxicities were hand-foot skin reaction (48.8%), diarrhea (32.6%), and hypertension (14%). The most common grade 3-4 toxicities were hypoalbuminemia (4.7%), anemia (4.7%), and thrombocytopenia (4.7%). Alpha-fetoprotein (AFP) ≥400, alanine transaminase (ALT) ≥60 IU/L, and aspartate aminotransferase (AST) ≥60 IU/L before 2nd-line treatment were associated with PFS in the univariable analyses. The Cox proportional-hazards regression analysis showed that AFP [hazard ratio (HR) =0.225; 95% CI: 0.073-0.688; P=0.009], ALT (HR =0.195; 95% CI: 0.051-0.741; P=0.016), AST (HR =0.209; 95% CI: 0.063-0.697; P=0.011), and presence of extrahepatic metastasis (HR =0.074; 95% CI: 0.009-0.608; P=0.015) before 2nd-line treatment were independently associated with PFS. CONCLUSIONS The sequential therapy of sorafenib and regorafenib is well-tolerated and effective in advanced HCC patients after sorafenib progression based on our two-center real-world data. Patients with good liver function reserve and a high level of AFP before 2nd-line treatment may benefit from sequential treatment. These results still need further validation.
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Affiliation(s)
- Shao-Hua Ren
- Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Zi-Lin Cui
- Department of Hepatobiliary Surgery, Tianjin First Central Hospital, Tianjin, China
| | - Meng-Ran Lang
- Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Qiang Li
- Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Wei Zhang
- Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Feng Fang
- Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Qiang Wu
- Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Yun-Long Cui
- Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Hui-Kai Li
- Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Ping Chen
- Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Yamin Zhang
- Department of Hepatobiliary Surgery, Tianjin First Central Hospital, Tianjin, China
| | - Tianqiang Song
- Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Tianjin’s Clinical Research Center for Cancer, Tianjin, China
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Afonso M, Brito MA. Therapeutic Options in Neuro-Oncology. Int J Mol Sci 2022; 23:5351. [PMID: 35628161 PMCID: PMC9140894 DOI: 10.3390/ijms23105351] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Revised: 04/29/2022] [Accepted: 05/04/2022] [Indexed: 12/22/2022] Open
Abstract
One of the biggest challenges in neuro-oncology is understanding the complexity of central nervous system tumors, such as gliomas, in order to develop suitable therapeutics. Conventional therapies in malignant gliomas reconcile surgery and radiotherapy with the use of chemotherapeutic options such as temozolomide, chloroethyl nitrosoureas and the combination therapy of procarbazine, lomustine and vincristine. With the unraveling of deregulated cancer cell signaling pathways, targeted therapies have been developed. The most affected signaling pathways in glioma cells involve tyrosine kinase receptors and their downstream pathways, such as the phosphatidylinositol 3-kinases (PI3K/AKT/mTOR) and mitogen-activated protein kinase pathways (MAPK). MAPK pathway inhibitors include farnesyl transferase inhibitors, Ras kinase inhibitors and mitogen-activated protein extracellular regulated kinase (MEK) inhibitors, while PI3K/AKT/mTOR pathway inhibitors are divided into pan-inhibitors, PI3K/mTOR dual inhibitors and AKT inhibitors. The relevance of the immune system in carcinogenesis has led to the development of immunotherapy, through vaccination, blocking of immune checkpoints, oncolytic viruses, and adoptive immunotherapy using chimeric antigen receptor T cells. In this article we provide a comprehensive review of the signaling pathways underlying malignant transformation, the therapies currently used in the treatment of malignant gliomas and further explore therapies under development, including several ongoing clinical trials.
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Affiliation(s)
- Mariana Afonso
- Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal;
| | - Maria Alexandra Brito
- Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal;
- Research Institute for Medicines (iMed), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal
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Chang YC, Li CH, Chan MH, Chen MH, Yeh CN, Hsiao M. Regorafenib inhibits epithelial-mesenchymal transition and suppresses cholangiocarcinoma metastasis via YAP1-AREG axis. Cell Death Dis 2022; 13:391. [PMID: 35449153 PMCID: PMC9023529 DOI: 10.1038/s41419-022-04816-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 03/24/2022] [Accepted: 03/31/2022] [Indexed: 12/22/2022]
Abstract
Cholangiocarcinoma (CCA) is a subtype of bile duct cancer usually diagnosed late with a low survival rate and no satisfactorily systemic treatment. Recently, regorafenib has been accepted as a second-line treatment for CCA patients. In this study, we investigated the potential signal transduction pathways mediated by regorafenib. We established a transcriptomic database for regorafenib-treated CCA cells using expression microarray chips. Our data indicate that regorafenib inhibits yes-associated protein 1 (YAP1) activity in various CCA cells. In addition, we demonstrated that YAP1 regulates epithelial-mesenchymal transition (EMT)-related genes, including E-cadherin and SNAI2. We further examined YAP1 activity, phosphorylation status, and expression levels of YAP1 downstream target genes in the regorafenib model. We found that regorafenib dramatically suppressed these events in CCA cells. Moreover, in vivo results revealed that regorafenib could significantly inhibit lung foci formation and tumorigenicity. Most importantly, regorafenib and amphiregulin (AREG) neutralize antibody exhibited synergistic effects against CCA cells. In a clinical setting, patients with high YAP1 and EMT expression had a worse survival rate than patients with low YAP1, and EMT expression did. In addition, we found that YAP1 upregulated the downstream target amphiregulin in CCA. Our findings suggest that AREG neutralizing antibody antibodies combined with regorafenib can reverse the CCA metastatic phenotype and EMT in vitro and in vivo. These findings provide novel therapeutic strategies to combat the metastasis of CCA.
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33
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Gaudino S, Marziali G, Giordano C, Gigli R, Varcasia G, Magnani F, Chiesa S, Balducci M, Costantini AM, Della Pepa GM, Olivi A, Russo R, Colosimo C. Regorafenib in Glioblastoma Recurrence: How to Deal With MR Imaging Treatments Changes. FRONTIERS IN RADIOLOGY 2022; 1:790456. [PMID: 37492166 PMCID: PMC10365006 DOI: 10.3389/fradi.2021.790456] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 12/29/2021] [Indexed: 07/27/2023]
Abstract
The treatment of recurrent high-grade gliomas remains a major challenge of daily neuro-oncology practice, and imaging findings of new therapies may be challenging. Regorafenib is a multi-kinase inhibitor that has recently been introduced into clinical practice to treat recurrent glioblastoma, bringing with it a novel panel of MRI imaging findings. On the basis of the few data in the literature and on our personal experience, we have identified the main MRI changes during regorafenib therapy, and then, we defined two different patterns, trying to create a simple summary line of the main changes of pathological tissue during therapy. We named these patterns, respectively, pattern A (less frequent, similar to classical progression disease) and pattern B (more frequent, with decreased diffusivity and decrease contrast-enhancement). We have also reported MR changes concerning signal intensity on T1-weighted and T2-weighted images, SWI, and perfusion imaging, derived from the literature (small series or case reports) and from our clinical experience. The clinical implication of these imaging modifications remains to be defined, taking into account that we are still at the dawn in the evaluation of such imaging modifications.
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Affiliation(s)
- Simona Gaudino
- Department of Diagnostic Imaging, Oncological Radiotherapy and Hematology, Institute of Radiology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Università Cattolica Sacro Cuore of Rome, Rome, Italy
| | - Giammaria Marziali
- Department of Diagnostic Imaging, Oncological Radiotherapy and Hematology, Institute of Radiology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Carolina Giordano
- Department of Diagnostic Imaging, Oncological Radiotherapy and Hematology, Institute of Radiology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Riccardo Gigli
- Department of Diagnostic Imaging, Oncological Radiotherapy and Hematology, Institute of Radiology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Giuseppe Varcasia
- Department of Diagnostic Imaging, Oncological Radiotherapy and Hematology, Institute of Radiology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Francesca Magnani
- Department of Diagnostic Imaging, Oncological Radiotherapy and Hematology, Institute of Radiology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Silvia Chiesa
- Department of Diagnostic Imaging, Oncological Radiotherapy, and Hematology, UOC di Radioterapia Oncologica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Mario Balducci
- Università Cattolica Sacro Cuore of Rome, Rome, Italy
- Department of Diagnostic Imaging, Oncological Radiotherapy, and Hematology, UOC di Radioterapia Oncologica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Alessandro Maria Costantini
- Department of Diagnostic Imaging, Oncological Radiotherapy and Hematology, Institute of Radiology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Giuseppe Maria Della Pepa
- Institute of Neurosurgery, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University, Rome, Italy
| | - Alessandro Olivi
- Università Cattolica Sacro Cuore of Rome, Rome, Italy
- Institute of Neurosurgery, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University, Rome, Italy
| | - Rosellina Russo
- Department of Diagnostic Imaging, Oncological Radiotherapy and Hematology, Institute of Radiology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Cesare Colosimo
- Department of Diagnostic Imaging, Oncological Radiotherapy and Hematology, Institute of Radiology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Università Cattolica Sacro Cuore of Rome, Rome, Italy
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Chen ZY, Li J, Zhu SD, Li ZD, Yu JL, Wu J, Zhang C, Zeng LH. Harmine reinforces the effects of regorafenib on suppressing cell proliferation and inducing apoptosis in liver cancer cells. Exp Ther Med 2022; 23:209. [PMID: 35126712 PMCID: PMC8796640 DOI: 10.3892/etm.2022.11132] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Accepted: 11/30/2021] [Indexed: 11/05/2022] Open
Affiliation(s)
- Zi-Yi Chen
- School of Medicine, Zhejiang University City College, Hangzhou, Zhejiang 310015, P.R. China
| | - Jie Li
- School of Medicine, Zhejiang University City College, Hangzhou, Zhejiang 310015, P.R. China
| | - Shu-Di Zhu
- School of Medicine, Zhejiang University City College, Hangzhou, Zhejiang 310015, P.R. China
| | - Zhi-Di Li
- School of Medicine, Zhejiang University City College, Hangzhou, Zhejiang 310015, P.R. China
| | - Jia-Lin Yu
- School of Medicine, Zhejiang University City College, Hangzhou, Zhejiang 310015, P.R. China
| | - Jie Wu
- School of Pharmaceutical and Materials Engineering and Institute for Advanced Studies, Taizhou University, Taizhou, Zhejiang 318000, P.R. China
| | - Chong Zhang
- School of Medicine, Zhejiang University City College, Hangzhou, Zhejiang 310015, P.R. China
| | - Ling-Hui Zeng
- School of Medicine, Zhejiang University City College, Hangzhou, Zhejiang 310015, P.R. China
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Lahooti B, Poudel S, Mikelis CM, Mattheolabakis G. MiRNAs as Anti-Angiogenic Adjuvant Therapy in Cancer: Synopsis and Potential. Front Oncol 2021; 11:705634. [PMID: 34956857 PMCID: PMC8695604 DOI: 10.3389/fonc.2021.705634] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 11/22/2021] [Indexed: 12/12/2022] Open
Abstract
Angiogenesis is a key mechanism for tumor growth and metastasis and has been a therapeutic target for anti-cancer treatments. Intensive vascular growth is concomitant with the rapidly proliferating tumor cell population and tumor outgrowth. Current angiogenesis inhibitors targeting either one or a few pro-angiogenic factors or a range of downstream signaling molecules provide clinical benefit, but not without significant side effects. miRNAs are important post-transcriptional regulators of gene expression, and their dysregulation has been associated with tumor progression, metastasis, resistance, and the promotion of tumor-induced angiogenesis. In this mini-review, we provide a brief overview of the current anti-angiogenic approaches, their molecular targets, and side effects, as well as discuss existing literature on the role of miRNAs in angiogenesis. As we highlight specific miRNAs, based on their activity on endothelial or cancer cells, we discuss their potential for anti-angiogenic targeting in cancer as adjuvant therapy and the importance of angiogenesis being evaluated in such combinatorial approaches.
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Affiliation(s)
- Behnaz Lahooti
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, United States
| | - Sagun Poudel
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, LA, United States
| | - Constantinos M. Mikelis
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, United States
- Department of Pharmacy, University of Patras, Patras, Greece
| | - George Mattheolabakis
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, LA, United States
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Sun EJ, Wankell M, Palamuthusingam P, McFarlane C, Hebbard L. Targeting the PI3K/Akt/mTOR Pathway in Hepatocellular Carcinoma. Biomedicines 2021; 9:biomedicines9111639. [PMID: 34829868 PMCID: PMC8615614 DOI: 10.3390/biomedicines9111639] [Citation(s) in RCA: 147] [Impact Index Per Article: 36.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 11/05/2021] [Accepted: 11/05/2021] [Indexed: 12/24/2022] Open
Abstract
Despite advances in the treatment of cancers through surgical procedures and new pharmaceuticals, the treatment of hepatocellular carcinoma (HCC) remains challenging as reflected by low survival rates. The PI3K/Akt/mTOR pathway is an important signaling mechanism that regulates the cell cycle, proliferation, apoptosis, and metabolism. Importantly, deregulation of the PI3K/Akt/mTOR pathway leading to activation is common in HCC and is hence the subject of intense investigation and the focus of current therapeutics. In this review article, we consider the role of this pathway in the pathogenesis of HCC, focusing on its downstream effectors such as glycogen synthase kinase-3 (GSK-3), cAMP-response element-binding protein (CREB), forkhead box O protein (FOXO), murine double minute 2 (MDM2), p53, and nuclear factor-κB (NF-κB), and the cellular processes of lipogenesis and autophagy. In addition, we provide an update on the current ongoing clinical development of agents targeting this pathway for HCC treatments.
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Affiliation(s)
- Eun Jin Sun
- Centre for Molecular Therapeutics, Department of Molecular and Cell Biology, Australian Institute of Tropical Medicine and Health, College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, QLD 4811, Australia; (E.J.S.); (M.W.); (C.M.)
- College of Medicine and Dentistry, James Cook University, Townsville, QLD 4811, Australia
| | - Miriam Wankell
- Centre for Molecular Therapeutics, Department of Molecular and Cell Biology, Australian Institute of Tropical Medicine and Health, College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, QLD 4811, Australia; (E.J.S.); (M.W.); (C.M.)
| | - Pranavan Palamuthusingam
- Institute of Surgery, The Townsville University Hospital, Townsville, QLD 4811, Australia;
- Mater Hospital, Townsville, QLD 4811, Australia
| | - Craig McFarlane
- Centre for Molecular Therapeutics, Department of Molecular and Cell Biology, Australian Institute of Tropical Medicine and Health, College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, QLD 4811, Australia; (E.J.S.); (M.W.); (C.M.)
| | - Lionel Hebbard
- Centre for Molecular Therapeutics, Department of Molecular and Cell Biology, Australian Institute of Tropical Medicine and Health, College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, QLD 4811, Australia; (E.J.S.); (M.W.); (C.M.)
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW 2145, Australia
- Correspondence:
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37
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Lafferty A, O'Farrell AC, Migliardi G, Khemka N, Lindner AU, Sassi F, Zanella ER, Salvucci M, Vanderheyden E, Modave E, Boeckx B, Halang L, Betge J, Ebert MPA, Dicker P, Argilés G, Tabernero J, Dienstmann R, Medico E, Lambrechts D, Bertotti A, Isella C, Trusolino L, Prehn JHM, Byrne AT. Molecular Subtyping Combined with Biological Pathway Analyses to Study Regorafenib Response in Clinically Relevant Mouse Models of Colorectal Cancer. Clin Cancer Res 2021; 27:5979-5992. [PMID: 34426441 DOI: 10.1158/1078-0432.ccr-21-0818] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 07/05/2021] [Accepted: 08/18/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE Regorafenib (REG) is approved for the treatment of metastatic colorectal cancer, but has modest survival benefit and associated toxicities. Robust predictive/early response biomarkers to aid patient stratification are outstanding. We have exploited biological pathway analyses in a patient-derived xenograft (PDX) trial to study REG response mechanisms and elucidate putative biomarkers. EXPERIMENTAL DESIGN Molecularly subtyped PDXs were annotated for REG response. Subtyping was based on gene expression (CMS, consensus molecular subtype) and copy-number alteration (CNA). Baseline tumor vascularization, apoptosis, and proliferation signatures were studied to identify predictive biomarkers within subtypes. Phospho-proteomic analysis was used to identify novel classifiers. Supervised RNA sequencing analysis was performed on PDXs that progressed, or did not progress, following REG treatment. RESULTS Improved REG response was observed in CMS4, although intra-subtype response was variable. Tumor vascularity did not correlate with outcome. In CMS4 tumors, reduced proliferation and higher sensitivity to apoptosis at baseline correlated with response. Reverse phase protein array (RPPA) analysis revealed 4 phospho-proteomic clusters, one of which was enriched with non-progressor models. A classification decision tree trained on RPPA- and CMS-based assignments discriminated non-progressors from progressors with 92% overall accuracy (97% sensitivity, 67% specificity). Supervised RNA sequencing revealed that higher basal EPHA2 expression is associated with REG resistance. CONCLUSIONS Subtype classification systems represent canonical "termini a quo" (starting points) to support REG biomarker identification, and provide a platform to identify resistance mechanisms and novel contexts of vulnerability. Incorporating functional characterization of biological systems may optimize the biomarker identification process for multitargeted kinase inhibitors.
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Affiliation(s)
- Adam Lafferty
- Department of Physiology and Medical Physics, Precision Cancer Medicine Group, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Alice C O'Farrell
- Department of Physiology and Medical Physics, Precision Cancer Medicine Group, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Giorgia Migliardi
- Department of Oncology, University of Torino, Candiolo, Italy
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | - Niraj Khemka
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
- Center for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Andreas U Lindner
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
- Center for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | | | | | - Manuela Salvucci
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
- Center for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Evy Vanderheyden
- Department of Human Genetics, VIB Center for Cancer Biology, Leuven, Belgium, Laboratory for Translational Genetics, KU Leuven, Leuven, Belgium
| | - Elodie Modave
- Department of Human Genetics, VIB Center for Cancer Biology, Leuven, Belgium, Laboratory for Translational Genetics, KU Leuven, Leuven, Belgium
| | - Bram Boeckx
- Department of Human Genetics, VIB Center for Cancer Biology, Leuven, Belgium, Laboratory for Translational Genetics, KU Leuven, Leuven, Belgium
| | - Luise Halang
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
- Center for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Johannes Betge
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Junior Clinical Cooperation Unit Translational Gastrointestinal Oncology and Preclinical Models, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Matthias P A Ebert
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Patrick Dicker
- Department of Epidemiology and Public Health Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Guillem Argilés
- Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, CIBERONC, Barcelona, Spain
| | - Josep Tabernero
- Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, CIBERONC, Barcelona, Spain
| | - Rodrigo Dienstmann
- Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, CIBERONC, Barcelona, Spain
| | - Enzo Medico
- Department of Oncology, University of Torino, Candiolo, Italy
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | - Diether Lambrechts
- Department of Human Genetics, VIB Center for Cancer Biology, Leuven, Belgium, Laboratory for Translational Genetics, KU Leuven, Leuven, Belgium
| | - Andrea Bertotti
- Department of Oncology, University of Torino, Candiolo, Italy
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | - Claudio Isella
- Department of Oncology, University of Torino, Candiolo, Italy
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | - Livio Trusolino
- Department of Oncology, University of Torino, Candiolo, Italy
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | - Jochen H M Prehn
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
- Center for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Annette T Byrne
- Department of Physiology and Medical Physics, Precision Cancer Medicine Group, Royal College of Surgeons in Ireland, Dublin, Ireland.
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
- UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin, Ireland
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Autophagy-Related Chemoprotection against Sorafenib in Human Hepatocarcinoma: Role of FOXO3 Upregulation and Modulation by Regorafenib. Int J Mol Sci 2021; 22:ijms222111770. [PMID: 34769197 PMCID: PMC8583804 DOI: 10.3390/ijms222111770] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 10/20/2021] [Accepted: 10/26/2021] [Indexed: 02/07/2023] Open
Abstract
Early acquisition of sorafenib resistance is responsible for the dismal prognosis of advanced hepatocarcinoma (HCC). Autophagy, a catabolic process involved in liver homeostasis, has been associated with chemosensitivity modulation. Forkhead box O3 (FOXO3) is a transcription factor linked to HCC pathogenesis whose role on autophagy-related sorafenib resistance remains controversial. Here, we unraveled the linkage between autophagy and sorafenib resistance in HCC, focusing on the implication of FOXO3 and its potential modulation by regorafenib. We worked with two HepG2-derived sorafenib-resistant HCC in vitro models (HepG2S1 and HepG2S3) and checked HCC patient data from the UALCAN database. Resistant cells displayed an enhanced basal autophagic flux compared to HepG2, showing higher autophagolysosome content and autophagy markers levels. Pharmacological inhibition of autophagy boosted HepG2S1 and HepG2S3 apoptosis and subG1 cells, but reduced viability, indicating the cytoprotective role of autophagy. HCC samples displayed higher FOXO3 levels, being associated with shorter survival and autophagic genes expression. Consistently, chemoresistant in vitro models showed significant FOXO3 upregulation. FOXO3 knockdown suppressed autophagy and caused resistant cell death, demonstrating that overactivation of such pro-survival autophagy during sorafenib resistance is FOXO3-dependent; a cytoprotective mechanism that the second-line drug regorafenib successfully abolished. Therefore, targeting FOXO3-mediated autophagy could significantly improve the clinical efficacy of sorafenib.
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Pyo J, Park HJ. Treatment Efficacy of Immune Checkpoint Inhibitors for Patients with Advanced or Metastatic Colorectal Cancer: A Systematic Review and Meta-Analysis. J Clin Med 2021; 10:3599. [PMID: 34441895 PMCID: PMC8397178 DOI: 10.3390/jcm10163599] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Revised: 08/11/2021] [Accepted: 08/12/2021] [Indexed: 12/13/2022] Open
Abstract
The treatment efficacy of immune checkpoint inhibitors (ICIs) in colorectal cancer (CRC) has been reported heterogeneously across clinical trials. We conducted a systematic review and meta-analysis to evaluate the efficacy of ICIs in patients with advanced/metastatic CRC. Ovid-Medline was searched to identify clinical trials providing the efficacy outcomes of overall response rate (ORR) or disease control rate (DCR). The pooled ORR and DCR were estimated across all studies and subgroups. Meta-regression was performed to find the influencing factors for treatment efficacy. A total of thirty studies (1870 patients) were eligible. The overall ORR and DCR were 20.1% and 58.5%, respectively, but these results were heterogeneous across studies. Multivariate meta-regression revealed that microsatellite phenotype (odds ratio of MSI-H/dMMR versus MSS/pMMR: 1.67, p < 0.001) and drug regimen (odds ratio of monotherapy versus combination therapy: 1.07, p = 0.019) were the source of heterogeneity and also significantly influenced factors for the efficacy of the treatment. Although the efficacy of ICIs as a first-line therapy was higher than that of ICIs as the second- or more-line therapy (ORR: 51.5% vs. 13.4%, DCR: 85% vs. 49.5%), multivariate regression showed that the line of therapy was not a significant factor for the treatment efficacy. Our study suggests that the microsatellite phenotype and drug regimen, rather than the line of treatment, are the primary factors influencing the treatment response among advanced/metastatic CRC patients treated with an ICI-based regimen.
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Affiliation(s)
- Junhee Pyo
- Asan Medical Center, Department of Biomedical Engineering, College of Medicine, University of Ulsan, Seoul 05505, Korea;
| | - Hyo-Jung Park
- Asan Medical Center, Department of Radiology and Research Institute of Radiology, College of Medicine, University of Ulsan, Seoul 05505, Korea
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Vandeputte C, Bregni G, Gkolfakis P, Guiot T, Pretta A, Kehagias P, Senti C, Reina EA, Van Bogaert C, Deleporte A, Geboes K, Delaunoit T, Demolin G, Peeters M, D'Hondt L, Janssens J, Carrasco J, Holbrechts S, Goeminne JC, Vergauwe P, Van Laethem JL, Flamen P, Hendlisz A, Sclafani F. Sex and Regorafenib Toxicity in Refractory Colorectal Cancer: Safety Analysis of the RegARd-C Trial. Clin Colorectal Cancer 2021; 20:326-333. [PMID: 34404621 DOI: 10.1016/j.clcc.2021.07.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 07/14/2021] [Accepted: 07/19/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND Regorafenib is a standard treatment for refractory metastatic colorectal cancer (mCRC). In view of the toxicity burden, significant research efforts have been made to increase the therapeutic ratio of this multikinase inhibitor. Predictive factors for treatment-related adverse events (TRAEs), however, are still lacking. MATERIALS AND METHODS We assessed the association between a number of baseline clinical, laboratory and imaging parameters and the occurrence of TRAEs in 136 patients who had received regorafenib (160 mg/day, 3-weeks-on/1-week-off) in a prospective phase II clinical trial. RESULTS Grade ≥ 2 TRAEs during the first cycle of treatment (84% vs. 60%, P = .002) and grade ≥ 3 TRAEs throughout the whole treatment (71% vs. 53%, P = .035) occurred more frequently in females, with sex being the only independent predictive factor of early and any-time toxicity (OR 3.4; 95% CI: 1.2-11.1, P = .02 and OR 2.1; 95% CI: 1.0-4.4, P = .045, respectively). Fatigue, anorexia, hypertension, and rash were reported significantly more frequently by females than males (P < .04). Females were also more likely to suffer early (19% vs. 5%, P = .014) and any-time serious AEs (28% vs. 9%, P = .005), and to require early dose modifications (55% vs. 37%, P = .055). CONCLUSION This is the first study showing an association between sex and TRAEs during regorafenib treatment for mCRC. If confirmed in larger, independent series, these results could pave the way for the implementation of personalized regorafenib dosing strategies with the potential to optimize oncological outcomes while reducing toxicity and preserving quality of life.
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Affiliation(s)
- Caroline Vandeputte
- GUTS research group, Department of Medical Oncology, Institut Jules Bordet, Brussels, Belgium
| | - Giacomo Bregni
- Gastrointestinal Unit, Department of Medical Oncology, Institut Jules Bordet, Brussels, Belgium
| | - Paraskevas Gkolfakis
- Gastrointestinal Unit, Department of Medical Oncology, Institut Jules Bordet, Brussels, Belgium
| | - Thomas Guiot
- Nuclear medicine Imaging and Therapy Department, Institut Jules Bordet, Brussels, Belgium
| | - Andrea Pretta
- Gastrointestinal Unit, Department of Medical Oncology, Institut Jules Bordet, Brussels, Belgium
| | - Pashalina Kehagias
- GUTS research group, Department of Medical Oncology, Institut Jules Bordet, Brussels, Belgium
| | - Chiara Senti
- GUTS research group, Department of Medical Oncology, Institut Jules Bordet, Brussels, Belgium
| | - Elena Acedo Reina
- GUTS research group, Department of Medical Oncology, Institut Jules Bordet, Brussels, Belgium
| | - Camille Van Bogaert
- GUTS research group, Department of Medical Oncology, Institut Jules Bordet, Brussels, Belgium
| | - Amélie Deleporte
- Gastrointestinal Unit, Department of Medical Oncology, Institut Jules Bordet, Brussels, Belgium
| | - Karen Geboes
- Service of digestive oncology, Universitair Ziekenhuis Gent, Gent, Belgium
| | | | - Gauthier Demolin
- Gastroenterology Department, Centre Hospitalier Chrétien St-Joseph, Liège, Belgium
| | - Marc Peeters
- Oncology department, Universitair Ziekenhuis Antwerpen, Antwerpen, Belgium
| | - Lionel D'Hondt
- Oncology department, Centre Hospitalier Universitaire, UCL Namur (site de Godinne), Belgium
| | - Jos Janssens
- Department of Gastroenterology, AZ Turnhout, Turnhout, Belgium
| | - Javier Carrasco
- Oncology department, Grand Hôpital de Charleroi, Charleroi, Belgium
| | - Stephane Holbrechts
- Service of Medical Oncology, Centre Hospitalier Universitaire Ambroise Paré, Mons, Belgium
| | | | | | - Jean-Luc Van Laethem
- Department of Gastroenterology and Digestive Oncology, Erasme Hospital, Brussels, Belgium
| | - Patrick Flamen
- Nuclear medicine Imaging and Therapy Department, Institut Jules Bordet, Brussels, Belgium
| | - Alain Hendlisz
- Gastrointestinal Unit, Department of Medical Oncology, Institut Jules Bordet, Brussels, Belgium; Université Libre de Bruxelles, Brussels, Belgium
| | - Francesco Sclafani
- Gastrointestinal Unit, Department of Medical Oncology, Institut Jules Bordet, Brussels, Belgium; Université Libre de Bruxelles, Brussels, Belgium.
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Dahiya M, Dureja H. Sorafenib for hepatocellular carcinoma: potential molecular targets and resistance mechanisms. J Chemother 2021; 34:286-301. [PMID: 34291704 DOI: 10.1080/1120009x.2021.1955202] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Hepatocellular carcinoma (HCC) is the most widespread typical therapy-resistant, unresectable type of malignant solid tumour with a high death rate constituting huge medical concern. Sorafenib is a small molecule oral multi-target kinase potent inhibitor that acts by suppressing/blocking the multiplication of the tumour cells, angiogenesis, and encouraging apoptosis of the tumour cells. Though, the precise mechanism of tumour cell death induction by sorafenib is yet under exploration. Furthermore, genetic heterogeneity plays a critical role in developing sorafenib resistance, which leads the way to identify the need for predictive biomarkers responsible for drug resistance. Therefore, it is essential to find out the fundamental resistance mechanisms to expand therapeutic plans. The authors summarize the molecular concepts of resistance, progression, potential molecular targets, HCC management therapies, and discussion on the advancements expected in the coming future, inclusive of biomarker-driven treatment strategies, which may provide the prospects to design innovative therapeutically targeted strategies for the HCC treatment and the clinical implementation of emerging targeted agents.
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Affiliation(s)
- Mandeep Dahiya
- Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, India
| | - Harish Dureja
- Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, India
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Ronchetti R, Moroni G, Carotti A, Gioiello A, Camaioni E. Recent advances in urea- and thiourea-containing compounds: focus on innovative approaches in medicinal chemistry and organic synthesis. RSC Med Chem 2021; 12:1046-1064. [PMID: 34355177 PMCID: PMC8293013 DOI: 10.1039/d1md00058f] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 04/23/2021] [Indexed: 12/18/2022] Open
Abstract
Urea and thiourea represent privileged structures in medicinal chemistry. Indeed, these moieties constitute a common framework of a variety of drugs and bioactive compounds endowed with a broad range of therapeutic and pharmacological properties. Herein, we provide an overview of the state-of-the-art of urea and thiourea-containing pharmaceuticals. We also review the diverse approaches pursued for (thio)urea bioisosteric replacements in medicinal chemistry applications. Finally, representative examples of recent advances in the synthesis of urea- and thiourea-based compounds by enabling chemical tools are discussed.
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Affiliation(s)
- Riccardo Ronchetti
- Department of Pharmaceutical Sciences, University of Perugia Via del Liceo 1 06123 Perugia Italy +39 075 5855161 +39 075 5855129
| | - Giada Moroni
- Department of Pharmaceutical Sciences, University of Perugia Via del Liceo 1 06123 Perugia Italy +39 075 5855161 +39 075 5855129
- Department of Chemistry "Giacomo Ciamician", Alma Mater Studiorum, University of Bologna Via Selmi 2 40126 Bologna Italy
| | - Andrea Carotti
- Department of Pharmaceutical Sciences, University of Perugia Via del Liceo 1 06123 Perugia Italy +39 075 5855161 +39 075 5855129
| | - Antimo Gioiello
- Department of Pharmaceutical Sciences, University of Perugia Via del Liceo 1 06123 Perugia Italy +39 075 5855161 +39 075 5855129
| | - Emidio Camaioni
- Department of Pharmaceutical Sciences, University of Perugia Via del Liceo 1 06123 Perugia Italy +39 075 5855161 +39 075 5855129
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Nwagwu CD, Adamson DC. Can we rely on synthetic pharmacotherapy for the treatment of glioblastoma? Expert Opin Pharmacother 2021; 22:1983-1994. [PMID: 34219576 DOI: 10.1080/14656566.2021.1950139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Introduction: Despite decades of clinical trials utilizing conventional and novel therapeutics, the effective treatment of glioblastoma remains one of the most formidable challenges in oncology. Current standard of care includes surgery and chemoradiation. Synthetic pharmacotherapies continue to be explored as potential therapeutic options for glioblastoma patients.Areas covered: This study reviews synthetic pharmacotherapies that are currently under investigation in phase I-III clinical trials. The authors of this study highlight the mechanisms of action of the synthetic pharmacotherapy agents under investigation, outline the available evidence for their utility based on the literature, and summarize the current landscape.Expert opinion: Although warranting further investigation, the studies generally highlighted here have not shown remarkable changes in clinical benefits beyond what has already been established with radiochemotherapy. As we develop more synthetics, we will likely need to combine them with other synthetics to target multiple separate molecular pathways. There is considerable potential when this treatment strategy is guided by molecular profiling approaches which seek to stratify patients based on treatments that would be most efficacious for them.
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Affiliation(s)
- Chibueze D Nwagwu
- Department of Neurosurgery, Emory University, Atlanta, 30322-1007, United States
| | - David C Adamson
- Department of Neurosurgery, Emory University, Atlanta, 30322-1007, United States
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Wang K, Yu G, Lin J, Wang Z, Lu Q, Gu C, Yang T, Liu S, Yang H. Berberine Sensitizes Human Hepatoma Cells to Regorafenib via Modulating Expression of Circular RNAs. Front Pharmacol 2021; 12:632201. [PMID: 34220494 PMCID: PMC8248669 DOI: 10.3389/fphar.2021.632201] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Accepted: 03/08/2021] [Indexed: 01/10/2023] Open
Abstract
Regorafenib resistance is a key limiting factor in the treatment of advanced hepatocellular carcinoma (HCC). Increasing evidence has demonstrated that Berberine (BBR) can synergistically enhance the therapeutic effect of various chemotherapeutic agents. However, the contribution of BBR on regorafenib therapy remains unclear. The purpose of this study was to explore the combined treatment effect of berberine and regorafenib in HCC. We found that BBR enhanced the cytotoxicity of regorafenib in HCC cells. Compared with regorafenib alone, the combined treatment of BBR and regorafenib significantly inhibited the proliferation of HCC cells and induced cellular apoptosis. Meanwhile, the combined treatment group with BBR (10mg/kg/day) and regorafenib (5mg/kg/day) had a dramatic inhibitory effect on the growth of HCC xenograft tumors in nude mice. The increased apoptosis of xenograft tumors was seen in the combined treatment group. Moreover, a comprehensive circular RNA sequencing was performed to identify differentially expressed circRNAs in HCC cells after exposure to 100µM BBR and 5µM regorafenib. The volcano plot and scatter plot analyses revealed that there were 58 up-regulated and 19 down-regulated differentially expressed circRNAs between the combination treatment and control groups. Among them, the expression of hsa_circ_0032029 and hsa_circ_0008928 were up-regulated in HCC cells after treatment with 100µM BBR and 5µM regorafenib. Taken together, this study demonstrated that BBR enhanced the anti-HCC effect of regorafenib both in vitro and in vivo. The synergistic anti-tumor effect of BBR and regorafenib might be related to the up-regulation of hsa_circ_0032029 and hsa_circ_0008928 in HCC cells.
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Affiliation(s)
- Kunyuan Wang
- Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Ganxiang Yu
- Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jiaen Lin
- Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Zhilei Wang
- Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Qianting Lu
- Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Chengxin Gu
- Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Tao Yang
- Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Shiming Liu
- Guangzhou Institute of Cardiovascular Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Hui Yang
- Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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Granito A, Forgione A, Marinelli S, Renzulli M, Ielasi L, Sansone V, Benevento F, Piscaglia F, Tovoli F. Experience with regorafenib in the treatment of hepatocellular carcinoma. Therap Adv Gastroenterol 2021; 14:17562848211016959. [PMID: 34104211 PMCID: PMC8165525 DOI: 10.1177/17562848211016959] [Citation(s) in RCA: 98] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 04/20/2021] [Indexed: 02/06/2023] Open
Abstract
Regorafenib is a diphenylurea oral multikinase inhibitor, structurally comparable to sorafenib, which targets a variety of kinases implicated in angiogenic and tumor growth-promoting pathways. Regorafenib was the first agent to positively show significant survival advantage as a second-line therapy in patients with unresectable hepatocellular carcinoma (HCC) who had previously failed first-line treatment with sorafenib. Recent evidence has shown that its antitumor efficacy is due to a comprehensive spectrum of tumor neo-angiogenesis and proliferation inhibition and immunomodulatory effects on the tumor microenvironment, which plays a crucial role in tumor development. This review addresses the rationale and supporting evidence for regorafenib's efficacy in HCC that led to regorafenib's approval as a second-line therapy. In addition, we review proof from clinical practice studies that validate the RESORCE trial results. We discuss regorafenib's potential role in the newly emerging therapeutic strategy based on combination with immune checkpoint blockade and its possible extensibility to patient categories not enrolled in the registrative study.
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Affiliation(s)
- Alessandro Granito
- Department of Medical and Surgical Sciences, University of Bologna, S. Orsola-Malpighi Hospital, Via Albertoni 15, Bologna, 40138, Italy
- Division of Internal Medicine IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Antonella Forgione
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italia
| | - Sara Marinelli
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Matteo Renzulli
- Radiology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Luca Ielasi
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italia
| | - Vito Sansone
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italia
| | - Francesca Benevento
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italia
| | - Fabio Piscaglia
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italia
| | - Francesco Tovoli
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italia
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Granito A, Marinelli S, Forgione A, Renzulli M, Benevento F, Piscaglia F, Tovoli F. Regorafenib Combined with Other Systemic Therapies: Exploring Promising Therapeutic Combinations in HCC. J Hepatocell Carcinoma 2021; 8:477-492. [PMID: 34079777 PMCID: PMC8165211 DOI: 10.2147/jhc.s251729] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 03/25/2021] [Indexed: 02/05/2023] Open
Abstract
Regorafenib was the first drug to demonstrate a survival benefit as a second-line agent after sorafenib failure in patients with unresectable hepatocellular carcinoma (HCC). Recent studies have shown that its mechanism of action is not only limited to its very broad spectrum of inhibition of angiogenesis, tumor proliferation, spread, and metastasis, but also to its immunomodulatory properties that have favorable effects on the very intricate role that the tumor microenvironment plays in carcinogenesis and tumor growth. In this review, we discuss rationale and evidence supporting regorafenib efficacy in HCC and that led to its approval as a second-line treatment, after sorafenib failure. We also discuss the evidence from clinical practice studies that confirm the results previously achieved in clinical trials. Finally, we analyze the potential role of regorafenib in emerging combined treatment approach with immunotherapy strategies using immune checkpoint blockade and its potential extension to patient categories not included in the registrative study.
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Affiliation(s)
- Alessandro Granito
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Sara Marinelli
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Antonella Forgione
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Matteo Renzulli
- Radiology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Francesca Benevento
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Fabio Piscaglia
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Francesco Tovoli
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
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Cruz Da Silva E, Mercier MC, Etienne-Selloum N, Dontenwill M, Choulier L. A Systematic Review of Glioblastoma-Targeted Therapies in Phases II, III, IV Clinical Trials. Cancers (Basel) 2021; 13:1795. [PMID: 33918704 PMCID: PMC8069979 DOI: 10.3390/cancers13081795] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 03/19/2021] [Accepted: 03/26/2021] [Indexed: 02/07/2023] Open
Abstract
Glioblastoma (GBM), the most frequent and aggressive glial tumor, is currently treated as first line by the Stupp protocol, which combines, after surgery, radiotherapy and chemotherapy. For recurrent GBM, in absence of standard treatment or available clinical trials, various protocols including cytotoxic drugs and/or bevacizumab are currently applied. Despite these heavy treatments, the mean overall survival of patients is under 18 months. Many clinical studies are underway. Based on clinicaltrials.org and conducted up to 1 April 2020, this review lists, not only main, but all targeted therapies in phases II-IV of 257 clinical trials on adults with newly diagnosed or recurrent GBMs for the last twenty years. It does not involve targeted immunotherapies and therapies targeting tumor cell metabolism, that are well documented in other reviews. Without surprise, the most frequently reported drugs are those targeting (i) EGFR (40 clinical trials), and more generally tyrosine kinase receptors (85 clinical trials) and (ii) VEGF/VEGFR (75 clinical trials of which 53 involving bevacizumab). But many other targets and drugs are of interest. They are all listed and thoroughly described, on an one-on-one basis, in four sections related to targeting (i) GBM stem cells and stem cell pathways, (ii) the growth autonomy and migration, (iii) the cell cycle and the escape to cell death, (iv) and angiogenesis.
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Affiliation(s)
- Elisabete Cruz Da Silva
- CNRS, UMR 7021, Laboratoire de Bioimagerie et Pathologies, Faculté de Pharmacie, Université de Strasbourg, 67401 Illkirch, France; (E.C.D.S.); (M.-C.M.); (N.E.-S.); (M.D.)
| | - Marie-Cécile Mercier
- CNRS, UMR 7021, Laboratoire de Bioimagerie et Pathologies, Faculté de Pharmacie, Université de Strasbourg, 67401 Illkirch, France; (E.C.D.S.); (M.-C.M.); (N.E.-S.); (M.D.)
| | - Nelly Etienne-Selloum
- CNRS, UMR 7021, Laboratoire de Bioimagerie et Pathologies, Faculté de Pharmacie, Université de Strasbourg, 67401 Illkirch, France; (E.C.D.S.); (M.-C.M.); (N.E.-S.); (M.D.)
- Service de Pharmacie, Institut de Cancérologie Strasbourg Europe, 67200 Strasbourg, France
| | - Monique Dontenwill
- CNRS, UMR 7021, Laboratoire de Bioimagerie et Pathologies, Faculté de Pharmacie, Université de Strasbourg, 67401 Illkirch, France; (E.C.D.S.); (M.-C.M.); (N.E.-S.); (M.D.)
| | - Laurence Choulier
- CNRS, UMR 7021, Laboratoire de Bioimagerie et Pathologies, Faculté de Pharmacie, Université de Strasbourg, 67401 Illkirch, France; (E.C.D.S.); (M.-C.M.); (N.E.-S.); (M.D.)
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Effect of Synchronous Versus Sequential Regimens on the Pharmacokinetics and Biodistribution of Regorafenib with Irradiation. Pharmaceutics 2021; 13:pharmaceutics13030386. [PMID: 33805831 PMCID: PMC8035703 DOI: 10.3390/pharmaceutics13030386] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 03/10/2021] [Accepted: 03/11/2021] [Indexed: 02/07/2023] Open
Abstract
This study was performed to evaluate the interaction between conventional or high-dose radiotherapy (RT) and the pharmacokinetics (PK) of regorafenib in concurrent or sequential regimens for the treatment of hepatocellular carcinoma. Concurrent and sequential in vitro and in vivo studies of irradiation and regorafenib were designed. The interactions of RT and regorafenib in vitro were examined in the human hepatoma Huh-7, HA22T and Hep G2 cell lines. The RT–PK phenomenon and biodistribution of regorafenib under RT were confirmed in a free-moving rat model. Regorafenib inhibited the viability of Huh-7 cells in a dose-dependent manner. Apoptosis in Huh-7 cells was enhanced by RT followed by regorafenib treatment. In the concurrent regimen, RT decreased the area under the concentration versus time curve (AUC)regorafenib by 74% (p = 0.001) in the RT2 Gy × 3 fraction (f’x) group and by 69% (p = 0.001) in the RT9 Gy × 3 f’x group. The AUCregorafenib was increased by 182.8% (p = 0.011) in the sequential RT2Gy × 1 f’x group and by 213.2% (p = 0.016) in the sequential RT9Gy × 1 f’x group. Both concurrent regimens, RT2Gy × 3 f’x and RT9Gy × 3 f’x, clearly decreased the biodistribution of regorafenib in the heart, liver, lung, spleen and kidneys, compared to the control (regorafenib × 3 d) group. The concurrent regimens, both RT2Gy × 3 f’x and RT9Gy × 3 f’x, significantly decreased the biodistribution of regorafenib, compared with the control group. The PK of regorafenib can be modulated both by off-target irradiation and stereotactic body radiation therapy (SBRT).
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Malik A, Thanekar U, Amarachintha S, Mourya R, Nalluri S, Bondoc A, Shivakumar P. "Complimenting the Complement": Mechanistic Insights and Opportunities for Therapeutics in Hepatocellular Carcinoma. Front Oncol 2021; 10:627701. [PMID: 33718121 PMCID: PMC7943925 DOI: 10.3389/fonc.2020.627701] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 12/22/2020] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and a leading cause of death in the US and worldwide. HCC remains a global health problem and is highly aggressive with unfavorable prognosis. Even with surgical interventions and newer medical treatment regimens, patients with HCC have poor survival rates. These limited therapeutic strategies and mechanistic understandings of HCC immunopathogenesis urgently warrant non-palliative treatment measures. Irrespective of the multitude etiologies, the liver microenvironment in HCC is intricately associated with chronic necroinflammation, progressive fibrosis, and cirrhosis as precedent events along with dysregulated innate and adaptive immune responses. Central to these immunological networks is the complement cascade (CC), a fundamental defense system inherent to the liver which tightly regulates humoral and cellular responses to noxious stimuli. Importantly, the liver is the primary source for biosynthesis of >80% of complement components and expresses a variety of complement receptors. Recent studies implicate the complement system in liver inflammation, abnormal regenerative responses, fibrosis, carcinogenesis, and development of HCC. Although complement activation differentially promotes immunosuppressive, stimulant, and angiogenic microenvironments conducive to HCC development, it remains under-investigated. Here, we review derangement of specific complement proteins in HCC in the context of altered complement regulatory factors, immune-activating components, and their implications in disease pathogenesis. We also summarize how complement molecules regulate cancer stem cells (CSCs), interact with complement-coagulation cascades, and provide therapeutic opportunities for targeted intervention in HCC.
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Affiliation(s)
- Astha Malik
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Unmesha Thanekar
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Surya Amarachintha
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Reena Mourya
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Shreya Nalluri
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Alexander Bondoc
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Pranavkumar Shivakumar
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
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50
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Ngo MHT, Jeng HY, Kuo YC, Nanda JD, Brahmadhi A, Ling TY, Chang TS, Huang YH. The Role of IGF/IGF-1R Signaling in Hepatocellular Carcinomas: Stemness-Related Properties and Drug Resistance. Int J Mol Sci 2021; 22:ijms22041931. [PMID: 33669204 PMCID: PMC7919800 DOI: 10.3390/ijms22041931] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 02/10/2021] [Accepted: 02/10/2021] [Indexed: 12/12/2022] Open
Abstract
Insulin-like Growth Factor (IGF)/IGF-1 Receptor (IGF-1R) signaling is known to regulate stem cell pluripotency and differentiation to trigger cell proliferation, organ development, and tissue regeneration during embryonic development. Unbalanced IGF/IGF-1R signaling can promote cancer cell proliferation and activate cancer reprogramming in tumor tissues, especially in the liver. Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death, with a high incidence and mortality rate in Asia. Most patients with advanced HCC develop tyrosine kinase inhibitor (TKI)-refractoriness after receiving TKI treatment. Dysregulation of IGF/IGF-1R signaling in HCC may activate expression of cancer stemness that leads to TKI refractoriness and tumor recurrence. In this review, we summarize the evidence for dysregulated IGF/IGF-1R signaling especially in hepatitis B virus (HBV)-associated HCC. The regulation of cancer stemness expression and drug resistance will be highlighted. Current clinical treatments and potential therapies targeting IGF/IGF-1R signaling for the treatment of HCC will be discussed.
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Affiliation(s)
- Mai-Huong Thi Ngo
- International PhD Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (M.-H.T.N.); (J.D.N.); (A.B.)
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Han-Yin Jeng
- Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei 11031, Taiwan; (H.-Y.J.); (Y.-C.K.)
| | - Yung-Che Kuo
- Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei 11031, Taiwan; (H.-Y.J.); (Y.-C.K.)
| | - Josephine Diony Nanda
- International PhD Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (M.-H.T.N.); (J.D.N.); (A.B.)
| | - Ageng Brahmadhi
- International PhD Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (M.-H.T.N.); (J.D.N.); (A.B.)
| | - Thai-Yen Ling
- Department and Graduate Institute of Pharmacology, National Taiwan University, Taipei 11031, Taiwan
- Correspondence: (T.-Y.L.); (T.-S.C.); (Y.-H.H.); Tel.: +886-2-2312-3456 (ext. 8-8322) (T.-Y.L.); +886-5-3621-000 (ext. 2242) (T.-S.C.); +886-2-2736-1661 (ext. 3150) (Y.-H.H.)
| | - Te-Sheng Chang
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 33382, Taiwan
- Division of Internal Medicine, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan
- Correspondence: (T.-Y.L.); (T.-S.C.); (Y.-H.H.); Tel.: +886-2-2312-3456 (ext. 8-8322) (T.-Y.L.); +886-5-3621-000 (ext. 2242) (T.-S.C.); +886-2-2736-1661 (ext. 3150) (Y.-H.H.)
| | - Yen-Hua Huang
- International PhD Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (M.-H.T.N.); (J.D.N.); (A.B.)
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei 11031, Taiwan; (H.-Y.J.); (Y.-C.K.)
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Center for Reproductive Medicine, Taipei Medical University Hospital, Taipei 11031, Taiwan
- Comprehensive Cancer Center, Taipei Medical University, Taipei 11031, Taiwan
- Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan
- PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
- Correspondence: (T.-Y.L.); (T.-S.C.); (Y.-H.H.); Tel.: +886-2-2312-3456 (ext. 8-8322) (T.-Y.L.); +886-5-3621-000 (ext. 2242) (T.-S.C.); +886-2-2736-1661 (ext. 3150) (Y.-H.H.)
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