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Zhang XY, Li C, Lin J, Zhou Y, Shi RZ, Wang ZY, Jiang HB, Wang YY. Intestinal obstruction caused by early stage primary ileum adenocarcinoma: A case report and review of literature. World J Gastrointest Oncol 2025; 17:104919. [DOI: 10.4251/wjgo.v17.i4.104919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 02/06/2025] [Accepted: 02/25/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Ileum adenocarcinoma (IA), a type of small bowel adenocarcinoma, is a rather uncommon factor associated with obstruction in small bowel. Owing to its location and indefinite clinical symptoms, the diagnosis of IA is difficult, and survival is usually poor. With respect to the rarity of this disease, very few studies have reported such cases to provide a reference for treatment.
CASE SUMMARY In this manuscript, a case of a 48-year-old man presented with chronic right lower abdominal pain and distention, queasiness and emesis. A computed tomography scan revealed intestinal wall thickening and an intestinal obstruction in the terminal ileum. He was diagnosed with inflammatory bowel disease. However, his symptoms were not relieved after conservative treatment. The patient subsequently underwent exploratory laparotomy, and a tumour in the ileum measuring approximately 2.0 cm × 2.0 cm that was located 20 cm from the ileocolic valve was discovered incidentally and was operatively resected along with the enlarged lymph nodes. Pathological examination revealed a stage IIA (T3N0M0) ulcerative IA. Along with imaging examinations, a diagnosis of primary IA with no lymph or distant metastases was considered. The patient was discharged and recovered well as of the writing of this manuscript.
CONCLUSION IA should be considered as a differential diagnosis in cases of intestinal obstruction, and the recommended method for local disease treatment is surgery.
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Affiliation(s)
- Xiao-Yue Zhang
- Gastrointestinal Disease Center, The First Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Chao Li
- Gastrointestinal Disease Center, The First Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Jie Lin
- Gastrointestinal Disease Center, The First Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Yan Zhou
- Gastrointestinal Disease Center, The First Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Rui-Zhe Shi
- Gastrointestinal Disease Center, The First Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Zhong-Yu Wang
- Gastrointestinal Disease Center, The First Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Hai-Bo Jiang
- Gastrointestinal Disease Center, The First Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Yuan-Yuan Wang
- Gastrointestinal Disease Center, The First Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
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Li J, Zhou X, Wu L, Ma J, Tan Y, Wu S, Zhu J, Wang Q, Shi Q. Optimal early endpoint for second-line or subsequent immune checkpoint inhibitors in previously treated advanced solid cancers: a systematic review. BMC Cancer 2025; 25:293. [PMID: 39966752 PMCID: PMC11837729 DOI: 10.1186/s12885-025-13712-0] [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: 06/01/2024] [Accepted: 02/11/2025] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND The administration of second-line or subsequent immune checkpoint inhibitors (ICIs) in previously treated patients with advanced solid cancers has been clinically investigated. However, previous clinical trials lacked an appropriate primary endpoint for efficacy assessment. This systematic review aimed to explore the most optimal early efficacy endpoint for such trials. METHODS Phase 2 or 3 clinical trials involving patients with advanced solid cancers with disease progression following standard first-line therapy receiving second-line or subsequent ICI administration, with adequate survival outcome data, were included from PubMed, Embase, Web of Science, and Cochrane Library databases before February 2023. Quality assessment was conducted using the Cochrane tool and Newcastle-Ottawa Quality Assessment Scale for Cohort Studies for randomized controlled trials (RCTs) and non-randomized trials, respectively. Objective response rate (ORR) and progression-free survival (PFS) at 3, 6, and 9 months were investigated as potential early efficacy endpoint candidates for 12-month overall survival (OS), with a strong correlation defined as Pearson's correlation coefficient r ≥ 0.8. RESULTS A total of 64 RCTs comprising 22,725 patients and 106 non-randomized prospective trials involving 10,608 participants were eligible for modeling and external validation, respectively. RCTs examined 15 different cancer types, predominantly non-small-cell lung cancer (NSCLC) (17, 28%), melanoma (9, 14%), and esophageal squamous cell carcinoma (5, 8%). The median sample size of RCTs was 124 patients, and the median follow-up time was 3.2-57.7 months. The ORR (r = 0.38; 95% confidence interval [CI], 0.18-0.54) and PFS (r = 0.42; 95% CI, 0.14-0.64) exhibited weak trial-level correlations with OS. Within ICI treatment arms, the r values of ORR and 3-, 6-, and 9-month PFS with 12-month OS were 0.61 (95% CI, 0.37-0.79), 0.78 (95% CI, 0.62-0.88), 0.84 (95% CI, 0.77-0.90), and 0.86 (95% CI, 0.79-0.90), respectively. External validation of 6-month PFS indicated an acceptable discrepancy between actual and predicted 12-month OS. CONCLUSIONS In non-randomized phase 2 trials on second-line or subsequent ICI therapy in patients with advanced solid cancers, 6-month PFS could serve as an early efficacy endpoint. However, early efficacy endpoints are not recommended in RCTs to replace OS.
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Affiliation(s)
- Jingqiu Li
- Department of Radiation Oncology, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, China
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Xiaoding Zhou
- Department of Radiation Oncology, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, China
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Lei Wu
- Department of Radiation Oncology, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, China
| | - Jiabao Ma
- Department of Radiation Oncology, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, China
| | - Yan Tan
- Department of Radiation Oncology, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, China
| | - Songke Wu
- Department of Oncology, People'S Hospital of Cangxi County, Guangyuan, China.
| | - Jie Zhu
- Department of Radiation Oncology, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, China.
| | - Qifeng Wang
- Department of Radiation Oncology, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, China.
| | - Qiuling Shi
- Center for Cancer Prevention Research, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, China
- State Key Laboratory of Ultrasound in Medicine and Engineering, School of Public Health and Management, Chongqing Medical University, Chongqing, China
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Yao Y, Yan Y, Suman VJ, Dietz AB, Erskine CL, Dimou A, Markovic SN, McWilliams RR, Montane HN, Block MS. Phase I study of pembrolizumab in combination with ibrutinib for the treatment of unresectable or metastatic melanoma. Front Immunol 2025; 16:1491448. [PMID: 39967670 PMCID: PMC11832643 DOI: 10.3389/fimmu.2025.1491448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Accepted: 01/13/2025] [Indexed: 02/20/2025] Open
Abstract
Background Immune checkpoint inhibitors (ICIs) have been transformative in the treatment of patients with metastatic melanoma, but primary and secondary resistance to ICI treatment is common. One key mechanism for ICI resistance is the skewing of the immune response from a cytotoxic (Th1) to a chronic inflammatory (Th2) profile. The small molecule ibrutinib is a dual-target agent that inhibits Bruton's Tyrosine Kinase (BTK) and Interleukin-2-inducible T-cell Kinase (ITK), a key regulator of Th2 immunity. Therefore, combining ibrutinib and pembrolizumab could potentially induce an increase in Th1 immune polarity in melanoma patients. We hypothesize that the combination would be well-tolerated and might result in clinical benefit for patients with metastatic melanoma. The primary aim of this phase I study was to evaluate the safety, tolerability, and determine the maximum tolerated dose (MTD) of ibrutinib in combination with pembrolizumab in patients with metastatic melanoma. Methods A 3 + 3 phase I clinical trial was conducted in patients with unresectable Stage III or metastatic melanoma (stage IV) not amenable to local therapy. Pembrolizumab (200 mg/kg every 3 weeks) was combined with ibrutinib, administered orally at the dose assigned at the time of registration (140 mg daily, 280 mg daily, and 420 mg daily). Patients were treated until disease progression, intolerability, or patient decision to discontinue. Blood samples were collected after each cycle of treatment for immunophenotyping and Th1/Th2 polarity assessment based on immune response markers. Results Between January 31, 2017 and January 9, 2023, 17 patients were enrolled. The MTD of ibrutinib in combination with pembrolizumab was determined to be 420 mg daily. The adverse events leading to discontinuation included: grade 4 ALT and AST increase (1 pt, DL0); grade 4 ALT increase with grade 3 AST increase (1 pt, DL1); and grade 3 hyponatremia, hypoxia, and maculo-papular rash (1 pt, DL1). Three of the 16 patients treated had objective responses (2 partial responses, 1 complete response) lasting over 8 months. The median progression-free survival was 3 months, and median and overall survival was 1.8 years. The combination treatment did not result in consistent increase in Th1 immune polarity. Conclusion In conclusion, the maximum tolerated dose of ibrutinib in combination with pembrolizumab in patients with advanced or metastatic melanoma was established at 420 mg by mouth once daily. The combination was well-tolerated but did not result in a consistent increase in Th1 immune polarity; further investigation is needed to assess the relative clinical efficacy of this approach. (Funded by Pharmacyclics; ClinicalTrials.gov number: NCT03021460). Clinical trial registration www.clinicaltrials.gov, identifier NCT03021460.
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Affiliation(s)
- Yuan Yao
- Department of Oncology, Mayo Clinic, Rochester, MN, United States
| | - Yiyi Yan
- Division of Hematology and Oncology, Department of Medicine, Mayo Clinic, Jacksonville, FL, United States
| | - Vera J. Suman
- Department of Health Sciences, Division of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, United States
| | - Allan B. Dietz
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
| | | | - Anastasios Dimou
- Department of Oncology, Mayo Clinic, Rochester, MN, United States
| | - Svetomir N. Markovic
- Department of Oncology, Mayo Clinic, Rochester, MN, United States
- Department of Immunology, Mayo Clinic, Rochester, MN, United States
| | | | | | - Matthew S. Block
- Department of Oncology, Mayo Clinic, Rochester, MN, United States
- Department of Immunology, Mayo Clinic, Rochester, MN, United States
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Smabers LP, Huismans MA, van Nieuwenhuijzen N, Minnema MC, Kranenburg O, Koopman M, Snippert HJG, May AM, Roodhart JML. Efficacy and safety in early-phase clinical trials for refractory colorectal cancer: A meta-analysis. Eur J Cancer 2024; 212:115059. [PMID: 39368225 DOI: 10.1016/j.ejca.2024.115059] [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: 06/05/2024] [Revised: 09/12/2024] [Accepted: 09/22/2024] [Indexed: 10/07/2024]
Abstract
BACKGROUND Despite recent metastatic colorectal cancer (mCRC) therapeutic innovations a comprehensive synthesis of patient outcome and risk-benefit assessment of phase 1/2 trials is missing. The aim of this meta-analysis is to assess efficacy, safety, and trends over time for phase 1 and 2 mCRC trials by examining clinical benefit rate (CBR), overall response rate (ORR), grade 3 or higher adverse events (AE), and discontinuation due to AE. METHODS The PRISMA guidelines were followed. We searched PubMed and Embase for publications of phase 1/2 trials between 2010-2021. Trials reporting on new therapies for treatment-refractory mCRC were included. RESULTS The search strategy yielded 4175 unique reports, of which 258 publications were eligible. These publications report data of 277 unique treatment arms. Overall ORR was 6 %, CBR was 27 % in phase 1 and 36 % in phase 2 trials. CBR increased from 23 % in 2010-2012 to 42 % in 2019-2021. Compared to 2010-2012, trials in 2019-2021 more often tested immunomodulators (4 % vs 23 %), included molecularly preselected populations (4 % vs 38 %) and younger patients (median age<60 44 % vs 66 %). Grade 3 + AE occurred in 35 % of patients, most frequently in trials investigating targeted treatments. CONCLUSIONS Treatment efficacy in phase 1/2 trials is modest but improved from 2010 to 2021. This improvement is accompanied by a shift towards testing in a younger, fitter, and more strictly molecularly preselected population, as well as an increased focus on targeted and immunotherapies.
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Affiliation(s)
- Lidwien P Smabers
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Laboratory of Translational Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Maarten A Huismans
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Oncode Institute, Utrecht, the Netherlands
| | - Niels van Nieuwenhuijzen
- Department of Hematology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Monique C Minnema
- Department of Hematology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Onno Kranenburg
- Laboratory of Translational Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Miriam Koopman
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Hugo J G Snippert
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Oncode Institute, Utrecht, the Netherlands
| | - Anne M May
- Department of Epidemiology, Julius Center for Health Sciences and Primary Care, Utrecht University, Utrecht, the Netherlands
| | - Jeanine M L Roodhart
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
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Gharib E, Robichaud GA. From Crypts to Cancer: A Holistic Perspective on Colorectal Carcinogenesis and Therapeutic Strategies. Int J Mol Sci 2024; 25:9463. [PMID: 39273409 PMCID: PMC11395697 DOI: 10.3390/ijms25179463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 08/19/2024] [Accepted: 08/24/2024] [Indexed: 09/15/2024] Open
Abstract
Colorectal cancer (CRC) represents a significant global health burden, with high incidence and mortality rates worldwide. Recent progress in research highlights the distinct clinical and molecular characteristics of colon versus rectal cancers, underscoring tumor location's importance in treatment approaches. This article provides a comprehensive review of our current understanding of CRC epidemiology, risk factors, molecular pathogenesis, and management strategies. We also present the intricate cellular architecture of colonic crypts and their roles in intestinal homeostasis. Colorectal carcinogenesis multistep processes are also described, covering the conventional adenoma-carcinoma sequence, alternative serrated pathways, and the influential Vogelstein model, which proposes sequential APC, KRAS, and TP53 alterations as drivers. The consensus molecular CRC subtypes (CMS1-CMS4) are examined, shedding light on disease heterogeneity and personalized therapy implications.
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Affiliation(s)
- Ehsan Gharib
- Département de Chimie et Biochimie, Université de Moncton, Moncton, NB E1A 3E9, Canada
- Atlantic Cancer Research Institute, Moncton, NB E1C 8X3, Canada
| | - Gilles A Robichaud
- Département de Chimie et Biochimie, Université de Moncton, Moncton, NB E1A 3E9, Canada
- Atlantic Cancer Research Institute, Moncton, NB E1C 8X3, Canada
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6
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Yu H, Liu Q, Wu K, Tang S. Biomarkers to predict efficacy of immune checkpoint inhibitors in colorectal cancer patients: a systematic review and meta-analysis. Clin Exp Med 2024; 24:143. [PMID: 38960935 PMCID: PMC11222262 DOI: 10.1007/s10238-024-01408-x] [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: 11/01/2023] [Accepted: 06/18/2024] [Indexed: 07/05/2024]
Abstract
Immune checkpoint inhibitors (ICIs) are approved to treat colorectal cancer (CRC) with mismatch-repair gene deficiency, but the response rate remains low. Value of current biomarkers to predict CRC patients' response to ICIs is unclear due to heterogeneous study designs and small sample sizes. Here, we aim to assess and quantify the magnitude of multiple biomarkers for predicting the efficacy of ICIs in CRC patients. We systematically searched MEDLINE, Embase, the Cochrane Library, and Web of Science databases (to June 2023) for clinical studies examining biomarkers for efficacy of ICIs in CRC patients. Random-effect models were performed for meta-analysis. We pooled odds ratio (OR) and hazard ratio (HR) with 95% confidence interval (CI) for biomarkers predicting response rate and survival. 36 studies with 1867 patients were included in systematic review. We found that a lower pre-treatment blood neutrophil-to-lymphocyte ratio (n=4, HR 0.37, 95%CI 0.21-0.67) predicts good prognosis, higher tumor mutation burden (n=10, OR 4.83, 95%CI 2.16-10.78) predicts response to ICIs, and liver metastasis (n=16, OR 0.32, 95%CI 0.16-0.63) indicates resistance to ICIs, especially when combined with VEGFR inhibitors. But the predictive value of tumor PD-L1 expression (n=9, OR 1.01, 95%CI 0.48-2.14) was insignificant in CRC. Blood neutrophil-to-lymphocyte ratio, tumor mutation burden, and liver metastasis, but not tumor PD-L1 expression, function as significant biomarkers to predict efficacy of ICIs in CRC patients. These findings help stratify CRC patients suitable for ICI treatments, improving efficacy of immunotherapy through precise patient management. (PROSPERO, CRD42022346716).
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Affiliation(s)
- Hang Yu
- Cancer Institute, Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, People's Republic of China
| | - Qingquan Liu
- School of Clinical Medicine, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
| | - Keting Wu
- School of Clinical Medicine, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
| | - Shuang Tang
- Cancer Institute, Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, People's Republic of China.
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, 200032, People's Republic of China.
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Yan S, Wang W, Feng Z, Xue J, Liang W, Wu X, Tan Z, Zhang X, Zhang S, Li X, Zhang C. Immune checkpoint inhibitors in colorectal cancer: limitation and challenges. Front Immunol 2024; 15:1403533. [PMID: 38919624 PMCID: PMC11196401 DOI: 10.3389/fimmu.2024.1403533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 05/23/2024] [Indexed: 06/27/2024] Open
Abstract
Colorectal cancer exhibits a notable prevalence and propensity for metastasis, but the current therapeutic interventions for metastatic colorectal cancer have yielded suboptimal results. ICIs can decrease tumor development by preventing the tumor's immune evasion, presenting cancer patients with a new treatment alternative. The increased use of immune checkpoint inhibitors (ICIs) in CRC has brought several issues. In particular, ICIs have demonstrated significant clinical effectiveness in patients with MSI-H CRC, whereas their efficacy is limited in MSS. Acquired resistance can still occur in patients with a positive response to ICIs. This paper describes the efficacy of ICIs currently in the clinical treatment of CRC, discusses the mechanisms by which acquired resistance occurs, primarily related to loss and impaired presentation of tumor antigens, reduced response of IFN-λ and cytokine or metabolic dysregulation, and summarizes the incidence of adverse effects. We posit that the future of ICIs hinges upon the advancement of precise prediction biomarkers and the implementation of combination therapies. This study aims to elucidate the constraints associated with ICIs in CRC and foster targeted problem-solving approaches, thereby enhancing the potential benefits for more patients.
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Affiliation(s)
- Suying Yan
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Wanting Wang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Zhiqiang Feng
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Jun Xue
- Department of General Surgery, The First Affiliated Hospital of Hebei North University, Zhangjiakou, China
| | - Weizheng Liang
- Central Laboratory, The First Affiliated Hospital of Hebei North University, Zhangjiakou, China
| | - Xueliang Wu
- Department of General Surgery, The First Affiliated Hospital of Hebei North University, Zhangjiakou, China
- Institute of Cancer, The First Affiliated Hospital of Hebei North University, Zhangjiakou, China
| | - Zhiquan Tan
- Department of Scientific and Technical Information, Tianjin Union Medical Center, Tianjin, China
| | - Xipeng Zhang
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, China
- The Institute of Translational Medicine, Tianjin Union Medical Center of Nankai University, Tianjin, China
- Tianjin Institute of Coloproctology, Tianjin, China
| | - Shuai Zhang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xichuan Li
- Tianjin Key Laboratory of Animal and Plant Resistance, College of Life Sciences, Tianjin Normal University, Tianjin, China
| | - Chunze Zhang
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, China
- The Institute of Translational Medicine, Tianjin Union Medical Center of Nankai University, Tianjin, China
- Tianjin Institute of Coloproctology, Tianjin, China
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Fares A, Carracedo Uribe C, Martinez D, Rehman T, Silva Rondon C, Sandoval-Sus J. Bruton's Tyrosine Kinase Inhibitors: Recent Updates. Int J Mol Sci 2024; 25:2208. [PMID: 38396884 PMCID: PMC10889086 DOI: 10.3390/ijms25042208] [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: 01/08/2024] [Revised: 02/03/2024] [Accepted: 02/04/2024] [Indexed: 02/25/2024] Open
Abstract
Bruton's tyrosine kinase (BTK) inhibitors have revolutionized the landscape for the treatment of hematological malignancies, solid tumors, and, recently, autoimmune disorders. The BTK receptor is expressed in several hematopoietic cells such as macrophages, neutrophils, mast cells, and osteoclasts. Similarly, the BTK receptor is involved in signaling pathways such as chemokine receptor signaling, Toll-like receptor signaling, and Fc receptor signaling. Due to their unique mechanism, these agents provide a diverse utility in a variety of disease states not limited to the field of malignant hematology and are generally well-tolerated.
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Affiliation(s)
- Amneh Fares
- Memorial Healthcare System, Pembroke Pines, FL 33021, USA; (C.C.U.); (D.M.)
- Moffitt Malignant Hematology at Memorial Healthcare System, Pembroke Pines, FL 33021, USA (J.S.-S.)
| | - Carlos Carracedo Uribe
- Memorial Healthcare System, Pembroke Pines, FL 33021, USA; (C.C.U.); (D.M.)
- Moffitt Malignant Hematology at Memorial Healthcare System, Pembroke Pines, FL 33021, USA (J.S.-S.)
| | - Diana Martinez
- Memorial Healthcare System, Pembroke Pines, FL 33021, USA; (C.C.U.); (D.M.)
- Moffitt Malignant Hematology at Memorial Healthcare System, Pembroke Pines, FL 33021, USA (J.S.-S.)
| | - Tauseef Rehman
- Memorial Healthcare System, Pembroke Pines, FL 33021, USA; (C.C.U.); (D.M.)
- Moffitt Malignant Hematology at Memorial Healthcare System, Pembroke Pines, FL 33021, USA (J.S.-S.)
| | - Carlos Silva Rondon
- Moffitt Malignant Hematology at Memorial Healthcare System, Pembroke Pines, FL 33021, USA (J.S.-S.)
| | - Jose Sandoval-Sus
- Moffitt Malignant Hematology at Memorial Healthcare System, Pembroke Pines, FL 33021, USA (J.S.-S.)
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Kim DW, Kim YC, Kovari BP, Martinez M, Miao R, Yu J, Mehta R, Strosberg J, Imanirad I, Kim RD. Biomarker Analysis from a Phase I/Ib Study of Regorafenib and Nivolumab in Mismatch Repair-Proficient Advanced Refractory Colorectal Cancer. Cancers (Basel) 2024; 16:556. [PMID: 38339307 PMCID: PMC10854756 DOI: 10.3390/cancers16030556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 01/23/2024] [Accepted: 01/24/2024] [Indexed: 02/12/2024] Open
Abstract
Previously, we reported the modest but durable anticancer activity of regorafenib/nivolumab in mismatch repair-proficient (pMMR) refractory colorectal cancer in our I/Ib study. Our finding suggests the necessity of biomarkers for better selection of patients. Baseline clinical and pathological characteristics, blood and tumor samples from the patients in the trial were collected and evaluated to discover potential biomarkers. The obtained samples were assessed for immunohistochemistry, ELISA and RNA sequencing. Their correlations with clinical outcome were analyzed. A high albumin level was significantly associated with improved progression-free survival (PFS), overall survival (OS) and disease control. Non-liver metastatic disease showed prolonged PFS and OS. Low regulatory T-cell (Treg) infiltration correlated with prolonged PFS. Low MIP-1β was associated with durable response and improved OS significantly. Upregulation of 23 genes, including CAPN9, NAPSA and ROS1, was observed in the durable disease control group, and upregulation of 10 genes, including MRPS18A, MAIP1 and CMTR2, was associated with a statistically significant improvement of PFS. This study suggests that pretreatment albumin, MIP-1β, non-liver metastatic disease and Treg infiltration may be potential predictive biomarkers of regorafenib/nivolumab in pMMR colorectal cancer. Further studies are needed to confirm these findings.
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Affiliation(s)
- Dae Won Kim
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA; (D.W.K.); (M.M.); (R.M.); (J.Y.); (R.M.); (J.S.); (I.I.)
| | - Young-Chul Kim
- Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL 33612, USA;
| | - Bence P. Kovari
- Department of Pathology, Moffitt Cancer Center, Tampa, FL 33612, USA;
| | - Maria Martinez
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA; (D.W.K.); (M.M.); (R.M.); (J.Y.); (R.M.); (J.S.); (I.I.)
| | - Ruoyu Miao
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA; (D.W.K.); (M.M.); (R.M.); (J.Y.); (R.M.); (J.S.); (I.I.)
| | - James Yu
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA; (D.W.K.); (M.M.); (R.M.); (J.Y.); (R.M.); (J.S.); (I.I.)
| | - Rutika Mehta
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA; (D.W.K.); (M.M.); (R.M.); (J.Y.); (R.M.); (J.S.); (I.I.)
| | - Jonathan Strosberg
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA; (D.W.K.); (M.M.); (R.M.); (J.Y.); (R.M.); (J.S.); (I.I.)
| | - Iman Imanirad
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA; (D.W.K.); (M.M.); (R.M.); (J.Y.); (R.M.); (J.S.); (I.I.)
| | - Richard D. Kim
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA; (D.W.K.); (M.M.); (R.M.); (J.Y.); (R.M.); (J.S.); (I.I.)
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10
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Das S, Acharya D. Immunological Assessment of Recent Immunotherapy for Colorectal Cancer. Immunol Invest 2023; 52:1065-1095. [PMID: 37812224 DOI: 10.1080/08820139.2023.2264906] [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] [Indexed: 10/10/2023]
Abstract
Colorectal cancer (CRC) is the third most prevalent malignancy with increased incidence and mortality rates worldwide. Traditional treatment approaches have attempted to efficiently target CRC; however, they have failed in most cases, owing to the cytotoxicity and non-specificity of these therapies. Therefore, it is essential to develop an effective alternative therapy to improve the clinical outcomes in heterogeneous CRC cases. Immunotherapy has transformed cancer treatment with remarkable efficacy and overcomes the limitations of traditional treatments. With an understanding of the cancer-immunity cycle and tumor microenvironment evolution, current immunotherapy approaches have elicited enhanced antitumor immune responses. In this comprehensive review, we outline the latest advances in immunotherapy targeting CRC and provide insights into antitumor immune responses reported in landmark clinical studies. We focused on highlighting the combination approaches that synergistically induce immune responses and eliminate immunosuppression. This review aimed to understand the limitations and potential of recent immunotherapy clinical studies conducted in the last five years (2019-2023) and to transform this knowledge into a rational design of clinical trials intended for effective antitumor immune responses in CRC.
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Affiliation(s)
- Subhadeep Das
- Department of Biotechnology, GIET University, Gunupur, India
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11
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Wu Q, Wang Z, Luo Y, Xie X. Efficacy and safety of immune checkpoint inhibitors in Proficient Mismatch Repair (pMMR)/ Non-Microsatellite Instability-High (non-MSI-H) metastatic colorectal cancer: a study based on 39 cohorts incorporating 1723 patients. BMC Immunol 2023; 24:27. [PMID: 37658314 PMCID: PMC10472580 DOI: 10.1186/s12865-023-00564-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 08/23/2023] [Indexed: 09/03/2023] Open
Abstract
PURPOSE This study was designed to investigate the efficacy and safety of immune checkpoint inhibitors (ICIs)-based therapy in proficient mismatch repair (pMMR)/non-microsatellite instability-high (non-MSI-H) metastatic colorectal cancer (mCRC). METHODS Electronic databases were screened to identify relevant trials. The primary endpoints were pooled objective response rate (ORR) and disease control rate (DCR). Stratified analysis was accomplished on ICIs-based regimens, treatment lines and RAS status. RESULTS Totally, 1723 mCRC patients from 39 cohorts were included. The pooled ORR, DCR, 12-month overall survival (OS) rate and 6-month progression-free survival (PFS) rate of ICIs-based therapy in pMMR/non-MSI-H mCRC were 8.5% (95% CI: 4.4%-13.5%), 48.2% (95% CI: 37.8%-58.6%), 52.3% (95% CI: 46.4%-58.1%) and 32.8% (95% CI: 23.5%-42.7%) respectively. As a whole, no significantly differences were shown between ICIs-based and non-ICIs-based therapy for pMMR/non-MSI-H mCRC in terms of both PFS (HR = 1.0, 95% CI: 0.9-1.1, P = 0.91) and OS (HR = 1.0, 95% CI: 0.9-1.2, P = 0.51). It was worth noting that the addition of ICIs to anti-vascular endothelial growth factor (VEGF) agent plus chemotherapy displayed excellent efficacy in pMMR/non-MSI-H mCRC (ORR = 42.4%, 95% CI: 10.0%-78.6%; DCR = 92.0%, 95% CI: 68.3%-100.0%; 12-month OS rate = 71.4%, 95% CI: 50.0%-89.1%; 6-month PFS rate = 55.2%, 95% CI: 24.8%-83.8%; and PFS (compared with non-ICIs-based therapy): HR = 0.9, 95% CI: 0.8-1.0, P = 0.02), especially served as first-line therapy (ORR = 74.2%, 95% CI: 61.4%-85.4%; DCR = 98.7%, 95% CI: 92.0%-100.0%); and without additional treatment related adverse events (TRAEs) were observed. CONCLUSIONS ICIs-based combination therapy, especially the addition of ICIs to first-line anti-VEGF agent plus chemotherapy, is promising in pMMR/non-MSI-H mCRC with good efficacy and controllable toxicity.
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Affiliation(s)
- Qing Wu
- Department of Oncology, Molecular Oncology Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
- Department of Oncology, National Regional Medical Center, Binhai Campus of The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Ziming Wang
- Department of Oncology, Molecular Oncology Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
| | - Yang Luo
- Department of Oncology, Molecular Oncology Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
| | - Xianhe Xie
- Department of Oncology, Molecular Oncology Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China.
- Department of Oncology, National Regional Medical Center, Binhai Campus of The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China.
- Fujian Key Laboratory of Precision Medicine for Cancer, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China.
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12
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To KKW, Cho WC. Drug Repurposing to Circumvent Immune Checkpoint Inhibitor Resistance in Cancer Immunotherapy. Pharmaceutics 2023; 15:2166. [PMID: 37631380 PMCID: PMC10459070 DOI: 10.3390/pharmaceutics15082166] [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: 06/15/2023] [Revised: 08/07/2023] [Accepted: 08/18/2023] [Indexed: 08/27/2023] Open
Abstract
Immune checkpoint inhibitors (ICI) have achieved unprecedented clinical success in cancer treatment. However, drug resistance to ICI therapy is a major hurdle that prevents cancer patients from responding to the treatment or having durable disease control. Drug repurposing refers to the application of clinically approved drugs, with characterized pharmacological properties and known adverse effect profiles, to new indications. It has also emerged as a promising strategy to overcome drug resistance. In this review, we summarized the latest research about drug repurposing to overcome ICI resistance. Repurposed drugs work by either exerting immunostimulatory activities or abolishing the immunosuppressive tumor microenvironment (TME). Compared to the de novo drug design strategy, they provide novel and affordable treatment options to enhance cancer immunotherapy that can be readily evaluated in the clinic. Biomarkers are exploited to identify the right patient population to benefit from the repurposed drugs and drug combinations. Phenotypic screening of chemical libraries has been conducted to search for T-cell-modifying drugs. Genomics and integrated bioinformatics analysis, artificial intelligence, machine and deep learning approaches are employed to identify novel modulators of the immunosuppressive TME.
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Affiliation(s)
- Kenneth K. W. To
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - William C. Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong SAR, China
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13
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Zhan J, Zhang M, Zhou L, He C. Combination of immune checkpoint blockade and targeted gene regulation of angiogenesis for facilitating antitumor immunotherapy. Front Bioeng Biotechnol 2023; 11:1065773. [PMID: 36994358 PMCID: PMC10040836 DOI: 10.3389/fbioe.2023.1065773] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 03/03/2023] [Indexed: 03/18/2023] Open
Abstract
The rapid development of tumor immunotherapy has improved the management of patients with cancer. However, several key problems of tumor immunotherapy, including the insufficient activation of effector T cells, poor tumor invasion, and poor immune killing ability, lead to a low response rate. In the present study, a synergistic strategy was developed by combining in situ tumor vaccines, gene-mediated downregulation of tumor angiogenesis, and anti-PD-L1 therapy. In situ tumor vaccines and antitumor angiogenesis were achieved by codelivering unmethylated cytosine-phosphate-guanine (CpG) and vascular endothelial growth factor (VEGF)-silencing gene (shVEGF) via a hyaluronic acid (HA)-modified HA/PEI/shVEGF/CpG system. Necrotic tumor cells and CpG adjuvants formed in situ tumor vaccines and activated the host immune response. Moreover, VEGF silencing reduced tumor angiogenesis and prompted the homogeneous distribution of tumor blood vessels to facilitate immune cell infiltration. Meanwhile, anti-angiogenesis also improved the immunosuppressive tumor microenvironment. To further improve the specific tumor-killing effect, an anti-PD-L1 antibody was introduced for immune checkpoint blockade, thereby boosting antitumor immune responses. The combination therapy strategy presented in the present study could act in the multiple stages of the tumor immunotherapy cycle, which is expected to offer a new avenue for clinical tumor immunotherapy.
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Affiliation(s)
- Jing Zhan
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
| | - Manli Zhang
- Department of Hepatology and Gastroenterology, The First Hospital of Jilin University, Changchun, China
| | - Lili Zhou
- Department of Radiology, The First Hospital of Jilin University, Changchun, China
| | - Chuan He
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
- *Correspondence: Chuan He,
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14
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Dostálová H, Jorda R, Řezníčková E, Kryštof V. Anticancer effect of zanubrutinib in HER2-positive breast cancer cell lines. Invest New Drugs 2023; 41:210-219. [PMID: 36913160 PMCID: PMC10140101 DOI: 10.1007/s10637-023-01346-7] [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: 01/26/2023] [Accepted: 02/23/2023] [Indexed: 03/14/2023]
Abstract
Small molecule Bruton's tyrosine kinase (BTK) inhibitors have been developed for the treatment of various haemato-oncological diseases, and ibrutinib was approved as the first BTK inhibitor for anticancer therapy in 2013. Previous reports proved the receptor kinase human epidermal growth factor receptor 2 (HER2) to be a valid off-target kinase of ibrutinib and potentially other irreversible BTK inhibitors, as it possesses a druggable cysteine residue in the active site of the enzyme. These findings suggest ibrutinib as a candidate drug for repositioning in HER2-positive breast cancer (BCa). This subtype of breast cancer belongs to one of the most common classes of breast tumours, and its prognosis is characterized by a high rate of recurrence and tumour invasiveness. Based on their similar kinase selectivity profiles, we investigated the anticancer effect of zanubrutinib, evobrutinib, tirabrutinib and acalabrutinib in different BCa cell lines and sought to determine whether it is linked with targeting the epidermal growth factor receptor family (ERBB) pathway. We found that zanubrutinib is a potential inhibitor of the HER2 signalling pathway, displaying an antiproliferative effect in HER2-positive BCa cell lines. Zanubrutinib effectively inhibits the phosphorylation of proteins in the ERBB signalling cascade, including the downstream kinases Akt and ERK, which mediate key signals ensuring the survival and proliferation of cancer cells. We thus propose zanubrutinib as another suitable candidate for repurposing in HER2-amplified solid tumours.
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Affiliation(s)
- Hana Dostálová
- Department of Experimental Biology, Faculty of Science, Palacký University Olomouc, Šlechtitelů 27, 78371, Olomouc, Czech Republic
| | - Radek Jorda
- Department of Experimental Biology, Faculty of Science, Palacký University Olomouc, Šlechtitelů 27, 78371, Olomouc, Czech Republic
| | - Eva Řezníčková
- Department of Experimental Biology, Faculty of Science, Palacký University Olomouc, Šlechtitelů 27, 78371, Olomouc, Czech Republic
| | - Vladimír Kryštof
- Department of Experimental Biology, Faculty of Science, Palacký University Olomouc, Šlechtitelů 27, 78371, Olomouc, Czech Republic.
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University Olomouc, Hněvotínská 5, 77900, Olomouc, Czech Republic.
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15
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Ros J, Balconi F, Baraibar I, Saoudi Gonzalez N, Salva F, Tabernero J, Elez E. Advances in immune checkpoint inhibitor combination strategies for microsatellite stable colorectal cancer. Front Oncol 2023; 13:1112276. [PMID: 36816981 PMCID: PMC9932591 DOI: 10.3389/fonc.2023.1112276] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 01/18/2023] [Indexed: 02/05/2023] Open
Abstract
Immune checkpoint inhibitors have reshaped the prognostic of several tumor types, including metastatic colorectal tumors with microsatellite instability (MSI). However, 90-95% of metastatic colorectal tumors are microsatellite stable (MSS) in which immunotherapy has failed to demonstrate meaningful clinical results. MSS colorectal tumors are considered immune-cold tumors. Several factors have been proposed to account for this lack of response to immune checkpoint blockade including low levels of tumor infiltrating lymphocytes, low tumor mutational burden, a high rate of WNT/β-catenin pathway mutations, and liver metastases which have been associated with immunosuppression. However, studies with novel combinations based on immune checkpoint inhibitors are showing promising activity in MSS colorectal cancer. Here, we review the underlying biological facts that preclude immunotherapy activity, and detail the different immune checkpoint inhibitor combinations evaluated, along with novel immune-based therapies, to overcome innate mechanisms of resistance in MSS colorectal cancer.
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Affiliation(s)
- Javier Ros
- Medical Oncology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain,Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy
| | - Francesca Balconi
- Medical Oncology, University Hospital and University of Cagliari, Cagliari, Italy
| | - Iosune Baraibar
- Medical Oncology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | | | - Francesc Salva
- Medical Oncology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Josep Tabernero
- Medical Oncology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Elena Elez
- Medical Oncology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain,*Correspondence: Elena Elez,
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16
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San-Román-Gil M, Torres-Jiménez J, Pozas J, Esteban-Villarrubia J, Albarrán-Fernández V, Álvarez-Ballesteros P, Chamorro-Pérez J, Rosero-Rodríguez D, Orejana-Martín I, Martínez-Delfrade Í, Reguera-Puertas P, Fuentes-Mateos R, Ferreiro-Monteagudo R. Current Landscape and Potential Challenges of Immune Checkpoint Inhibitors in Microsatellite Stable Metastatic Colorectal Carcinoma. Cancers (Basel) 2023; 15:863. [PMID: 36765821 PMCID: PMC9913409 DOI: 10.3390/cancers15030863] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 01/25/2023] [Accepted: 01/27/2023] [Indexed: 01/31/2023] Open
Abstract
Colorectal cancer (CRC) is the third most frequent cancer and the second most common cause of cancer-related death in Europe. High microsatellite instability (MSI-H) due to a deficient DNA mismatch repair (dMMR) system can be found in 5% of metastatic CRC (mCRC) and has been established as a biomarker of response to immunotherapy in these tumors. Therefore, immune checkpoint inhibitors (ICIs) in mCRC with these characteristics were evaluated with results showing remarkable response rates and durations of response. The majority of mCRC cases have high levels of DNA mismatch repair proteins (pMMR) with consequent microsatellite stability or low instability (MSS or MSI-low), associated with an inherent resistance to ICIs. This review aims to provide a comprehensive analysis of the possible approaches to overcome the mechanisms of resistance and evaluates potential biomarkers to establish the role of ICIs in pMMR/MSS/MSI-L (MSS) mCRC.
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Affiliation(s)
- María San-Román-Gil
- Medical Oncology Department, Ramón y Cajal University Hospital, 28034 Madrid, Spain
| | - Javier Torres-Jiménez
- Medical Oncology Department, Clínico San Carlos University Hospital, 28040 Madrid, Spain
| | - Javier Pozas
- Medical Oncology Department, Ramón y Cajal University Hospital, 28034 Madrid, Spain
| | | | | | | | - Jesús Chamorro-Pérez
- Medical Oncology Department, Ramón y Cajal University Hospital, 28034 Madrid, Spain
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17
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AmeliMojarad M, AmeliMojarad M, Cui X. Prospective role of PD-1/PD-L1 immune checkpoint inhibitors in GI cancer. Pathol Res Pract 2023; 244:154338. [PMID: 36905697 DOI: 10.1016/j.prp.2023.154338] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 01/16/2023] [Accepted: 01/21/2023] [Indexed: 01/24/2023]
Abstract
One of the mechanisms by which tumor cells can evade the immune system is over activation of the programmed cell death protein-1 (PD-1) / programmed death-ligand 1 (PD-L1) pathway. The binding of PD-1 to its ligand PD-L1 can trigger an inhibitory signal for reducing T-cell proliferation, inhibiting the anticancer effect of T cells, and limiting the anti-tumor immunity of effectors T cell responses to protect tissues from immune-mediated tissue damage in the tumor microenvironment (TME). PD-1/PD-L1 immune checkpoint inhibitors have created a new pattern in cancer immunotherapy and can increase T cell- surveillance; therefore, the development of better clinical application of PD-1/PD-L1 inhibitors can significantly enhance antitumor immunity and prolong survival in GI cancer patients.
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Affiliation(s)
- Mandana AmeliMojarad
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, PR China
| | - Melika AmeliMojarad
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, PR China
| | - Xiaonan Cui
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, PR China.
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18
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Lote H, Starling N, Pihlak R, Gerlinger M. Advances in immunotherapy for MMR proficient colorectal cancer. Cancer Treat Rev 2022; 111:102480. [DOI: 10.1016/j.ctrv.2022.102480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 10/23/2022] [Accepted: 10/26/2022] [Indexed: 11/02/2022]
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19
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Tang Q, Chen Y, Li X, Long S, Shi Y, Yu Y, Wu W, Han L, Wang S. The role of PD-1/PD-L1 and application of immune-checkpoint inhibitors in human cancers. Front Immunol 2022; 13:964442. [PMID: 36177034 PMCID: PMC9513184 DOI: 10.3389/fimmu.2022.964442] [Citation(s) in RCA: 227] [Impact Index Per Article: 75.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 08/23/2022] [Indexed: 11/13/2022] Open
Abstract
Programmed cell death protein-1 (PD-1) is a checkpoint receptor expressed on the surface of various immune cells. PD-L1, the natural receptor for PD-1, is mainly expressed in tumor cells. Studies have indicated that PD-1 and PD-L1 are closely associated with the progression of human cancers and are promising biomarkers for cancer therapy. Moreover, the interaction of PD-1 and PD-L1 is one of the important mechanism by which human tumors generate immune escape. This article provides a review on the role of PD-L1/PD-1, mechanisms of immune response and resistance, as well as immune-related adverse events in the treatment of anti-PD-1/PD-L1 immunotherapy in human cancers. Moreover, we summarized a large number of clinical trials to successfully reveal that PD-1/PD-L1 Immune-checkpoint inhibitors have manifested promising therapeutic effects, which have been evaluated from different perspectives, including overall survival, objective effective rate and medium progression-free survival. Finally, we pointed out the current problems faced by PD-1/PD-L1 Immune-checkpoint inhibitors and its future prospects. Although PD-1/PD-L1 immune checkpoint inhibitors have been widely used in the treatment of human cancers, tough challenges still remain. Combination therapy and predictive models based on integrated biomarker determination theory may be the future directions for the application of PD-1/PD-L1 Immune-checkpoint inhibitors in treating human cancers.
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Affiliation(s)
- Qing Tang
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Clinical and Basic Research Team of Traditional Chinese Medicine (TCM) Prevention and Treatment of Non small cell lung cancer (NSCLC), Department of Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yun Chen
- Department of Organ Transplantation, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xiaojuan Li
- Institute of Rehabilitation Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Shunqin Long
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Clinical and Basic Research Team of Traditional Chinese Medicine (TCM) Prevention and Treatment of Non small cell lung cancer (NSCLC), Department of Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yao Shi
- Department of Cerebrovascular Disease, Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yaya Yu
- Department of Oncology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - Wanyin Wu
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Clinical and Basic Research Team of Traditional Chinese Medicine (TCM) Prevention and Treatment of Non small cell lung cancer (NSCLC), Department of Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Wanyin Wu, ; Ling Han, ; Sumei Wang,
| | - Ling Han
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Wanyin Wu, ; Ling Han, ; Sumei Wang,
| | - Sumei Wang
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Clinical and Basic Research Team of Traditional Chinese Medicine (TCM) Prevention and Treatment of Non small cell lung cancer (NSCLC), Department of Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Wanyin Wu, ; Ling Han, ; Sumei Wang,
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Ibrutinib Inhibits Angiogenesis and Tumorigenesis in a BTK-Independent Manner. Pharmaceutics 2022; 14:pharmaceutics14091876. [PMID: 36145624 PMCID: PMC9506105 DOI: 10.3390/pharmaceutics14091876] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 07/31/2022] [Accepted: 09/02/2022] [Indexed: 11/17/2022] Open
Abstract
BTK inhibitor (BTKi) Ibrutinib carries an increased bleeding risk compared to more selective BTKis Acalabrutinib and Zanubrutinib, however, its impact on vascular endothelium remains unknown. In this study, we found that Ibrutinib induced stronger cytotoxic effect on endothelial cells than Zanubrutinib, however, Acalabrutinib cytotoxicity was extremely weak. RNA-seq, followed by KEGG analysis and quantitative RT-PCR validation, was conducted to identify the differential apoptotic target genes of BTKis, leading to their distinct cytotoxic effects on endothelial cells, which showed that Ibrutinib and Zanubrutinib dramatically modulated the expression of critical apoptotic genes, GADD45B, FOS, and BCL2A1, among which FOS and GADD45B were upregulated more significantly by Ibrutinib than Zanubrutinib, however, Acalabrutinib downregulated BCL2A1 moderately and was not able to modulate the expression of FOS and GADD45B. Next, we performed in vitro angiogenesis assays and found that Ibrutinib was more able to induce endothelial dysfunction than Zanubrutinib via stimulating more BMP4 expression, however, Acalabrutinib had no such effect. Especially, the capacity of Ibrutinib to induce endothelial dysfunction can be antagonized by targeting BMP4. Accordingly, Ibrutinib, as an angiogenesis inhibitor, inhibited ovarian and breast cancer progression in vivo. Collectively, our findings addressed a novel molecular basis underlying Ibrutinib-induced endothelial cell dysfunction and suggested the potential application of Ibrutinib to treat angiogenesis-dependent cancers.
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Chen Y, Bai B, Ying K, Pan H, Xie B. Anti-PD-1 combined with targeted therapy: Theory and practice in gastric and colorectal cancer. Biochim Biophys Acta Rev Cancer 2022; 1877:188775. [DOI: 10.1016/j.bbcan.2022.188775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 07/31/2022] [Accepted: 08/01/2022] [Indexed: 10/16/2022]
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22
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Zhang HC, Deng SH, Pi YN, Guo JN, Xi H, Shi X, Yang XF, Zhang BM, Xue WN, Cui BB, Liu YL. Identification and Validation in a Novel Quantification System of Ferroptosis Patterns for the Prediction of Prognosis and Immunotherapy Response in Left- and Right-Sided Colon Cancer. Front Immunol 2022; 13:855849. [PMID: 35444656 PMCID: PMC9014300 DOI: 10.3389/fimmu.2022.855849] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Accepted: 03/07/2022] [Indexed: 12/20/2022] Open
Abstract
Background This study aimed to establish a novel quantification system of ferroptosis patterns and comprehensively analyze the relationship between ferroptosis score (FS) and the immune cell infiltration (ICI) characterization, tumor mutation burden (TMB), prognosis, and therapeutic sensitivity in left-sided and right-sided colon cancers (LCCs and RCCs, respectively). Methods We comprehensively evaluated the ferroptosis patterns in 444 LCCs and RCCs based on 59 ferroptosis-related genes (FRGs). The FS was constructed to quantify ferroptosis patterns by using principal component analysis algorithms. Next, the prognostic value and therapeutic sensitivities were evaluated using multiple methods. Finally, we performed weighted gene co-expression network analysis (WGCNA) to identify the key FRGs. The IMvigor210 cohort, TCGA-COAD proteomics cohort, and Immunophenoscores were used to verify the predictive abilities of FS and the key FRGs. Results Two ferroptosis clusters were determined. Ferroptosis cluster B demonstrated a high degree of congenital ICI and stromal-related signal enrichment with a poor prognosis. The prognosis, response of targeted inhibitors, and immunotherapy were significantly different between high and low FS groups (HSG and LSG, respectively). HSG was characterized by high TMB and microsatellite instability-high subtype with poor prognosis. Meanwhile, LSG was more likely to benefit from immunotherapy. ALOX5 was identified as a key FRG based on FS. Patients with high protein levels of ALOX5 had poorer prognoses. Conclusion This work revealed that the evaluation of ferroptosis subtypes will contribute to gaining insight into the heterogeneity in LCCs and RCCs. The quantification for ferroptosis patterns played a non-negligible role in predicting ICI characterization, prognosis, and individualized immunotherapy strategies.
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Affiliation(s)
- Heng-Chun Zhang
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Shen-Hui Deng
- Department of Anesthesiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Ya-Nan Pi
- Department of Gynecology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Jun-Nan Guo
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Hua Xi
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xin Shi
- Department of Rehabilitation Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xue-Fei Yang
- The First Department of Oncology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Bo-Miao Zhang
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Wei-Nan Xue
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Bin-Bin Cui
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yan-Long Liu
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
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23
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Szklener K, Michalski A, Żak K, Piwoński M, Mańdziuk S. Ibrutinib in the Treatment of Solid Tumors: Current State of Knowledge and Future Directions. Cells 2022; 11:1338. [PMID: 35456016 PMCID: PMC9032968 DOI: 10.3390/cells11081338] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 04/10/2022] [Accepted: 04/12/2022] [Indexed: 12/24/2022] Open
Abstract
Bruton's Tyrosine Kinase (BTK) is considered crucial in the activation and survival of both physiological and malignant B-cells. In recent years, ibrutinib, an oral BTK inhibitor, became a breakthrough therapy for hematological malignancies, such as chronic lymphocytic. However, ibrutinib's feasibility might not end there. Several other kinases with established involvement with solid malignancies (i.e., EGFR, HER2) have been found to be inhibited by this agent. Recent discoveries indicate that BTK is a potential anti-solid tumor therapy target. Consequently, ibrutinib, a BTK-inhibitor, has been studied as a therapeutic option in solid malignancies. While most preclinical studies indicate ibrutinib to be an effective therapeutic option in some specific indications, such as NSCLC and breast cancer, clinical trials contradict these observations. Nevertheless, while ibrutinib failed as a monotherapy, it might become an interesting part of a multidrug regime: not only has a synergism between ibrutinib and other compounds, such as trametinib or dactolisib, been observed in vitro, but this BTK inhibitor has also been established as a radio- and chemosensitizer. This review aims to describe the milestones in translating BTK inhibitors to solid tumors in order to understand the future potential of this agent better.
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Affiliation(s)
- Katarzyna Szklener
- Department of Clinical Oncology and Chemotherapy, Medical University of Lublin, 20-090 Lublin, Poland; (A.M.); (K.Ż.); (M.P.); (S.M.)
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24
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Boukouris AE, Theochari M, Stefanou D, Papalambros A, Felekouras E, Gogas H, Ziogas DC. Latest evidence on immune checkpoint inhibitors in metastatic colorectal cancer: A 2022 update. Crit Rev Oncol Hematol 2022; 173:103663. [PMID: 35351582 DOI: 10.1016/j.critrevonc.2022.103663] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 03/21/2022] [Accepted: 03/22/2022] [Indexed: 02/07/2023] Open
Abstract
The long-term remissions induced by immune-checkpoint inhibitors (ICIs) in many types of cancers have opened up the possibility of a broader use of immunotherapy in less immunogenic but genetically heterogeneous tumours. Regarding metastatic colorectal cancer (mCRC), in first-line setting, pembrolizumab has been approved as preferred option and nivolumab, alone or in combination with ipilimumab as alternative option for patients with mismatch-repair-deficient and microsatellite instability-high (dMMR/MSI-H) disease, independently of their eligibility for intensive chemotherapy. In subsequent lines, both these immunotherapeutic regimens (e.g., pembrolizumab and nivolumab+/-ipilimumab) as well as dostarlimab-gxly are currently recommended for patients with dMMR/MSI-H chemo-resistant mCRC who have not previously received an ICI. Beginning from the rationale behind the immune-mediated interplay in the dMMR/MSI-H bowel microenvironment, we provide here an update on the evolution status of all available, approved or not, ICIs in mCRC, describing their efficacy and toxicity profile with an emphasis on the pivotal trials supporting current colorectal indications. For each ICI agent, the results from combinations under investigation, particularly for those being upgraded in clinical phasing, the perspectives but also the limitations of main ongoing trials are thoroughly discussed. In the close future, upcoming data are expected to confirm the clinical benefit of ICIs and to further expand their role in mCRC.
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Affiliation(s)
- Aristeidis E Boukouris
- First Department of Internal Medicine, Korgialeneion-Benakeion General Hospital, Athens, Greece.
| | - Maria Theochari
- First Department of Medicine, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece.
| | - Dimitra Stefanou
- First Department of Medicine, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece.
| | - Alexandros Papalambros
- First Department of Surgery, Laikon General Hospital, School of Medicine, National Kapodistrian University of Athens, Athens, Greece.
| | - Evangelos Felekouras
- First Department of Surgery, Laikon General Hospital, School of Medicine, National Kapodistrian University of Athens, Athens, Greece.
| | - Helen Gogas
- First Department of Medicine, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece.
| | - Dimitrios C Ziogas
- First Department of Medicine, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece.
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25
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Zhu S, Jung J, Victor E, Arceo J, Gokhale S, Xie P. Clinical Trials of the BTK Inhibitors Ibrutinib and Acalabrutinib in Human Diseases Beyond B Cell Malignancies. Front Oncol 2021; 11:737943. [PMID: 34778053 PMCID: PMC8585514 DOI: 10.3389/fonc.2021.737943] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 10/11/2021] [Indexed: 12/13/2022] Open
Abstract
The BTK inhibitors ibrutinib and acalabrutinib are FDA-approved drugs for the treatment of B cell malignances. Both drugs have demonstrated clinical efficacy and safety profiles superior to chemoimmunotherapy regimens in patients with chronic lymphocytic leukemia. Mounting preclinical and clinical evidence indicates that both ibrutinib and acalabrutinib are versatile and have direct effects on many immune cell subsets as well as other cell types beyond B cells. The versatility and immunomodulatory effects of both drugs have been exploited to expand their therapeutic potential in a wide variety of human diseases. Over 470 clinical trials are currently registered at ClinicalTrials.gov to test the efficacy of ibrutinib or acalabrutinib not only in almost every type of B cell malignancies, but also in hematological malignancies of myeloid cells and T cells, solid tumors, chronic graft versus host disease (cGHVD), autoimmune diseases, allergy and COVID-19 (http:www.clinicaltrials.gov). In this review, we present brief discussions of the clinical trials and relevant key preclinical evidence of ibrutinib and acalabrutinib as monotherapies or as part of combination therapies for the treatment of human diseases beyond B cell malignancies. Adding to the proven efficacy of ibrutinib for cGVHD, preliminary results of clinical trials have shown promising efficacy of ibrutinib or acalabrutinib for certain T cell malignancies, allergies and severe COVID-19. However, both BTK inhibitors have no or limited efficacy for refractory or recurrent solid tumors. These clinical data together with additional pending results from ongoing trials will provide valuable information to guide the design and improvement of future trials, including optimization of combination regimens and dosing sequences as well as better patient stratification and more efficient delivery strategies. Such information will further advance the precise implementation of BTK inhibitors into the clinical toolbox for the treatment of different human diseases.
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Affiliation(s)
- Sining Zhu
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United States.,Graduate Program in Cellular and Molecular Pharmacology, Rutgers University, Piscataway, NJ, United States
| | - Jaeyong Jung
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United States.,Graduate Program in Cellular and Molecular Pharmacology, Rutgers University, Piscataway, NJ, United States
| | - Eton Victor
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United States
| | - Johann Arceo
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United States
| | - Samantha Gokhale
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United States.,Graduate Program in Cellular and Molecular Pharmacology, Rutgers University, Piscataway, NJ, United States
| | - Ping Xie
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United States.,Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, United States
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