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Li LB, Yang LX, Liu L, Liu FR, Li AH, Zhu YL, Wen H, Xue X, Tian ZX, Sun H, Li PC, Zhao XG. Targeted inhibition of the HNF1A/SHH axis by triptolide overcomes paclitaxel resistance in non-small cell lung cancer. Acta Pharmacol Sin 2024; 45:1060-1076. [PMID: 38228910 PMCID: PMC11053095 DOI: 10.1038/s41401-023-01219-y] [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: 07/17/2023] [Accepted: 12/17/2023] [Indexed: 01/18/2024]
Abstract
Paclitaxel resistance is associated with a poor prognosis in non-small cell lung cancer (NSCLC) patients, and currently, there is no promising drug for paclitaxel resistance. In this study, we investigated the molecular mechanisms underlying the chemoresistance in human NSCLC-derived cell lines. We constructed paclitaxel-resistant NSCLC cell lines (A549/PR and H460/PR) by long-term exposure to paclitaxel. We found that triptolide, a diterpenoid epoxide isolated from the Chinese medicinal herb Tripterygium wilfordii Hook F, effectively enhanced the sensitivity of paclitaxel-resistant cells to paclitaxel by reducing ABCB1 expression in vivo and in vitro. Through high-throughput sequencing, we identified the SHH-initiated Hedgehog signaling pathway playing an important role in this process. We demonstrated that triptolide directly bound to HNF1A, one of the transcription factors of SHH, and inhibited HNF1A/SHH expression, ensuing in attenuation of Hedgehog signaling. In NSCLC tumor tissue microarrays and cancer network databases, we found a positive correlation between HNF1A and SHH expression. Our results illuminate a novel molecular mechanism through which triptolide targets and inhibits HNF1A, thereby impeding the activation of the Hedgehog signaling pathway and reducing the expression of ABCB1. This study suggests the potential clinical application of triptolide and provides promising prospects in targeting the HNF1A/SHH pathway as a therapeutic strategy for NSCLC patients with paclitaxel resistance. Schematic diagram showing that triptolide overcomes paclitaxel resistance by mediating inhibition of the HNF1A/SHH/ABCB1 axis.
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Affiliation(s)
- Ling-Bing Li
- Department of Thoracic Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Ji-nan, 250012, China
| | - Ling-Xiao Yang
- Department of Thoracic Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Ji-nan, 250012, China
| | - Lei Liu
- Department of Thoracic Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Ji-nan, 250012, China
| | - Fan-Rong Liu
- Department of Thoracic Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Ji-nan, 250012, China
| | - Alex H Li
- Division of Environmental Medicine, Department of Medicine, New York University Grossman School of Medicine, New York, NY, 10010, USA
| | - Yi-Lin Zhu
- Department of Thoracic Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Ji-nan, 250012, China
| | - Hao Wen
- Department of Thoracic Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Ji-nan, 250012, China
| | - Xia Xue
- Department of Pharmacy, The Second Hospital, Cheeloo College of Medicine, Shandong University, Ji-nan, 250012, China
| | - Zhong-Xian Tian
- Department of Thoracic Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Ji-nan, 250012, China
- Key Laboratory of Chest Cancer, The Second Hospital, Cheeloo College of Medicine, Shandong University, Ji-nan, 250012, China
| | - Hong Sun
- Division of Environmental Medicine, Department of Medicine, New York University Grossman School of Medicine, New York, NY, 10010, USA
| | - Pei-Chao Li
- Department of Thoracic Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Ji-nan, 250012, China.
- Key Laboratory of Chest Cancer, The Second Hospital, Cheeloo College of Medicine, Shandong University, Ji-nan, 250012, China.
| | - Xiao-Gang Zhao
- Department of Thoracic Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Ji-nan, 250012, China.
- Key Laboratory of Chest Cancer, The Second Hospital, Cheeloo College of Medicine, Shandong University, Ji-nan, 250012, China.
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Araujo RLC, Carvalho CGCY, Maeda CT, Milani JM, Bugano DG, de Moraes PHZ, Linhares MM. Oncologic aspects of the decision-making process for surgical approach for colorectal liver metastases progressing during chemotherapy. World J Gastrointest Surg 2022; 14:877-886. [PMID: 36185562 PMCID: PMC9521463 DOI: 10.4240/wjgs.v14.i9.877] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 07/27/2022] [Accepted: 08/18/2022] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer represents the third most diagnosed malignancy in the world. The liver is the main site of metastatic disease, affected in 30% of patients with newly diagnosed disease. Complete resection is considered the only potentially curative treatment for colorectal liver metastasis (CRLM), with a 5-year survival rate ranging from 35% to 58%. However, up to 80% of patients have initially unresectable disease, due to extrahepatic disease or bilobar multiple liver nodules. The availability of increasingly effective systemic chemotherapy has contributed to converting patients with initially unresectable liver metastases to resectable disease, improving long-term outcomes, and accessing tumor biology. In recent years, response to preoperative systemic chemotherapy before liver resection has been established as a major prognostic factor. Some studies have demonstrated that patients with regression of hepatic metastases while on chemotherapy have improved outcomes when compared to patients with stabilization or progression of the disease. Even if disease progression during chemotherapy represents an independent negative prognostic factor, some patients may still benefit from surgery, given the role of this modality as the main treatment with curative intent for patients with CRLM. In selected cases, based on size, the number of lesions, and tumor markers, surgery may be offered despite the less favorable prognosis and as an option for non-chemo responders.
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Affiliation(s)
- Raphael L C Araujo
- Department of Surgery, Universidade Federal de São Paulo, São Paulo 04024-002, Brazil
- Department of Oncology, Hospital Israelita Albert Einstein, São Paulo 05652-900, Brazil
- Department of Surgical Oncology, Hospital e Maternidade Brasil Rede D'Or São Luiz, Santo André 09030-590, São Paulo, Brazil
| | - Camila G C Y Carvalho
- Department of Surgical Oncology, Hospital e Maternidade Brasil Rede D'Or São Luiz, Santo André 09030-590, São Paulo, Brazil
| | - Carlos T Maeda
- Department of Surgery, Universidade Federal de São Paulo, São Paulo 04024-002, Brazil
| | - Jean Michel Milani
- Department of Surgery, Universidade Federal de São Paulo, São Paulo 04024-002, Brazil
| | - Diogo G Bugano
- Department of Oncology, Hospital Israelita Albert Einstein, São Paulo 05652-900, Brazil
| | | | - Marcelo M Linhares
- Department of Surgery, Universidade Federal de São Paulo, São Paulo 04024-002, Brazil
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De Raffele E, Mirarchi M, Cuicchi D, Lecce F, Casadei R, Ricci C, Selva S, Minni F. Simultaneous colorectal and parenchymal-sparing liver resection for advanced colorectal carcinoma with synchronous liver metastases: Between conventional and mini-invasive approaches. World J Gastroenterol 2020; 26:6529-6555. [PMID: 33268945 PMCID: PMC7673966 DOI: 10.3748/wjg.v26.i42.6529] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Revised: 10/05/2020] [Accepted: 10/26/2020] [Indexed: 02/06/2023] Open
Abstract
The optimal timing of surgery in case of synchronous presentation of colorectal cancer and liver metastases is still under debate. Staged approach, with initial colorectal resection followed by liver resection (LR), or even the reverse, liver-first approach in specific situations, is traditionally preferred. Simultaneous resections, however, represent an appealing strategy, because may have perioperative risks comparable to staged resections in appropriately selected patients, while avoiding a second surgical procedure. In patients with larger or multiple synchronous presentation of colorectal cancer and liver metastases, simultaneous major hepatectomies may determine worse perioperative outcomes, so that parenchymal-sparing LR should represent the most appropriate option whenever feasible. Mini-invasive colorectal surgery has experienced rapid spread in the last decades, while laparoscopic LR has progressed much slower, and is usually reserved for limited tumours in favourable locations. Moreover, mini-invasive parenchymal-sparing LR is more complex, especially for larger or multiple tumours in difficult locations. It remains to be established if simultaneous resections are presently feasible with mini-invasive approaches or if we need further technological advances and surgical expertise, at least for more complex procedures. This review aims to critically analyze the current status and future perspectives of simultaneous resections, and the present role of the available mini-invasive techniques.
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Affiliation(s)
- Emilio De Raffele
- Division of Pancreatic Surgery, Department of Digestive Diseases, Azienda Ospedaliero-Universitaria di Bologna, Policlinico S.Orsola-Malpighi, 40138 Bologna, Italy
| | - Mariateresa Mirarchi
- Dipartimento Strutturale Chirurgico, Ospedale SS Antonio e Margherita, 15057 Tortona (AL), Italy
| | - Dajana Cuicchi
- Surgery of the Alimentary Tract, Department of Digestive Diseases, Azienda Ospedaliero-Universitaria di Bologna, Policlinico S.Orsola-Malpighi, 40138 Bologna, Italy
| | - Ferdinando Lecce
- Surgery of the Alimentary Tract, Department of Digestive Diseases, Azienda Ospedaliero-Universitaria di Bologna, Policlinico S.Orsola-Malpighi, 40138 Bologna, Italy
| | - Riccardo Casadei
- Division of Pancreatic Surgery, Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum, University of Bologna, 40138 Bologna, Italy
| | - Claudio Ricci
- Division of Pancreatic Surgery, Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum, University of Bologna, 40138 Bologna, Italy
| | - Saverio Selva
- Division of Pancreatic Surgery, Department of Digestive Diseases, Azienda Ospedaliero-Universitaria di Bologna, Policlinico S.Orsola-Malpighi, 40138 Bologna, Italy
| | - Francesco Minni
- Division of Pancreatic Surgery, Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum, University of Bologna, 40138 Bologna, Italy
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Pugh SA, Bridgewater JA, Primrose JN. Hepatic metastases resection after cetuximab: are we missing something? - Authors' reply. Lancet Oncol 2020; 21:e229. [PMID: 32359494 DOI: 10.1016/s1470-2045(20)30239-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Affiliation(s)
| | | | - John N Primrose
- Department of Surgery, University of Southampton, Southampton SO16 6YD, UK.
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Bridgewater JA, Pugh SA, Maishman T, Eminton Z, Mellor J, Whitehead A, Stanton L, Radford M, Corkhill A, Griffiths GO, Falk S, Valle JW, O'Reilly D, Siriwardena AK, Hornbuckle J, Rees M, Iveson TJ, Hickish T, Garden OJ, Cunningham D, Maughan TS, Primrose JN. Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis (New EPOC): long-term results of a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol 2020; 21:398-411. [PMID: 32014119 PMCID: PMC7052737 DOI: 10.1016/s1470-2045(19)30798-3] [Citation(s) in RCA: 144] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 11/06/2019] [Accepted: 11/14/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND The interim analysis of the multicentre New EPOC trial in patients with resectable colorectal liver metastasis showed a significant reduction in progression-free survival in patients allocated to cetuximab plus chemotherapy compared with those given chemotherapy alone. The focus of the present analysis was to assess the effect on overall survival. METHODS New EPOC was a multicentre, open-label, randomised, controlled, phase 3 trial. Adult patients (aged ≥18 years) with KRAS wild-type (codons 12, 13, and 61) resectable or suboptimally resectable colorectal liver metastases and a WHO performance status of 0-2 were randomly assigned (1:1) to receive chemotherapy with or without cetuximab before and after liver resection. Randomisation was done centrally with minimisation factors of surgical centre, poor prognosis cancer, and previous adjuvant treatment with oxaliplatin. Chemotherapy consisted of oxaliplatin 85 mg/m2 administered intravenously over 2 h, l-folinic acid (175 mg flat dose administered intravenously over 2 h) or d,l-folinic acid (350 mg flat dose administered intravenously over 2 h), and fluorouracil bolus 400 mg/m2 administered intravenously over 5 min, followed by a 46 h infusion of fluorouracil 2400 mg/m2 repeated every 2 weeks (regimen one), or oxaliplatin 130 mg/m2 administered intravenously over 2 h and oral capecitabine 1000 mg/m2 twice daily on days 1-14 repeated every 3 weeks (regimen two). Patients who had received adjuvant oxaliplatin could receive irinotecan 180 mg/m2 intravenously over 30 min with fluorouracil instead of oxaliplatin (regimen three). Cetuximab was given intravenously, 500 mg/m2 every 2 weeks with regimen one and three or a loading dose of 400 mg/m2 followed by a weekly infusion of 250 mg/m2 with regimen two. The primary endpoint of progression-free survival was published previously. Secondary endpoints were overall survival, preoperative response, pathological resection status, and safety. Trial recruitment was halted prematurely on the advice of the Trial Steering Committee on Nov 1, 2012. All analyses (except safety) were done on the intention-to-treat population. Safety analyses included all randomly assigned patients. This trial is registered with ISRCTN, number 22944367. FINDINGS Between Feb 26, 2007, and Oct 12, 2012, 257 eligible patients were randomly assigned to chemotherapy with cetuximab (n=129) or without cetuximab (n=128). This analysis was carried out 5 years after the last patient was recruited, as defined in the protocol, at a median follow-up of 66·7 months (IQR 58·0-77·5). Median progression-free survival was 22·2 months (95% CI 18·3-26·8) in the chemotherapy alone group and 15·5 months (13·8-19·0) in the chemotherapy plus cetuximab group (hazard ratio [HR] 1·17, 95% CI 0·87-1·56; p=0·304). Median overall survival was 81·0 months (59·6 to not reached) in the chemotherapy alone group and 55·4 months (43·5-71·5) in the chemotherapy plus cetuximab group (HR 1·45, 1·02-2·05; p=0·036). There was no significant difference in the secondary outcomes of preoperative response or pathological resection status between groups. Five deaths might have been treatment-related (one in the chemotherapy alone group and four in the chemotherapy plus cetuximab group). The most common grade 3-4 adverse events reported were: neutrophil count decreased (26 [19%] of 134 in the chemotherapy alone group vs 21 [15%] of 137 in the chemotherapy plus cetuximab group), diarrhoea (13 [10%] vs 14 [10%]), skin rash (one [1%] vs 22 [16%]), thromboembolic events (ten [7%] vs 11 [8%]), lethargy (ten [7%] vs nine [7%]), oral mucositis (three [2%] vs 14 [10%]), vomiting (seven [5%] vs seven [5%]), peripheral neuropathy (eight [6%] vs five [4%]), and pain (six [4%] vs six [4%]). INTERPRETATION Although the addition of cetuximab to chemotherapy improves the overall survival in some studies in patients with advanced, inoperable metastatic disease, its use in the perioperative setting in patients with operable disease confers a significant disadvantage in terms of overall survival. Cetuximab should not be used in this setting. FUNDING Cancer Research UK.
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Affiliation(s)
| | | | - Tom Maishman
- Southampton Clinical Trials Unit, University of Southampton, Southampton, UK
| | - Zina Eminton
- Southampton Clinical Trials Unit, University of Southampton, Southampton, UK
| | - Jane Mellor
- Southampton Clinical Trials Unit, University of Southampton, Southampton, UK
| | - Amy Whitehead
- Southampton Clinical Trials Unit, University of Southampton, Southampton, UK
| | - Louise Stanton
- Southampton Clinical Trials Unit, University of Southampton, Southampton, UK
| | - Michael Radford
- Southampton Clinical Trials Unit, University of Southampton, Southampton, UK
| | - Andrea Corkhill
- Southampton Clinical Trials Unit, University of Southampton, Southampton, UK
| | - Gareth O Griffiths
- Southampton Clinical Trials Unit, University of Southampton, Southampton, UK
| | | | - Juan W Valle
- Division of Cancer Sciences/The Christie NHS Foundation Trust, University of Manchester, Manchester, UK
| | | | | | | | - Myrddin Rees
- Basingstoke and North Hampshire Hospital, Basingstoke, UK
| | - Timothy J Iveson
- University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Tamas Hickish
- Dorset Cancer Centre/Bournemouth University, Bournemouth, UK
| | | | | | - Timothy S Maughan
- MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK
| | - John N Primrose
- Department of Surgery, University of Southampton, Southampton, UK.
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BrintzenhofeSzoc K, Krok-Schoen JL, Canin B, Parker I, MacKenzie AR, Koll T, Vankina R, Hsu CD, Jang B, Pan K, Lund JL, Starbuck E, Shahrokni A. The underreporting of phase III chemo-therapeutic clinical trial data of older patients with cancer: A systematic review. J Geriatr Oncol 2020; 11:369-379. [PMID: 31932259 DOI: 10.1016/j.jgo.2019.12.007] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 11/25/2019] [Accepted: 12/16/2019] [Indexed: 12/23/2022]
Abstract
PURPOSE Inspired by the American Society of Clinical Oncology's recommendations to strengthen the evidence base for older adults with cancer, the purpose of this systematic review is to identify the reporting of treatment efficacy and adverse events specific to older adults with cancer in Phase III chemo-therapeutic clinical trials. This review also investigates the frequency with which these data points were reported in the literature to identify gaps in reporting and opportunities to expand the knowledge base on clinical outcomes for older adults with cancer. METHODS Chemo-therapeutic clinical trial data published from July 1, 2016 to June 30, 2017 was reviewed. Manuscripts (n = 929) were identified based on keyword searches of EMBASE and PubMed. After removal of duplicates (n = 116) and articles that did not meet this study's inclusion criteria (n = 654), 159 articles were identified for review. RESULTS Reviewed papers were published in 36 different scientific journals and included twenty-five different cancer types. Of the 159 articles, 117 (73.6%) reported age-specific medians and 75 (47.2%) included stratifications of data by age. Treatment efficacy was reported in 96.2% of the articles with 39.9% reporting effectiveness of treatment by age. Reporting of adverse events was included in 84.9% of the articles with only 8.9% reporting these events stratified by age. CONCLUSION Results suggest inadequate reporting of treatment efficacy and adverse events as well as basic descriptive statistics about the age distribution of study subjects. Conscious efforts are needed to address these deficiencies at every level of planning and conducting clinical trials as wells as reporting outcomes stratified by age. Ultimately, standardized reporting could lead to improved treatment decisions and outcomes for older adults with cancer.
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Affiliation(s)
| | | | | | | | | | - Thuy Koll
- Department of Internal Medicine, University of Nebraska Medical Center, USA
| | | | | | - Brian Jang
- Tulane University School of Medicine, USA
| | | | | | - Edith Starbuck
- University of Cincinnati Libraries, University of Cincinnati, USA
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Haraldsdottir S, Goldberg RM. Conversion Therapy for Initially Borderline/Unresectable Metastases in Colon Cancer: What Is the Best Neoadjuvant Chemotherapy? CURRENT COLORECTAL CANCER REPORTS 2017. [DOI: 10.1007/s11888-017-0393-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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