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Yu R, Ji X, Zhang P, Zhang H, Qu H, Dong W. The potential of chimeric antigen receptor -T cell therapy for endocrine cancer. World J Surg Oncol 2025; 23:153. [PMID: 40264184 PMCID: PMC12012980 DOI: 10.1186/s12957-025-03745-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Accepted: 03/07/2025] [Indexed: 04/24/2025] Open
Abstract
Endocrine cancer, a relatively rare and heterogeneous tumor with diverse clinical features. The facile synthesis of hormones further complicates endocrine cancer treatment. Thus, the development of safe and effective systemic treatment approaches, such as chimeric antigen receptor (CAR) T cell therapy, is imperative to enhance the prognosis of patients with endocrine cancer. Although this therapy has achieved good results in the treatment of hematological malignancies, it encounters diverse complications and challenges in the context of endocrine cancer. This review delineates the generation of CAR-T cells, examines the potential of CAR-T cell therapy for endocrine cancer, enumerates pivotal antigens linked to endocrine cancer, encapsulates the challenges confronted with CAR-T cell therapy for endocrine cancer, and expounds upon strategies to overcome these limitations. The primary objective is to provide insightful perspectives that can contribute to the advancement of CAR-T cell therapy in the field of endocrine cancer.
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Affiliation(s)
- Ruonan Yu
- Department of Thyroid Surgery, The First Hospital of China Medical University, No. 155 Nanjing North Street, Shenyang, Liaoning, 110001, China
| | - Xiaoyu Ji
- Department of Thyroid Surgery, The First Hospital of China Medical University, No. 155 Nanjing North Street, Shenyang, Liaoning, 110001, China
| | - Ping Zhang
- Department of Thyroid Surgery, The First Hospital of China Medical University, No. 155 Nanjing North Street, Shenyang, Liaoning, 110001, China
| | - Hao Zhang
- Department of Thyroid Surgery, The First Hospital of China Medical University, No. 155 Nanjing North Street, Shenyang, Liaoning, 110001, China
| | - Huiling Qu
- Department of Neurology, The General Hospital of Northern Theater Command, 83 Wen Hua Road, Shenyang, Liaoning, 110840, China.
| | - Wenwu Dong
- Department of Thyroid Surgery, The First Hospital of China Medical University, No. 155 Nanjing North Street, Shenyang, Liaoning, 110001, China.
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Netto D, Frizziero M, Foy V, McNamara MG, Backen A, Hubner RA. Systemic Therapy for Metastatic Pancreatic Cancer-Current Landscape and Future Directions. Curr Oncol 2024; 31:5206-5223. [PMID: 39330013 PMCID: PMC11430697 DOI: 10.3390/curroncol31090385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 08/22/2024] [Accepted: 08/25/2024] [Indexed: 09/28/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a significant cause of cancer-associated mortality, with a rising global incidence. A paucity of strong predictive risk factors mean screening programmes are difficult to implement. Historically, a lack of identifiable and actionable driver mutations, coupled with a relatively immunosuppressed tumour microenvironment, has led to a reliance on cytotoxic chemotherapy. The NAPOLI-3 trial has reported data supporting consideration of NALIRIFOX as a new first-line standard of care. Kirsten Rat Sarcoma Virus (KRAS) G12D mutations are present in >90% of all PDAC's; exciting breakthroughs in small molecule inhibitors targeting KRAS G12D may open new modalities of treatment, and therapies targeting multiple KRAS mutations are also in early clinical trials. Although immunotherapy strategies to date have been disappointing, combination with chemotherapy and/or small molecule inhibitors hold promise and warrant further exploration.
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Affiliation(s)
- Daniel Netto
- The Christie NHS Foundation Trust, 550 Wilmslow Road, Manchester M20 4BX, UK
| | - Melissa Frizziero
- The Christie NHS Foundation Trust, 550 Wilmslow Road, Manchester M20 4BX, UK
| | - Victoria Foy
- The Christie NHS Foundation Trust, 550 Wilmslow Road, Manchester M20 4BX, UK
| | - Mairéad G. McNamara
- The Christie NHS Foundation Trust, 550 Wilmslow Road, Manchester M20 4BX, UK
- Division of Cancer Sciences, University of Manchester, Oxford Road, Manchester M13 9PL, UK
| | - Alison Backen
- The Christie NHS Foundation Trust, 550 Wilmslow Road, Manchester M20 4BX, UK
- Division of Cancer Sciences, University of Manchester, Oxford Road, Manchester M13 9PL, UK
| | - Richard A. Hubner
- The Christie NHS Foundation Trust, 550 Wilmslow Road, Manchester M20 4BX, UK
- Division of Cancer Sciences, University of Manchester, Oxford Road, Manchester M13 9PL, UK
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Qin S, Li J, Bai Y, Wang Z, Chen Z, Xu R, Xu J, Zhang H, Chen J, Yuan Y, Liu T, Yang L, Zhong H, Chen D, Shen L, Hao C, Fu D, Cheng Y, Yang J, Wang Q, Qin B, Pan H, Zhang J, Bai X, Zheng Q. Nimotuzumab Plus Gemcitabine for K-Ras Wild-Type Locally Advanced or Metastatic Pancreatic Cancer. J Clin Oncol 2023; 41:5163-5173. [PMID: 37647576 PMCID: PMC10666986 DOI: 10.1200/jco.22.02630] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 06/19/2023] [Accepted: 07/20/2023] [Indexed: 09/01/2023] Open
Abstract
PURPOSE In a phase IIb trial of nimotuzumab plus gemcitabine, substantial clinical benefits were observed in patients with locally advanced or metastatic pancreatic cancer (PC). Therefore, we conducted a phase III clinical study to verify the efficacy and safety of this combination regimen in patients with K-Ras wild-type tumors (ClinicalTrials.gov identifier: NCT02395016). PATIENTS AND METHODS Eligible patients were randomly assigned to receive nimotuzumab (400 mg once per week) or placebo followed by gemcitabine (1,000 mg/m2 on days 1, 8, and 15, once every 4 weeks) until disease progression or unacceptable toxicity. The primary end point was overall survival (OS) and the secondary end points were progression-free survival (PFS), response rates, and safety. RESULTS A total of 480 patients were screened; 92 patients were enrolled and 82 patients with K-Ras wild-type tumors were eligible. In the full analysis set, the median OS was 10.9 versus 8.5 months, while the restricted mean survival time (RMST) was 18.05 versus 11.14 months for the investigational versus control arm (ratio of control v investigation = 0.62 [0.40-0.97]; P = .036). Median PFS was 4.2 versus 3.6 months in the investigational versus control arm (log-rank P = .04; hazard ratio, 0.60 [0.37-0.99]) and the restricted mean PFS time was 8.08 versus 4.76 months (RMST ratio, 0.58 [0.38-0.90]; P = .036). Both OS and PFS were longer in the nimotuzumab group than in the placebo group. The objective response rates and disease control rates were 7% versus 10% and 68% versus 63% for the investigational and control groups, respectively. The incidence of adverse events were comparable between the two groups. CONCLUSION In patients with locally advanced or metastatic K-Ras wild-type PC, nimotuzumab plus gemcitabine significantly improved OS and PFS with a good safety profile.
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Affiliation(s)
- Shukui Qin
- Cancer Center of Jinling Hospital, Nanjing, China
| | - Jin Li
- Shanghai East Hospital, Shanghai, China
| | - Yuxian Bai
- Harbin Medical University Cancer Hospital, Harbin, China
| | - Zishu Wang
- The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Zhendong Chen
- The Second Hospital of Anhui Medical University, Hefei, China
| | - Ruihua Xu
- Cancer Center of Sun Yat-sen University, Guangzhou, China
| | - Jianming Xu
- The Fifth Medical Center, General Hospital of People's Liberation Army, Beijing, China
| | - Hongmei Zhang
- Xijing Hospital, Air Force Medical University of PLA, Xi'an, China
| | - Jia Chen
- Jiangsu Cancer Hospital, Nanjing, China
| | - Ying Yuan
- The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Tianshu Liu
- Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lin Yang
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Haijun Zhong
- Zhejiang Cancer Hospital, Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Cancer Hospital of the University of Chinese Academy of Sciences, Hangzhou, China
| | - Donghui Chen
- The First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Lin Shen
- Peking University Cancer Hospital & Institute, Beijing, China
| | - Chunyi Hao
- Peking University Cancer Hospital & Institute, Beijing, China
| | - Deliang Fu
- Huashan Hospital, Fudan University, Shanghai, China
| | | | - Jianwei Yang
- Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, China
| | - Qiong Wang
- Jiangyin People's Hospital, Jiangyin, China
| | - Baoli Qin
- Liaoning Cancer Hospital & Institute, Shenyang, China
| | - Hongming Pan
- Sir Run Run Shaw Hospital Zhejiang University School of Medicine, Hangzhou, China
| | - Jun Zhang
- Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xianhong Bai
- Biotech Pharmaceutical Ltd, Corp, Beijing, China
| | - Qingshan Zheng
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Otowa Y, Kishimoto S, Saida Y, Yamashita K, Yamamoto K, Chandramouli GV, Devasahayam N, Mitchell JB, Krishna MC, Brender JR. Evofosfamide and Gemcitabine Act Synergistically in Pancreatic Cancer Xenografts by Dual Action on Tumor Vasculature and Inhibition of Homologous Recombination DNA Repair. Antioxid Redox Signal 2023; 39:432-444. [PMID: 37051681 PMCID: PMC10623073 DOI: 10.1089/ars.2022.0118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 03/02/2023] [Accepted: 03/13/2023] [Indexed: 04/14/2023]
Abstract
Aims: Pancreatic ductal adenocarcinomas (PDACs) form hypovascular and hypoxic tumors, which are difficult to treat with current chemotherapy regimens. Gemcitabine (GEM) is often used as a first-line treatment for PDACs but has issues with chemoresistance and penetration in the interior of the tumor. Evofosfamide, a hypoxia-activated prodrug, has been shown to be effective in combination with GEM, although the mechanism of each drug on the other has not been established. We used mouse xenografts from two cell lines (MIA Paca-2 and SU.86.86) with different tumor microenvironmental characteristics to probe the action of each drug on the other. Results: GEM treatment enhanced survival times in mice with SU.86.86 leg xenografts (hazard ratio [HR] = 0.35, p = 0.03) but had no effect on MIA Paca-2 mice (HR = 0.91, 95% confidence interval = 0.37-2.25, p = 0.84). Conversely, evofosfamide did not improve survival times in SU.86.86 mice to a statistically significant degree (HR = 0.57, p = 0.22). Electron paramagnetic resonance imaging showed that oxygenation worsened in MIA Paca-2 tumors when treated with GEM, providing a direct mechanism for the activation of the hypoxia-activated prodrug evofosfamide by GEM. Sublethal amounts of either treatment enhanced the toxicity of other treatment in vitro in SU.86.86 but not in MIA Paca-2. By the biomarker γH2AX, combination treatment increased the number of double-stranded DNA lesions in vitro for SU.86.86 but not MIA Paca-2. Innovation and Conclusion: The synergy between GEM and evofosfamide appears to stem from the dual action of GEMs effect on tumor vasculature and inhibition by GEM of the homologous recombination DNA repair process. Antioxid. Redox Signal. 39, 432-444.
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Affiliation(s)
- Yasunori Otowa
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA
| | - Shun Kishimoto
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA
| | - Yu Saida
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA
| | - Kota Yamashita
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA
| | - Kazutoshi Yamamoto
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA
| | - Gadisetti V.R. Chandramouli
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA
| | - Nallathamby Devasahayam
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA
| | - James B. Mitchell
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA
| | - Murali C. Krishna
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA
| | - Jeffrey R. Brender
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA
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Imran KM, Tintera B, Morrison HA, Tupik JD, Nagai-Singer MA, Ivester H, Council-Troche M, Edwards M, Coutermarsh-Ott S, Byron C, Clark-Deener S, Uh K, Lee K, Boulos P, Rowe C, Coviello C, Allen IC. Improved Therapeutic Delivery Targeting Clinically Relevant Orthotopic Human Pancreatic Tumors Engrafted in Immunocompromised Pigs Using Ultrasound-Induced Cavitation: A Pilot Study. Pharmaceutics 2023; 15:1585. [PMID: 37376034 PMCID: PMC10302458 DOI: 10.3390/pharmaceutics15061585] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 05/03/2023] [Accepted: 05/22/2023] [Indexed: 06/29/2023] Open
Abstract
Pancreatic tumors can be resistant to drug penetration due to high interstitial fluid pressure, dense stroma, and disarrayed vasculature. Ultrasound-induced cavitation is an emerging technology that may overcome many of these limitations. Low-intensity ultrasound, coupled with co-administered cavitation nuclei consisting of gas-stabilizing sub-micron scale SonoTran Particles, is effective at increasing therapeutic antibody delivery to xenograft flank tumors in mouse models. Here, we sought to evaluate the effectiveness of this approach in situ using a large animal model that mimics human pancreatic cancer patients. Immunocompromised pigs were surgically engrafted with human Panc-1 pancreatic ductal adenocarcinoma (PDAC) tumors in targeted regions of the pancreas. These tumors were found to recapitulate many features of human PDAC tumors. Animals were intravenously injected with the common cancer therapeutics Cetuximab, gemcitabine, and paclitaxel, followed by infusion with SonoTran Particles. Select tumors in each animal were targeted with focused ultrasound to induce cavitation. Cavitation increased the intra-tumor concentrations of Cetuximab, gemcitabine, and paclitaxel by 477%, 148%, and 193%, respectively, compared to tumors that were not targeted with ultrasound in the same animals. Together, these data show that ultrasound-mediated cavitation, when delivered in combination with gas-entrapping particles, improves therapeutic delivery in pancreatic tumors under clinically relevant conditions.
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Affiliation(s)
- Khan Mohammad Imran
- Graduate Program in Translational Biology, Medicine and Health, Virginia Polytechnic Institute and State University, Roanoke, VA 24061, USA
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA 24061, USA
| | - Benjamin Tintera
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA 24061, USA
| | - Holly A. Morrison
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA 24061, USA
| | - Juselyn D. Tupik
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA 24061, USA
| | - Margaret A. Nagai-Singer
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA 24061, USA
| | - Hannah Ivester
- Graduate Program in Translational Biology, Medicine and Health, Virginia Polytechnic Institute and State University, Roanoke, VA 24061, USA
| | - McAlister Council-Troche
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA 24061, USA
| | - Michael Edwards
- Department of Small Animal Clinical Sciences, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA 24061, USA
| | - Sheryl Coutermarsh-Ott
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA 24061, USA
| | - Christopher Byron
- Department of Large Animal Clinical Sciences, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA 24061, USA
| | - Sherrie Clark-Deener
- Department of Large Animal Clinical Sciences, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA 24061, USA
| | - Kyungjun Uh
- Division of Animal Science, College of Agriculture Food and Natural Resources, University of Missouri, Columbia, MO 65211, USA
| | - Kiho Lee
- Division of Animal Science, College of Agriculture Food and Natural Resources, University of Missouri, Columbia, MO 65211, USA
| | - Paul Boulos
- OxSonics Therapeutics, Oxford Science Park, Oxford OX4 4GA, UK
| | - Cliff Rowe
- OxSonics Therapeutics, Oxford Science Park, Oxford OX4 4GA, UK
| | | | - Irving C. Allen
- Graduate Program in Translational Biology, Medicine and Health, Virginia Polytechnic Institute and State University, Roanoke, VA 24061, USA
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA 24061, USA
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Wang Q, Zeng A, Zhu M, Song L. Dual inhibition of EGFR‑VEGF: An effective approach to the treatment of advanced non‑small cell lung cancer with EGFR mutation (Review). Int J Oncol 2023; 62:26. [PMID: 36601768 PMCID: PMC9851127 DOI: 10.3892/ijo.2023.5474] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 12/01/2022] [Indexed: 01/04/2023] Open
Abstract
On a global scale, the incidence and mortality rates of lung cancer are gradually increasing year by year. A number of bad habits and environmental factors are associated with lung cancer, including smoking, second‑hand smoke exposure, occupational exposure, respiratory diseases and genetics. At present, low‑dose spiral computed tomography is routinely the first choice in the diagnosis of lung cancer. However, pathological examination is still the gold standard for the diagnosis of lung cancer. Based on the classification and stage of the cancer, treatment options such as surgery, radiotherapy, chemotherapy, targeted therapy and immunotherapy are available. The activation of the EGFR pathway can promote the survival and proliferation of tumor cells, and the VEGF pathway can promote the formation of blood vessels, thereby promoting tumor growth. In non‑small cell lung cancer (NSCLC) with EGFR mutation, EGFR activation can promote tumor growth by promoting VEGF upregulation through a hypoxia‑independent mechanism. The upregulation of VEGF can make tumor cells resistant to EGFR inhibitors. In addition, the expression of the VEGF signal is also affected by other factors. Therefore, the use of a single EGFR inhibitor cannot completely inhibit the expression of the VEGF signal. In order to overcome this problem, the combination of VEGF inhibitors and EGFR inhibitors has become the method of choice. Dual inhibition can not only overcome the resistance of tumor cells to EGFR inhibitors, but also significantly increase the progression‑free survival time of patients with NSCLC. The present review discusses the associations between the EGFR and VEGF pathways, and the characteristics of dual inhibition of the EGFR‑VEGF pathway.
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Affiliation(s)
- Qian Wang
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, P.R. China
| | - Anqi Zeng
- Institute of Translational Pharmacology and Clinical Application, Sichuan Academy of Chinese Medical Science, Chengdu, Sichuan 610041, P.R. China
| | - Min Zhu
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, P.R. China,Correspondence to: Dr Linjiang Song or Dr Min Zhu, School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Chengdu, Sichuan 611137, P.R. China, E-mail: , E-mail:
| | - Linjiang Song
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, P.R. China,Correspondence to: Dr Linjiang Song or Dr Min Zhu, School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Chengdu, Sichuan 611137, P.R. China, E-mail: , E-mail:
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Hypoxia activated HGF expression in pancreatic stellate cells confers resistance of pancreatic cancer cells to EGFR inhibition. EBioMedicine 2022; 86:104352. [PMID: 36371988 PMCID: PMC9664470 DOI: 10.1016/j.ebiom.2022.104352] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 09/18/2022] [Accepted: 10/21/2022] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND Epidermal growth factor receptor (EGFR) is an essential target for cancer treatment. However, EGFR inhibitor erlotinib showed limited clinical benefit in pancreatic cancer therapy. Here, we showed the underlying mechanism of tumor microenvironment suppressing the sensitivity of EGFR inhibitor through the pancreatic stellate cell (PSC). METHODS The expression of alpha-smooth muscle actin (α-SMA) and hypoxia marker in human pancreatic cancer tissues were detected by immunohistochemistry, and their correlation with overall survival was evaluated. Human immortalized PSC was constructed and used to investigate the potential effect on pancreatic cancer cell lines in hypoxia and normoxia. Luciferase reporter assay and Chromatin immunoprecipitation were performed to explore the potential mechanisms in vitro. The combined inhibition of EGFR and Met was evaluated in an orthotopic xenograft mouse model of pancreatic cancer. FINDINGS We found that high expression levels of α-SMA and hypoxia markers are associated with poor prognosis of pancreatic cancer patients. Mechanistically, we demonstrated that hypoxia induced the expression and secretion of HGF in PSC via transcription factor HIF-1α. PSC-derived HGF activates Met, the HGF receptor, suppressing the sensitivity of pancreatic cancer cells to EGFR inhibitor in a KRAS-independent manner by activating the PI3K-AKT pathway. Furthermore, we found that the combination of EGFR inhibitor and Met inhibitor significantly suppressed tumor growth in an orthotopic xenograft mouse model. INTERPRETATION Our study revealed a previously uncharacterized HIF1α-HGF-Met-PI3K-AKT signaling axis between PSC and cancer cells and indicated that EGFR inhibition plus Met inhibition might be a promising strategy for pancreatic cancer treatment. FUNDING This study was supported by The National Natural Science Foundation of China.
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Zhang D, Cui F, Peng L, Wang M, Yang X, Xia C, Li K, Yin H, Zhang Y, Yu Q, Jin Z, Huang H. Establishing and validating an ADCP-related prognostic signature in pancreatic ductal adenocarcinoma. Aging (Albany NY) 2022; 14:6299-6315. [PMID: 35963640 PMCID: PMC9417234 DOI: 10.18632/aging.204221] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 07/16/2022] [Indexed: 11/25/2022]
Abstract
With the progress of precision medicine treatment in pancreatic ductal adenocarcinoma (PDAC), individualized cancer-related examination and prediction is of great importance in this high malignant tumor, and antibody-dependent cell phagocytosis (ADCP) with changed pathways highly enrolled in the carcinogenesis of PDAC. High-throughput data of pancreatic ductal adenocarcinoma were downloaded and 160 differentially expressed ADCP-related genes (ARGs) were obtained. Secondly, GO and KEGG enrichment analyses show that ADCP is a pivotal biologic process in pancreatic carcinogenesis. Next, CALB2, NLGN2, NCAPG and SERTAD2 are identified through multivariate Cox regression. These 4 genes are confirmed with significant prognostic value in PDAC. Then, a risk score formula is constructed and tested in PDAC samples. Finally, the correlation between these 4 genes and M2 macrophage polarization was screened. Some pivotal differentially expressed ADCP-related genes and biologic processes, four pivotal subgroup was among identified in the protein-protein network, and hub genes was found in these sub group. Then, an ADCP-related formula was set: CALB2* 0.355526 + NLGN2* -0.86862 + NCAPG* 0.932348 + SERTAD2* 1.153568. Additionally, the significant correlation between M2 macrophage-infiltration and the expression of each genes in PDAC samples was identified. Finally, the somatic mutation landscape and sensitive chemotherapy drug between high risk group and low risk group was explored. This study provides a potential prognostic signature for predicting prognosis of PDAC patients and molecular insights of ADCP in PDAC, and the formula focusing on the prognosis of PDAC can be effective. These findings will contribute to the precision medicine of pancreatic ductal adenocarcinoma treatment.
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Affiliation(s)
- Deyu Zhang
- Department of Gastroenterology, Changhai Hospital, Shanghai, China
| | - Fang Cui
- Department of Gastroenterology, Changhai Hospital, Shanghai, China
| | - Lisi Peng
- Department of Gastroenterology, Changhai Hospital, Shanghai, China
| | - Meiqi Wang
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, China
| | - Xiaoli Yang
- Department of Gastroenterology, Changhai Hospital, Shanghai, China
| | - Chuanchao Xia
- Department of Gastroenterology, Changhai Hospital, Shanghai, China
| | - Keliang Li
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, China
| | - Hua Yin
- Department of Gastroenterology, Changhai Hospital, Shanghai, China
| | - Yang Zhang
- Department of Gastroenterology, Changhai Hospital, Shanghai, China
| | - Qihong Yu
- Department of Gastroenterology, Changhai Hospital, Shanghai, China
| | - Zhendong Jin
- Department of Gastroenterology, Changhai Hospital, Shanghai, China
| | - Haojie Huang
- Department of Gastroenterology, Changhai Hospital, Shanghai, China
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9
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Baleeiro RB, Bouwens CJ, Liu P, Di Gioia C, Dunmall LSC, Nagano A, Gangeswaran R, Chelala C, Kocher HM, Lemoine NR, Wang Y. MHC class II molecules on pancreatic cancer cells indicate a potential for neo-antigen-based immunotherapy. Oncoimmunology 2022; 11:2080329. [PMID: 35655709 PMCID: PMC9154752 DOI: 10.1080/2162402x.2022.2080329] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 05/17/2022] [Accepted: 05/17/2022] [Indexed: 11/05/2022] Open
Abstract
MHC class II expression is a hallmark of professional antigen-presenting cells and key to the induction of CD4+ T helper cells. We found that these molecules are ectopically expressed on tumor cells in a large proportion of patients with pancreatic ductal adenocarcinoma (PDAC) and on several PDAC cell lines. In contrast to the previous reports that tumoral expression of MHC-II in melanoma enabled tumor cells to evade immunosurveillance, the expression of MHC-II on PDAC cells neither protected cancer cells from Fas-mediated cell death nor caused T-cell suppression by engagement with its ligand LAG-3 on activated T-cells. In fact and surprisingly, the MHC-II/LAG-3 pathway contributed to CD4+ and CD8+ T-cell cytotoxicity toward MHC-II-positive PDAC cells. By combining bioinformatic tools and cell-based assays, we identified a number of immunogenic neo-antigens that can be presented by the patients' HLA class II alleles. Furthermore, CD4+ T-cells stimulated with neo-antigens were capable of recognizing and killing a human PDAC cell line expressing the mutated genes. To expand this approach to a larger number of PDAC patients, we show that co-treatment with IFN-γ and/or MEK/HDAC inhibitors induced tumoral MHC-II expression on MHC-II-negative tumors that are IFN-γ-resistant. Taken together, our data point to the possibility of harnessing MHC-II expression on PDAC cells for neo-antigen-based immunotherapy.
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Affiliation(s)
- Renato B. Baleeiro
- Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Christian J. Bouwens
- Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Peng Liu
- Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Carmela Di Gioia
- Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Louisa S. Chard Dunmall
- Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Ai Nagano
- Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Rathistevy Gangeswaran
- Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Claude Chelala
- Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Hemant M. Kocher
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Nicholas R. Lemoine
- Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
- Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou UniversitySino-British, Zhengzhou, Henan, China
| | - Yaohe Wang
- Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
- Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou UniversitySino-British, Zhengzhou, Henan, China
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Liermann J, Munter M, Naumann P, Abdollahi A, Krempien R, Debus J. Cetuximab, gemcitabine and radiotherapy in locally advanced pancreatic cancer: Long-term results of the randomized controlled phase II PARC trial. Clin Transl Radiat Oncol 2022; 34:15-22. [PMID: 35300246 PMCID: PMC8921472 DOI: 10.1016/j.ctro.2022.03.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 03/02/2022] [Accepted: 03/07/2022] [Indexed: 01/18/2023] Open
Abstract
Final results of a randomized controlled phase II trial. OS and PFS data of neoadjuvant chemoradiation in pancreatic cancer. Combination of cetuximab, gemcitabine and IMRT is safe and feasible. Improvement of local tumor control and secondary resection rate by combined maintenance therapy with cetuximab and gemcitabine. Purpose Addressing the epidermal growth factor receptor (EGFR)-pathway by the competitive receptor ligand cetuximab is a promising strategy in pancreatic cancer. In the prospective randomized controlled phase II PARC-study (PARC: Pancreatic cancer treatment with radiotherapy (RT) and cetuximab), we evaluated safety and efficacy of a trimodal treatment scheme consisting of cetuximab, gemcitabine and RT in locally advanced pancreatic cancer (LAPC). Methods Between January 2005 and April 2007, 68 patients with inoperable pancreatic ductal adenocarcinoma were randomized in either trimodal therapy followed by gemcitabine maintenance (Arm A) or in trimodal therapy followed by gemcitabine plus cetuximab maintenance (Arm B). Intensity-modulated RT (IMRT) was performed with a total dose of 45 Gy in 25 fractions and with a simultaneous integrated boost to the gross tumor (54 Gy). Within the trimodal therapy, gemcitabine and cetuximab were administered weekly. Maintenance therapy consisted of gemcitabine only or gemcitabine plus cetuximab. Toxicity, overall survival (OS), secondary resection rate, local control and progression free survival (PFS) were evaluated. Results With a median followup time of 13 months (range: 2 – 184 months), one patient is still alive and one patient is lost to follow-up. Nausea and gastrointestinal hemorrhage were the most important higher-graded (>°II) acute and late non-hematological toxicity (13% and 7%). Median OS was 13.1 months without significant difference between both treatment arms (Arm A: 11.9 months; Arm B: 14.2 months). Compared to historical data, cetuximab did not improve OS. One- and two-year local control rates were 76.6% and 68.9%. Local tumor control and secondary resection rate (Arm A: 4%; Arm B: 16%) were significantly improved in Arm B. Median PFS was 6.8 months with distant metastasis as main treatment failure. Conclusion Trimodal therapy consisting of IMRT, gemcitabine and cetuximab can be considered safe and feasible. Compared to historical data, cetuximab does not improve treatment efficacy in LAPC patients treated with chemoradiation.
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Affiliation(s)
- Jakob Liermann
- Heidelberg University Hospital, Department of Radiation Oncology, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany
- Heidelberg Institute of Radiation Oncology (HIRO), Im Neuenheimer Feld 400, 69120 Heidelberg, Germany
- National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, 69120 Heidelberg, Germany
- Heidelberg Ion-Beam Therapy Center (HIT), Im Neuenheimer Feld 450, 69120 Heidelberg, Germany
- Corresponding author at: Department of Radiation Oncology, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.
| | - Marc Munter
- Klinikum Stuttgart, Department of Radiation Oncology, Kriegsbergstraße 60, 70174 Stuttgart, Germany
| | - Patrick Naumann
- Heidelberg University Hospital, Department of Radiation Oncology, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany
- Heidelberg Institute of Radiation Oncology (HIRO), Im Neuenheimer Feld 400, 69120 Heidelberg, Germany
- National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, 69120 Heidelberg, Germany
| | - Amir Abdollahi
- Heidelberg University Hospital, Department of Radiation Oncology, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany
- Heidelberg Institute of Radiation Oncology (HIRO), Im Neuenheimer Feld 400, 69120 Heidelberg, Germany
- National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, 69120 Heidelberg, Germany
- Heidelberg Ion-Beam Therapy Center (HIT), Im Neuenheimer Feld 450, 69120 Heidelberg, Germany
- German Cancer Consortium (DKTK), Partner Site Heidelberg, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Robert Krempien
- Helios Clinic Berlin-Buch, Department of Radiation Oncology, Schwanebecker Chaussee 50, 13125 Berlin, Germany
| | - Juergen Debus
- Heidelberg University Hospital, Department of Radiation Oncology, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany
- Heidelberg Institute of Radiation Oncology (HIRO), Im Neuenheimer Feld 400, 69120 Heidelberg, Germany
- National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, 69120 Heidelberg, Germany
- Heidelberg Ion-Beam Therapy Center (HIT), Im Neuenheimer Feld 450, 69120 Heidelberg, Germany
- German Cancer Consortium (DKTK), Partner Site Heidelberg, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
- Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg
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11
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Yeo D, Giardina C, Saxena P, Rasko JE. The next wave of cellular immunotherapies in pancreatic cancer. Mol Ther Oncolytics 2022; 24:561-576. [PMID: 35229033 PMCID: PMC8857655 DOI: 10.1016/j.omto.2022.01.010] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Pancreatic cancer is an aggressive disease that is predicted to become the second leading cause of cancer-related death worldwide by 2030. The overall 5-year survival rate is around 10%. Pancreatic cancer typically presents late with locally advanced or metastatic disease, and there are limited effective treatments available. Cellular immunotherapy, such as chimeric antigen receptor (CAR) T cell therapy, has had significant success in treating hematological malignancies. However, CAR T cell therapy efficacy in pancreatic cancer has been limited. This review provides an overview of current and ongoing CAR T cell clinical studies of pancreatic cancer and the major challenges and strategies to improve CAR T cell efficacy. These strategies include arming CAR T cells; developing off-the-shelf allogeneic CAR T cells; using other immune CAR cells, like natural killer cells and tumor-infiltrating lymphocytes; and combination therapy. Careful incorporation of preclinical models will enhance management of affected individuals, assisting incorporation of cellular immunotherapies. A multifaceted, personalized approach involving cellular immunotherapy treatment is required to improve pancreatic cancer outcomes.
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Affiliation(s)
- Dannel Yeo
- Li Ka Shing Cell & Gene Therapy Program, The University of Sydney, Camperdown, NSW 2050, Australia
- Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia
- Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District, Camperdown, NSW 2050, Australia
| | - Caroline Giardina
- Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia
- Gene and Stem Cell Therapy Program, Centenary Institute, The University of Sydney, Camperdown, NSW 2050, Australia
| | - Payal Saxena
- Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia
- Division of Gastroenterology, Department of Medicine, Royal Prince Alfred Hospital, Sydney Local Health District, Camperdown, NSW 2050, Australia
| | - John E.J. Rasko
- Li Ka Shing Cell & Gene Therapy Program, The University of Sydney, Camperdown, NSW 2050, Australia
- Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia
- Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District, Camperdown, NSW 2050, Australia
- Gene and Stem Cell Therapy Program, Centenary Institute, The University of Sydney, Camperdown, NSW 2050, Australia
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12
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Jin X, Dong C, Zheng K, Shi X, Liu Y, Huo L, Wang F, Li F. Scintigraphic Imaging of Neovascularization With 99mTc-3PRGD 2 for Evaluating Early Response to Endostar Involved Therapies on Pancreatic Cancer Xenografts In Vivo. Front Oncol 2021; 11:792431. [PMID: 35769548 PMCID: PMC9236135 DOI: 10.3389/fonc.2021.792431] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Accepted: 11/22/2021] [Indexed: 01/14/2023] Open
Abstract
Background Molecular imaging targeting angiogenesis can specifically monitor the early therapeutic effect of antiangiogenesis therapy. We explore the predictive values of an integrin αvβ3-targeted tracer, 99mTc-PEG4-E[PEG4-c(RGDfK)]2 (99mTc-3PRGD2), for monitoring the efficacy of Endostar antiangiogenic therapy and chemotherapy in animal models. Methods The pancreatic cancer xenograft mice were randomly divided into four groups, with seven animals in each group and treated in different groups with 10 mg/kg/day of Endostar, 10 mg/kg/day of gemcitabine, 10 mg/kg/day of Endostar +10 mg/kg/day of gemcitabine at the same time, and the control group with 0.9% saline (0.1 ml/day). 99mTc-3PRGD2 scintigraphic imaging was carried out to monitor therapeutic effects. Microvessel density (MVD) was measured using immunohistochemical staining of the tumor tissues. The region of interest (ROI) of tumor (T) and contralateral corresponding site (NT) was delineated, and the ratio of radioactivity (T/NT) was calculated. Two-way repeated-measure analysis of variance (ANOVA) was used to assess differences between treatment groups. Results Tumor growth was significantly lower in treatment groups than that in the control group (p < 0.05), and the differences were noted on day 28 posttreatment. The differences of 99mTc-3PRGD2 uptakes were observed between the control group and Endostar group (p = 0.033) and the combined treatment group (p < 0.01) on day 7 posttreatment and on day 14 posttreatment between the control group and gemcitabine group (p < 0.01). The accumulation of 99mTc-3PRGD2 was significantly correlated with MVD (r = 0.998, p = 0.002). Conclusion With 99mTc-3PRGD2 scintigraphic imaging, the tumor response to antiangiogenic therapy, chemotherapy, and the combined treatment can be observed at an early stage of the treatments, much earlier than the tumor volume change. It provides new opportunities for developing individualized therapies and dose optimization.
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Affiliation(s)
- Xiaona Jin
- Department of Nuclear Medicine, Peking Union Medical College Hospital,
Chinese Academy of Medical Sciences and Peking Union Medical
College, Beijing, China
- Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in
Nuclear Medicine, Beijing,
China
| | | | - Kun Zheng
- Department of Nuclear Medicine, Peking Union Medical College Hospital,
Chinese Academy of Medical Sciences and Peking Union Medical
College, Beijing, China
- Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in
Nuclear Medicine, Beijing,
China
| | - Ximin Shi
- Department of Nuclear Medicine, Peking Union Medical College Hospital,
Chinese Academy of Medical Sciences and Peking Union Medical
College, Beijing, China
- Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in
Nuclear Medicine, Beijing,
China
| | - Yu Liu
- Department of Nuclear Medicine, Peking Union Medical College Hospital,
Chinese Academy of Medical Sciences and Peking Union Medical
College, Beijing, China
- Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in
Nuclear Medicine, Beijing,
China
| | - Li Huo
- Department of Nuclear Medicine, Peking Union Medical College Hospital,
Chinese Academy of Medical Sciences and Peking Union Medical
College, Beijing, China
- Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in
Nuclear Medicine, Beijing,
China
| | - Fan Wang
- Medical Isotopes Research Center, Peking University,
Beijing, China
| | - Fang Li
- Department of Nuclear Medicine, Peking Union Medical College Hospital,
Chinese Academy of Medical Sciences and Peking Union Medical
College, Beijing, China
- Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in
Nuclear Medicine, Beijing,
China
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13
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De Silva P, Bano S, Pogue BW, Wang KK, Maytin EV, Hasan T. Photodynamic priming with triple-receptor targeted nanoconjugates that trigger T cell-mediated immune responses in a 3D in vitro heterocellular model of pancreatic cancer. NANOPHOTONICS 2021; 10:3199-3214. [PMID: 37485044 PMCID: PMC10361703 DOI: 10.1515/nanoph-2021-0304] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 07/25/2023]
Abstract
Photodynamic priming (PDP), a collateral effect of photodynamic therapy, can transiently alter the tumor microenvironment (TME) beyond the cytotoxic zone. Studies have demonstrated that PDP increases tumor permeability and modulates immune-stimulatory effects by inducing immunogenic cell death, via the release of damage-associated molecular patterns and tumor-associated antigens. Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest of cancers with a stubborn immunosuppressive TME and a dense stroma, representing a challenge for current molecular targeted therapies often involving macromolecules. We, therefore, tested the hypothesis that PDP's TME modulation will enable targeted therapy and result in immune stimulation. Using triple-receptor-targeted photoimmuno-nanoconjugate (TR-PINs)-mediated PDP, targeting epidermal growth factor receptor, transferrin receptor, and human epidermal growth factor receptor 2 we show light dose-dependent TR-PINs mediated cytotoxicity inhuman PDA Ccells (MIAPaCa-2),co-cultured with human pancreatic cancer-associated fibroblasts (PCAFs) in spheroids. Furthermore, TR-PINs induced the expression of heat shock proteins (Hsp60, Hsp70), Calreticulin, and high mobility group box 1 in a light dose and time-dependent manner.TR-PINs-mediated T cell activation was observed in co-cultures of immune cells with the MIA PaCa-2-PCAF spheroids. Both CD4+ T and CD8+ T cells showed light dose and time-dependant antitumor reactivity by upregulating degranulation marker CD107a and interferon-gamma post-PDP. Substantial tumor cell death in immune cell-spheroid co-cultures by day 3 shows the augmentation by antitumor T cell activation and their ability to recognize tumors for a light dose-dependent kill. These data confirm enhanced destruction of heterogeneous pancreatic spheroids mediated by PDP-induced phototoxicity, TME modulation and increased immunogenicity with targeted nanoconstructs.
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Affiliation(s)
- Pushpamali De Silva
- Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Shazia Bano
- Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Brian W. Pogue
- Thayer School of Engineering, Dartmouth College, Hanover, NH, 03755, USA
| | - Kenneth K. Wang
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Edward V. Maytin
- Departments of Dermatology and Biomedical Engineering, Cleveland Clinic, Cleveland, OH, 44195, USA
| | - Tayyaba Hasan
- Corresponding author: Tayyaba Hasan, Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, 40 Blossom Street, BAR 314A, Boston, MA, 02114, USA; and Division of Health Sciences and Technology, Massachusetts Institute of Technology, Harvard University, Cambridge, MA, 02139, USA,
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14
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Karelia DN, Kim S, K. Pandey M, Plano D, Amin S, Lu J, Sharma AK. Novel Seleno-Aspirinyl Compound AS-10 Induces Apoptosis, G1 Arrest of Pancreatic Ductal Adenocarcinoma Cells, Inhibits Their NF-κB Signaling, and Synergizes with Gemcitabine Cytotoxicity. Int J Mol Sci 2021; 22:4966. [PMID: 34067020 PMCID: PMC8124556 DOI: 10.3390/ijms22094966] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 05/04/2021] [Accepted: 05/05/2021] [Indexed: 02/06/2023] Open
Abstract
Current available therapies for pancreatic ductal adenocarcinoma (PDAC) provide minimal overall survival benefits and cause severe adverse effects. We have identified a novel molecule AS-10, a selenazolidine-bis-aspirinyl derivative, that was two to three orders of magnitude more potent than aspirin and at least one to two orders of magnitude more potent than gemcitabine in inhibiting PDAC cancer cell growth/viability against three PDAC cell lines while sparing mouse embryonic fibroblasts in the same exposure range. In Panc-1 cells, AS-10 induced apoptosis without necrosis, principally through caspase-3/7 cascade and reactive oxygen species, in addition to an induction of G1 cell cycle block. Transcriptomic profiling with RNA-seq indicated the top responses to AS-10 exposure as CDKN1A (P21Cip1), CCND1, and nuclear transcription factor-kappa B (NF-κB) complex and the top functions as cell cycle, cell death, and survival without inducing the DNA damage gene signature. AS-10 pretreatment (6 h) decreased cytokine tumor necrosis factor-alpha (TNF-α)-stimulated NF-κB nuclear translocation, DNA binding activity, and degradation of cytosolic inhibitor of κB (IκB) protein. As NF-κB activation in PDAC cells confers resistance to gemcitabine, the AS-10 combination with gemcitabine increased the in vitro cytotoxicity more than the additivity of both compounds. Overall, our results suggest AS-10 may be a promising drug lead for PDAC, both as a single agent and in combination therapy.
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Affiliation(s)
- Deepkamal N. Karelia
- Department of Pharmacology, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA; (D.N.K.); (S.K.); (M.K.P.); (D.P.); (S.A.)
| | - Sangyub Kim
- Department of Pharmacology, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA; (D.N.K.); (S.K.); (M.K.P.); (D.P.); (S.A.)
| | - Manoj K. Pandey
- Department of Pharmacology, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA; (D.N.K.); (S.K.); (M.K.P.); (D.P.); (S.A.)
| | - Daniel Plano
- Department of Pharmacology, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA; (D.N.K.); (S.K.); (M.K.P.); (D.P.); (S.A.)
| | - Shantu Amin
- Department of Pharmacology, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA; (D.N.K.); (S.K.); (M.K.P.); (D.P.); (S.A.)
- Penn State Cancer Institute, 500 University Drive, Hershey, PA 17033, USA
| | - Junxuan Lu
- Department of Pharmacology, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA; (D.N.K.); (S.K.); (M.K.P.); (D.P.); (S.A.)
- Penn State Cancer Institute, 500 University Drive, Hershey, PA 17033, USA
| | - Arun K. Sharma
- Department of Pharmacology, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA; (D.N.K.); (S.K.); (M.K.P.); (D.P.); (S.A.)
- Penn State Cancer Institute, 500 University Drive, Hershey, PA 17033, USA
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15
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Antibody therapy in pancreatic cancer: mAb-ye we're onto something? Biochim Biophys Acta Rev Cancer 2021; 1876:188557. [PMID: 33945846 DOI: 10.1016/j.bbcan.2021.188557] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 04/23/2021] [Accepted: 04/25/2021] [Indexed: 02/07/2023]
Abstract
Pancreatic cancer remains an extremely deadly disease, with little improvement seen in treatment or outcomes over the last 40 years. Targeted monoclonal antibody therapy is one area that has been explored in attempts to tackle this disease. This review examines antibodies that have undergone clinical evaluation in pancreatic cancer. These antibodies target a wide variety of molecules, including tumour cell surface, stromal, immune and embryonic pathway targets. We discuss the therapeutic utility of these therapies both as monotherapeutics and in combination with other treatments such as chemotherapy. While antibody therapy for pancreatic cancer has yet to yield significant success, lessons learned from research thus far highlights future directions that may help overcome observed hurdles to yield clinically efficacious results.
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16
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Arias-Pinilla GA, Modjtahedi H. Therapeutic Application of Monoclonal Antibodies in Pancreatic Cancer: Advances, Challenges and Future Opportunities. Cancers (Basel) 2021; 13:1781. [PMID: 33917882 PMCID: PMC8068268 DOI: 10.3390/cancers13081781] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 03/31/2021] [Accepted: 04/04/2021] [Indexed: 02/07/2023] Open
Abstract
Pancreatic cancer remains as one of the most aggressive cancer types. In the absence of reliable biomarkers for its early detection and more effective therapeutic interventions, pancreatic cancer is projected to become the second leading cause of cancer death in the Western world in the next decade. Therefore, it is essential to discover novel therapeutic targets and to develop more effective and pancreatic cancer-specific therapeutic agents. To date, 45 monoclonal antibodies (mAbs) have been approved for the treatment of patients with a wide range of cancers; however, none has yet been approved for pancreatic cancer. In this comprehensive review, we discuss the FDA approved anticancer mAb-based drugs, the results of preclinical studies and clinical trials with mAbs in pancreatic cancer and the factors contributing to the poor response to antibody therapy (e.g. tumour heterogeneity, desmoplastic stroma). MAb technology is an excellent tool for studying the complex biology of pancreatic cancer, to discover novel therapeutic targets and to develop various forms of antibody-based therapeutic agents and companion diagnostic tests for the selection of patients who are more likely to benefit from such therapy. These should result in the approval and routine use of antibody-based agents for the treatment of pancreatic cancer patients in the future.
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Affiliation(s)
- Gustavo A. Arias-Pinilla
- Department of Oncology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2JF, UK;
- School of Life Sciences, Pharmacy and Chemistry, Kingston University London, Kingston-upon-Thames, Surrey KT1 2EE, UK
| | - Helmout Modjtahedi
- School of Life Sciences, Pharmacy and Chemistry, Kingston University London, Kingston-upon-Thames, Surrey KT1 2EE, UK
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17
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Wei J, Guo Y, Wang Y, Wu Z, Bo J, Zhang B, Zhu J, Han W. Clinical development of CAR T cell therapy in China: 2020 update. Cell Mol Immunol 2021; 18:792-804. [PMID: 32999455 PMCID: PMC8115146 DOI: 10.1038/s41423-020-00555-x] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 09/04/2020] [Accepted: 09/08/2020] [Indexed: 02/07/2023] Open
Abstract
Chimeric antigen receptor (CAR) T-cell therapy has achieved significant success in the treatment of hematological malignancies. In recent years, fast-growing CAR T clinical trials have actively explored their potential application scenarios. According to the data from the clinicaltrials.gov website, China became the country with the most registered CAR T trials in September 2017. As of June 30, 2020, the number of registered CAR T trials in China has reached 357. In addition, as many as 150 other CAR T trials have been registered on ChiCTR. Although CAR T therapy is flourishing in China, there are still some problems that cannot be ignored. In this review, we aim to systematically summarize the clinical practice of CAR T-cell therapy in China. This review will provide an informative reference for colleagues in the field, and a better understanding of the history and current situation will help us more reasonably conduct research and promote cooperation.
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Affiliation(s)
- Jianshu Wei
- Department of Bio-Therapeutic, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
| | - Yelei Guo
- Department of Bio-Therapeutic, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
| | - Yao Wang
- Department of Bio-Therapeutic, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
| | - Zhiqiang Wu
- Department of Bio-Therapeutic, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
| | - Jian Bo
- Department of Hematology, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China.
| | - Bin Zhang
- Department of Hematopoietic Stem Cell Transplantation, The Fifth Medical Center, Chinese PLA General Hospital, Beijing, 100071, China
| | - Jun Zhu
- Key Laboratory of Carcinogenesis and Translational Research, Departments of Lymphoma, Radiology and Nuclear Medicine, Peking University Cancer Hospital and Institute, Beijing, 100036, China.
| | - Weidong Han
- Department of Bio-Therapeutic, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China.
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Liu T, Han X, Zheng S, Liu Q, Tuerxun A, Zhang Q, Yang L, Lu X. CALM1 promotes progression and dampens chemosensitivity to EGFR inhibitor in esophageal squamous cell carcinoma. Cancer Cell Int 2021; 21:121. [PMID: 33602237 PMCID: PMC7890995 DOI: 10.1186/s12935-021-01801-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 02/03/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Calmodulin1 (CALM1) has been identified as one of the overexpression genes in a variety of cancers and EGFR inhibitor have been widely used in clinical treatment but it is unknown whether CALM1 and epidermal growth factor receptor (EGFR) have a synergistic effect in esophageal squamous cell carcinoma (ESCC). The aim of the present study was to explore the synergistic effects of knock-out CALM1 combined with EGFR inhibitor (Afatinib) and to elucidate the role of CALM1 in sensitizing the resistance to Afatinib in ESCC. METHOD Immunohistochemistry (IHC) and qRT-PCR were used to examine the expression of CALM1 and EGFR in ESCC tissues. Kaplan-Meier survival analysis was used to analyze the clinical and prognostic significance of CALM1 and EGFR expression in ESCC. Furthermore, to evaluate the biological function of CALM1 in ESCC, the latest gene editing technique CRISPR/Cas9(Clustered regularly interspaced short palindromic repeats)was applied to knockout CALM1 in ESCC cell lines KYSE150, Eca109 and TE-1. MTT, flow cytometry, Transwell migration, scratch wound-healing and colony formation assays were performed to assay the combined effect of knock-out CALM1 and EGFR inhibitor on ESCC cell proliferation and migration. In addition, nude mice xenograft model was used to observe the synergistic inhibition of knock-out CALM1 and Afatinib. RESULTS Both CALM1 and EGFR were found to be significantly over-expressed in ESCC compared with paired normal control. Over-expressed CALM1 and EGFR were significantly associated with clinical stage, T classification and poor overall prognosis, respectively. In vitro, the combined effect of knock-out CALM1 mediated by the lentivirus and EGFR inhibitor was shown to be capable of inhibiting the proliferation, inducing cell cycle arrest at G1/S stage and increasing apoptosis of KYSE-150 and Eca109 cells; invasion and migration were also suppressed. In vivo, the results of tumor weight and total fluorescence were markedly reduced compared with the sgCtrl-infected group and sgCAML1 group. CONCLUSION Our data demonstrated that knock-out of CALM1 could sensitize ESCC cells to EGFR inhibitor, and it may exert oncogenic role via promotion of EMT. Taken together, CALM1 may be a tempting target to overcome Afatinib resistance.
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Affiliation(s)
- Tao Liu
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Disease in Central Asia, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region, Urumqi, PR China
- Department of Clinical Laboratory, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region, Urumqi, PR China
| | - Xiujuan Han
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Disease in Central Asia, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region, Urumqi, PR China
| | - Shutao Zheng
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Disease in Central Asia, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region, Urumqi, PR China
| | - Qing Liu
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Disease in Central Asia, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region, Urumqi, PR China
| | - Aerziguli Tuerxun
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Disease in Central Asia, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region, Urumqi, PR China
| | - Qiqi Zhang
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Disease in Central Asia, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region, Urumqi, PR China
| | - Lifei Yang
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Disease in Central Asia, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region, Urumqi, PR China
| | - Xiaomei Lu
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Disease in Central Asia, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region, Urumqi, PR China.
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Garcia-Sampedro A, Gaggia G, Ney A, Mahamed I, Acedo P. The State-of-the-Art of Phase II/III Clinical Trials for Targeted Pancreatic Cancer Therapies. J Clin Med 2021; 10:566. [PMID: 33546207 PMCID: PMC7913382 DOI: 10.3390/jcm10040566] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 01/28/2021] [Accepted: 01/30/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is a devastating disease with very poor prognosis. Currently, surgery followed by adjuvant chemotherapy represents the only curative option which, unfortunately, is only available for a small group of patients. The majority of pancreatic cancer cases are diagnosed at advanced or metastatic stage when surgical resection is not possible and treatment options are limited. Thus, novel and more effective therapeutic strategies are urgently needed. Molecular profiling together with targeted therapies against key hallmarks of pancreatic cancer appear as a promising approach that could overcome the limitations of conventional chemo- and radio-therapy. In this review, we focus on the latest personalised and multimodal targeted therapies currently undergoing phase II or III clinical trials. We discuss the most promising findings of agents targeting surface receptors, angiogenesis, DNA damage and cell cycle arrest, key signalling pathways, immunotherapies, and the tumour microenvironment.
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Affiliation(s)
| | | | | | | | - Pilar Acedo
- Institute for Liver and Digestive Health, Royal Free Hospital Campus, University College London, London NW3 2QG, UK; (A.G.-S.); (G.G.); (A.N.); (I.M.)
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20
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Yeh C, Bates SE. Two decades of research toward the treatment of locally advanced and metastatic pancreatic cancer: Remarkable effort and limited gain. Semin Oncol 2021; 48:34-46. [PMID: 33712267 DOI: 10.1053/j.seminoncol.2021.01.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 01/20/2021] [Indexed: 01/04/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy that is diagnosed at the locally advanced or metastatic stage in approximately 80% of cases. Relative to other tumor types, progress in the treatment of this disease has been painfully slow. While agents targeting DNA repair have proven successful in a subset of patients, the majority of PDACs do not exhibit validated molecular targets. Hence, conventional chemotherapy remains at the forefront of therapy for this disease. In this review, we study two decades of efforts to improve upon the gemcitabine backbone - 67 phase II and III trials enrolling 16,446 patients - that culminated in the approvals of gemcitabine/nab-paclitaxel (Gem/NabP) and FOLFIRINOX. Today, these remain gold standards for the first-line treatment of locally advanced unresectable and metastatic PDAC, while ongoing efforts focus on improving upon the Gem/NabP backbone. Because real world data often do not reflect the data of randomized controlled trials (RCTs), we also summarize the retrospective evidence comparing the efficacy of Gem/NabP and FOLFIRINOX in the first-line setting - 29 studies reporting a median overall survival of 10.7 and 9.1 months for FOLFIRINOX and Gem/NabP, respectively. These values are surprisingly comparable to those reported by the pivotal RCTs at 11.1 and 8.5 months. Finally, there is a paucity of RCT data regarding the efficacy of second-line therapy. Hence, we conclude this review by summarizing the data that ultimately demonstrate a small but significant survival benefit of second-line therapy with Gem/NabP or FOLFIRINOX. Collectively, these studies describe the long journey, the steady effort, and the myriad lessons to be learned from 20 years of PDAC trials to inform strategies for success in clinical trials moving forward.
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Affiliation(s)
- Celine Yeh
- Department of Medicine, Columbia University Irving Medical Center, New York, NY
| | - Susan E Bates
- James J. Peters VA Medical Center, Bronx, NY; Columbia University Herbert Irving Comprehensive Cancer Center, New York, NY.
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21
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Liu Y, Guo Y, Wu Z, Feng K, Tong C, Wang Y, Dai H, Shi F, Yang Q, Han W. Anti-EGFR chimeric antigen receptor-modified T cells in metastatic pancreatic carcinoma: A phase I clinical trial. Cytotherapy 2020; 22:573-580. [PMID: 32527643 DOI: 10.1016/j.jcyt.2020.04.088] [Citation(s) in RCA: 111] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 03/26/2020] [Accepted: 04/13/2020] [Indexed: 12/11/2022]
Abstract
The current clinical outcome for patients with metastatic pancreatic carcinoma (PC) remains poor. Epidermal growth factor receptor (EGFR) is detectable in PC, suggesting that EGFR is a rational target in PC. We conducted a phase I clinical trial to evaluate the safety and efficacy of autologous anti-EGFR chimeric antigen receptor-modified T (CAR T-EGFR) cells in patients with metastatic PC. The expression levels of EGFR on tumor cells detected by immunohistochemistry were required to be more than 50%. Sixteen patients were enrolled and received one to three cycles of the CAR T-EGFR cell infusion within 6 months (median dose of CAR T cells: 3.48 × 106/kg; range, 1.31 to 8.9 × 106/kg) after the conditioning regimen with 100 to 200 mg/m2 nab-paclitaxel and 15 to 35 mg/kg cyclophosphamide. Grade ≥3 adverse events included fever/fatigue, nausea/vomiting, mucosal/cutaneous toxicities, pleural effusion and pulmonary interstitial exudation and were reversible. Of 14 evaluable patients, four achieved partial response for 2-4 months, and eight had stable disease for 2-4 months. The median progression-free survival was 3 months (range, 4-months) from the first cycle of CAR T-EGFR cell treatment, and the median overall survival of all 14 evaluable patients was 4.9 months (range, 2.9-30 months). Decreased EGFR expression on tumor cells was observed in patients who achieved stable disease with shrinkage of metastatic lesions in the liver, and enrichment of central memory T cells in infused cells improved the clinical response. In conclusion, the treatment with CAR T-EGFR cells is safe and effective in patients with metastatic PC. This trial was registered at www.clinicaltrials.gov (identifier no: NCT01869166).
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Affiliation(s)
- Yang Liu
- Department of Bio-therapeutic, the First Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Yelei Guo
- Department of Bio-therapeutic, the First Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Zhiqiang Wu
- Department of Bio-therapeutic, the First Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Kaichao Feng
- Department of Bio-therapeutic, the First Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Chuan Tong
- Department of Bio-therapeutic, the First Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Yao Wang
- Department of Bio-therapeutic, the First Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Hanren Dai
- Department of Bio-therapeutic, the First Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Fengxia Shi
- Department of Bio-therapeutic, the First Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Qingming Yang
- Department of Bio-therapeutic, the First Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Weidong Han
- Department of Bio-therapeutic, the First Medical Centre, Chinese PLA General Hospital, Beijing, China.
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22
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Liu Y, Awadia S, Delaney A, Sitto M, Engelke CG, Patel H, Calcaterra A, Zelenka-Wang S, Lee H, Contessa J, Neamati N, Ljungman M, Lawrence TS, Morgan MA, Rehemtulla A. UAE1 inhibition mediates the unfolded protein response, DNA damage and caspase-dependent cell death in pancreatic cancer. Transl Oncol 2020; 13:100834. [PMID: 32688248 PMCID: PMC7369648 DOI: 10.1016/j.tranon.2020.100834] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 06/10/2020] [Accepted: 06/19/2020] [Indexed: 12/31/2022] Open
Abstract
The Unfolded Protein Response (UPR) plays a key role in the adaptive response to loss of protein homeostasis within the endoplasmic reticulum (ER). The UPR has an adaptive function in protein homeostasis, however, sustained activation of the UPR due to hypoxia, nutrient deprivation, and increased demand for protein synthesis, alters the UPR program such that additional perturbation of ER homeostasis activates a pro-apoptotic program. Since ubiquitination followed by proteasomal degradation of misfolded proteins within the ER is a central mechanism for restoration of ER homeostasis, inhibitors of this pathway have proven to be valuable anti-cancer therapeutics. Ubiquitin activating enzyme 1(UAE1), activates ubiquitin for transfer to target proteins for proteasomal degradation in conjunction with E2 and E3 enzymes. Inhibition of UAE1 activity in response to TAK-243, leads to an accumulation of misfolded proteins within the ER, thereby aggravating ER stress, leading to DNA damage and arrest of cells in the G2/M phase of the cell cycle. Persistent drug treatment mediates a robust induction of apoptosis following a transient cell cycle arrest. These biological effects of TAK-243 were recapitulated in mouse models of PDAC demonstrating antitumor activity at a dose and schedule that did not exhibit obvious normal tissue toxicity. In vitro as well as studies in mouse models failed to show enhanced efficacy when TAK-243 was combined with ionizing radiation or gemcitabine, providing an impetus for future studies to identify agents that synergize with this class of agents for improved tumor control in PDAC. Significance The UAE1 inhibitor TAK-243, mediates activation of the unfolded protein response, accumulation of DNA breaks and apoptosis, providing a rationale for the use as a safe and efficacious anti-cancer therapeutic for PDAC.
Inhibition of Ubiquitin activating enzyme 1(UAE1) leads to an accumulation of misfolded proteins within the ER. Persistent drug treatment mediates a robust induction of apoptosis in mouse models of Pancreatic Cancer demonstrating antitumor activity at a dose and schedule that did not exhibit obvious normal tissue toxicity.
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Affiliation(s)
- Yajing Liu
- Department of Radiation Oncology, University of Michigan Medical School and Rogel Cancer Center, Ann Arbor, MI, USA
| | - Sahezeel Awadia
- Department of Radiation Oncology, University of Michigan Medical School and Rogel Cancer Center, Ann Arbor, MI, USA
| | - Amy Delaney
- Department of Radiation Oncology, University of Michigan Medical School and Rogel Cancer Center, Ann Arbor, MI, USA
| | - Merna Sitto
- Department of Radiation Oncology, University of Michigan Medical School and Rogel Cancer Center, Ann Arbor, MI, USA
| | - Carl G Engelke
- Department of Radiation Oncology, University of Michigan Medical School and Rogel Cancer Center, Ann Arbor, MI, USA
| | - Heli Patel
- Department of Radiation Oncology, University of Michigan Medical School and Rogel Cancer Center, Ann Arbor, MI, USA
| | - Andrew Calcaterra
- Department of Radiation Oncology, University of Michigan Medical School and Rogel Cancer Center, Ann Arbor, MI, USA
| | | | - Hojin Lee
- Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, USA
| | - Joseph Contessa
- Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, USA
| | - Nouri Neamati
- Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Mats Ljungman
- Department of Radiation Oncology, University of Michigan Medical School and Rogel Cancer Center, Ann Arbor, MI, USA
| | - Theodore S Lawrence
- Department of Radiation Oncology, University of Michigan Medical School and Rogel Cancer Center, Ann Arbor, MI, USA
| | - Meredith A Morgan
- Department of Radiation Oncology, University of Michigan Medical School and Rogel Cancer Center, Ann Arbor, MI, USA
| | - Alnawaz Rehemtulla
- Department of Radiation Oncology, University of Michigan Medical School and Rogel Cancer Center, Ann Arbor, MI, USA.
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Taghizadeh H, Müllauer L, Mader RM, Schindl M, Prager GW. Applied precision medicine in metastatic pancreatic ductal adenocarcinoma. Ther Adv Med Oncol 2020; 12:1758835920938611. [PMID: 32699558 PMCID: PMC7357054 DOI: 10.1177/1758835920938611] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 06/05/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Metastatic pancreatic ductal adenocarcinoma (mPDAC) bears a dismal prognosis due to the limited activity of systemic chemotherapy. In our platform for precision medicine, we aim to offer molecular-guided treatments to patients without further standard therapy options. METHODS In this single center, real-world retrospective analysis of our platform, we describe the molecular-based therapy approaches used in all 50 patients diagnosed with therapy-refractory mPDAC. A molecular portrait of the tumor specimens was created by next-generation sequencing, immunohistochemistry (IHC), microsatellite instability (MSI) testing, and fluorescence in situ hybridization. RESULTS In total, we detected 123 mutations in 50 patients. The five most frequent mutations were KRAS (n = 40; 80%), TP53 (n = 29; 58%), CDKN2A (n = 8; 16%), SMAD4 (n = 4; 8%), and NOTCH1 (n = 4; 8%), which together accounted for 40.2% of all mutations. Two patients had gene fusions, namely, TBL1XR1-PIK3CA and EIF3E-RSPO2. IHC detected expression of EGFR, phosphorylated mTOR, and PTEN in 36 (72%), 33 (66%), and 17 patients (34%), respectively. For 14 (28%) of the 50 patients, a targeted therapy was suggested based on the identified molecular targets. The recommended treatments included the mTOR inhibitor everolimus (n = 3), pembrolizumab (n = 3), palbociclib (n = 2), nintedanib (n = 2), and cetuximab, crizotinib, tamoxifen, and the combination of lapatinib and trastuzumab, in one patient each.Finally, five patients received the recommended therapy. Four patients died due to disease progression before radiological assessment. One patient was treated with nintedanib and achieved stable disease for 6 months. CONCLUSION Based on our observations, precision medicine approaches are feasible and implementable in clinical routine and may provide molecular-based therapy recommendations for mPDAC.
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Affiliation(s)
- Hossein Taghizadeh
- Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Austria
- Comprehensive Cancer Center Vienna, Austria
| | - Leonhard Müllauer
- Comprehensive Cancer Center Vienna, Austria
- Clinical Institute of Pathology, Medical University Vienna, Vienna, Austria
| | - Robert M. Mader
- Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Austria
- Comprehensive Cancer Center Vienna, Austria
| | - Martin Schindl
- Comprehensive Cancer Center Vienna, Austria
- Department of Surgery, Division of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Gerald W. Prager
- Department of Medicine I, Clinical Division of Oncology, Comprehensive Cancer Center Vienna, Precision Cancer Medicine Unit, Medical University of Vienna, Währinger Gürtel 18–20, 1090 Vienna, Austria
- Comprehensive Cancer Center Vienna, Austria
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Er O, Tuncel A, Ocakoglu K, Ince M, Kolatan EH, Yilmaz O, Aktaş S, Yurt F. Radiolabeling, In Vitro Cell Uptake, and In Vivo Photodynamic Therapy Potential of Targeted Mesoporous Silica Nanoparticles Containing Zinc Phthalocyanine. Mol Pharm 2020; 17:2648-2659. [PMID: 32412765 DOI: 10.1021/acs.molpharmaceut.0c00331] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Photodynamic therapy (PDT) is a noninvasive therapy based on the photodynamic effect. In this study, we sought to determine intracellular uptake and in vivo photodynamic therapy potential of Zn phthalocyanine-loaded mesoporous silica nanoparticles (MSNP5) against pancreatic cancer cells. MSNP5 were labeled with 131I; the radiolabeling efficiency was found to 95.5 ± 1.2% in pH 9 and 60 min reaction time. Besides, the highest intracellular uptake yields of 131I-MSNP5 nanoparticles in MIA PaCa-2, AsPC-1, and PANC-1 cells were determined as 43.9 ± 3.8%, 41.8 ± 0.2%, and 37.9 ± 1.3%, respectively, at 24 h incubation time. In vivo PDT studies were performed with subcutaneous xenograft cancer model nude mice with AsPC-1 pancreatic cancer cells. For photodynamic therapy, 685 nm red laser light 100 J/cm2 light dose using and 5-20 μM ZnPc containing MSNP5 concentrations were applied. Histopathological studies revealed that the ratio of necrosis in tumor tissue was higher in the treatment group than the control groups.
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Affiliation(s)
- Ozge Er
- Department of Nuclear Applications, Institute of Nuclear Science, Ege University, Bornova, 35100, Izmir, Izmir, Turkey
| | - Ayca Tuncel
- Department of Nuclear Applications, Institute of Nuclear Science, Ege University, Bornova, 35100, Izmir, Izmir, Turkey
| | - Kasim Ocakoglu
- Department of Energy Systems Engineering, Faculty of Technology, Tarsus University, 33400 Tarsus, Mersin, Turkey
| | - Mine Ince
- Department of Energy Systems Engineering, Faculty of Technology, Tarsus University, 33400 Tarsus, Mersin, Turkey
| | - Efsun Hatice Kolatan
- Department of Animal Research Center, Dokuz Eylul University, 35340, Izmir, Izmir,Turkey
| | - Osman Yilmaz
- Department of Animal Research Center, Dokuz Eylul University, 35340, Izmir, Izmir,Turkey
| | - Safiye Aktaş
- Department of Basic Oncology, Institute of Oncology, Dokuz Eylül University, 35340, Izmir, Izmir,Turkey
| | - Fatma Yurt
- Department of Nuclear Applications, Institute of Nuclear Science, Ege University, Bornova, 35100, Izmir, Izmir, Turkey
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25
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Lu G, van den Berg NS, Martin BA, Nishio N, Hart ZP, van Keulen S, Fakurnejad S, Chirita SU, Raymundo RC, Yi G, Zhou Q, Fisher GA, Rosenthal EL, Poultsides GA. Tumour-specific fluorescence-guided surgery for pancreatic cancer using panitumumab-IRDye800CW: a phase 1 single-centre, open-label, single-arm, dose-escalation study. Lancet Gastroenterol Hepatol 2020; 5:753-764. [PMID: 32416764 DOI: 10.1016/s2468-1253(20)30088-1] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 03/12/2020] [Accepted: 03/23/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND Complete surgical resection remains the primary curative option for pancreatic ductal adenocarcinoma, with positive margins in 30-70% of patients. In this study, we aimed to evaluate the use of intraoperative tumour-specific imaging to enhance a surgeon's ability to detect visually occult cancer in real time. METHODS In this single-centre, open-label, single-arm study, done in the USA, we enrolled patients who had clinically suspicious or biopsy-confirmed pancreatic ductal adenocarcinomas and were scheduled for curative surgery. Eligible patients were 19 years of age or older with a life expectancy of more than 12 weeks and a Karnofsky performance status of at least 70% or an Eastern Cooperative Oncology Group or Zubrod level of one or lower, who were scheduled to undergo curative surgery. Patients were sequentially enrolled into each dosing group and 2-5 days before surgery, patients were intravenously infused with 100 mg of unlabelled panitumumab followed by 25 mg, 50 mg, or 75 mg of the near-infrared fluorescently labelled antibody (panitumumab-IRDye800CW). The primary endpoint was to determine the optimal dose of panitumumab-IRDye800CW in identifying pancreatic ductal adenocarcinomas as measured by tumour-to-background ratio in all patients. The tumour-to-background ratio was defined as the fluorescence signal of the tumour divided by the fluorescence signal of the surrounding healthy tissue. The dose-finding part of this study has been completed. This study is registered with ClinicalTrials.gov, NCT03384238. FINDINGS Between April, 2018, and July, 2019, 16 patients were screened for enrolment onto the study. Of the 16 screened patients, two (12%) patients withdrew from the study and three (19%) were not eligible; 11 (69%) patients completed the trial, all of whom were clinically diagnosed with pancreatic ductal adenocarcinoma. The mean tumour-to-background ratio of primary tumours was 3·0 (SD 0·5) in the 25 mg group, 4·0 (SD 0·6) in the 50 mg group, and 3·7 (SD 0·4) in the 75 mg group; the optimal dose was identified as 50 mg. Intraoperatively, near-infrared fluorescence imaging provided enhanced visualisation of the primary tumours, metastatic lymph nodes, and small (<2 mm) peritoneal metastasis. Intravenous administration of panitumumab-IRDye800CW at the doses of 25 mg, 50 mg, and 75 mg did not result in any grade 3 or higher adverse events. There were no serious adverse events attributed to panitumumab-IRDye800CW, although four possibly related adverse events (grade 1 and 2) were reported in four patients. INTERPRETATION To our knowledge, this study presents the first clinical use of panitumumab-IRDye800CW for detecting pancreatic ductal adenocarcinomas and shows that panitumumab-IRDye800CW is safe and feasible to use during pancreatic cancer surgery. Tumour-specific intraoperative imaging might have added value for treatment of patients with pancreatic ductal adenocarcinomas through improved patient selection and enhanced visualisation of surgical margins, metastatic lymph nodes, and distant metastasis. FUNDING National Institutes of Health and the Netherlands Organization for Scientific Research.
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Affiliation(s)
- Guolan Lu
- Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford University, CA, USA
| | - Nynke S van den Berg
- Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford University, CA, USA
| | - Brock A Martin
- Department of Pathology, Stanford University School of Medicine, Stanford University, CA, USA
| | - Naoki Nishio
- Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford University, CA, USA
| | - Zachary P Hart
- Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford University, CA, USA
| | - Stan van Keulen
- Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford University, CA, USA
| | - Shayan Fakurnejad
- Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford University, CA, USA
| | - Stefania U Chirita
- Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford University, CA, USA; Cancer Clinical Trials Office, Stanford University School of Medicine, Stanford University, CA, USA
| | - Roan C Raymundo
- Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford University, CA, USA; Cancer Clinical Trials Office, Stanford University School of Medicine, Stanford University, CA, USA
| | - Grace Yi
- Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford University, CA, USA; Cancer Clinical Trials Office, Stanford University School of Medicine, Stanford University, CA, USA
| | - Quan Zhou
- Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford University, CA, USA
| | - George A Fisher
- Department of Medical Oncology, Stanford University School of Medicine, Stanford University, CA, USA
| | - Eben L Rosenthal
- Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford University, CA, USA; Stanford Cancer Center, Stanford University School of Medicine, Stanford University, CA, USA
| | - George A Poultsides
- Department of Surgery, Stanford University School of Medicine, Stanford University, CA, USA.
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Banstola A, Pham TT, Jeong JH, Yook S. Polydopamine-tailored paclitaxel-loaded polymeric microspheres with adhered NIR-controllable gold nanoparticles for chemo-phototherapy of pancreatic cancer. Drug Deliv 2019; 26:629-640. [PMID: 31237149 PMCID: PMC6598510 DOI: 10.1080/10717544.2019.1628118] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 06/03/2019] [Accepted: 06/03/2019] [Indexed: 12/19/2022] Open
Abstract
Chemotherapeutic drugs often used as a first-line treatment of pancreatic cancer (PC) exhibit challenges due to resistance development, lack of selectivity, and tumor heterogeneity. Currently, combination chemo-photothermal therapy is known to enhance the therapeutic efficacy of chemotherapeutic drugs in PC. In this study, we develop adherent gold nanoparticles (GNPs) and paclitaxel (PTX)-loaded PLGA microspheres for the treatment of PC. Polydopamine (pD) was used as a linker to adhere GNPs to the surface of PLGA-Ms and characterized using TEM. Short-term cytotoxicity of GNPs-pD-PTX-PLGA-Ms with or without NIR treatment was evaluated using CCK-8 assays. ROS and western blot assay were performed to determine the intensity of ROS following the treatment of GNPs-pD-PTX-PLGA-Ms with or without NIR in Panc-1 cell line. Successful adhesion of GNPs on the microspheres was confirmed by TEM. CCK-8 assay revealed that GNPs-pD-PTX-PLGA-Ms with NIR showed three-fold higher cytotoxicity, compared to the group without NIR. Furthermore, ROS and western blot assay suggest that GNPs-pD-PTX-PLGA-Ms with NIR showed more ROS generation, followed by downregulation of the expression levels of antioxidant enzyme (SOD2 and CATALASE). These results suggest that the GNPs-pD-PTX-PLGA-Ms in combination with NIR irradiation can provide a synergistic chemo-photothermal therapy for the treatment of PC.
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Affiliation(s)
- Asmita Banstola
- College of Pharmacy, Keimyung University, Daegu, South Korea
| | - Tung Thanh Pham
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, South Korea
| | - Jee-Heon Jeong
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, South Korea
| | - Simmyung Yook
- College of Pharmacy, Keimyung University, Daegu, South Korea
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Abstract
OBJECTIVES We evaluated how well phase II trials in locally advanced and metastatic pancreatic cancer (LAMPC) meet current recommendations for trial design. METHODS We conducted a systematic review of phase II first-line treatment trial for LAMPC. We assessed baseline characteristics, type of comparison, and primary end point to examine adherence to the National Cancer Institute recommendations for trial design. RESULTS We identified 148 studies (180 treatment arms, 7505 participants). Forty-seven (32%) studies adhered to none of the 5 evaluated National Cancer Institute recommendations, 62 (42%) followed 1, 31 (21%) followed 2, and 8 (5%) followed 3 recommendations. Studies varied with respect to the proportion of patients with good performance status (range, 0%-80%) and locally advanced disease (range, 14%-100%). Eighty-two (55%) studies concluded that investigational agents should progress to phase III testing; of these, 24 (16%) had documented phase III trials. Three (8%) phase III trials demonstrated clinically meaningful improvements for investigational agents. One of 38 phase II trials that investigated biological investigational agents was enriched for a biomarker. CONCLUSIONS Phase II trials do not conform well to current recommendations for trial design in LAMPC.
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Abstract
Abstract
Geometry optimization of gemcitabine was carried out by DFT with B3LYP/6-311++G(d,p) level in the gas phase. Chemical activity (electronegativity, electrophilicity, hardness, chemical softness and chemical potential) was predicted with the help of HOMO-LUMO energy values. Experimental FT-IR was recorded and computed values are also analyzed using the same level of DFT. A complete vibrational spectrum was made to analyze the potential energy distribution (PED). Stability of the molecule arising from the hyper-conjugative interaction was analyzed by the natural bond orbital (NBO). The molecular electrostatic potential map was used to detect the possible electrophilic and nucleophilic sites in the molecule. Nonisothermal decomposition of gemcitabine was carried out in an air atmosphere. The two decomposition steps of the molecule were analyzed kinetically by linear and nonlinear methods for elucidation of the kinetic triplet (Ea
, ln A and f(α)) of the decomposition processes. Powder X-ray diffraction indicated that gemcitabine crystallizes in the monoclinic system (SG P2/m). Molecular docking studies were also described.
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29
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Forster T, Huettner F, Springfeld C, Loehr M, Kalkum E, Hackbusch M, Hackert T, Diener M, Probst P. Cetuximab in Pancreatic Cancer Therapy: A Systematic Review and Meta-Analysis. Oncology 2019; 98:53-60. [DOI: 10.1159/000502844] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Accepted: 08/05/2019] [Indexed: 11/19/2022]
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Momeny M, Esmaeili F, Hamzehlou S, Yousefi H, Javadikooshesh S, Vahdatirad V, Alishahi Z, Mousavipak SH, Bashash D, Dehpour AR, Tavangar SM, Tavakkoly-Bazzaz J, Haddad P, Kordbacheh F, Alimoghaddam K, Ghavamzadeh A, Ghaffari SH. The ERBB receptor inhibitor dacomitinib suppresses proliferation and invasion of pancreatic ductal adenocarcinoma cells. Cell Oncol (Dordr) 2019; 42:491-504. [PMID: 31025257 DOI: 10.1007/s13402-019-00448-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/16/2019] [Indexed: 12/23/2022] Open
Abstract
PURPOSE Pancreatic ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, is the fourth most common cause of cancer-related death in the USA. Local progression, early tumor dissemination and low efficacy of current treatments are the major reasons for its high mortality rate. The ERBB family is over-expressed in PDAC and plays essential roles in its tumorigenesis; however, single-targeted ERBB inhibitors have shown limited activity in this disease. Here, we examined the anti-tumor activity of dacomitinib, a pan-ERBB receptor inhibitor, on PDAC cells. METHODS Anti-proliferative effects of dacomitinib were determined using a cell proliferation assay and crystal violet staining. Annexin V/PI staining, radiation therapy and cell migration and invasion assays were carried out to examine the effects of dacomitinib on apoptosis, radio-sensitivity and cell motility, respectively. Quantitative reverse transcription-PCR (qRT-PCR) and Western blot analyses were applied to elucidate the molecular mechanisms underlying the anti-tumor activity of dacomitinib. RESULTS We found that dacomitinib diminished PDAC cell proliferation via inhibition of FOXM1 and its targets Aurora kinase B and cyclin B1. Moreover, we found that dacomitinib induced apoptosis and potentiated radio-sensitivity via inhibition of the anti-apoptotic proteins survivin and MCL1. Treatment with dacomitinib attenuated cell migration and invasion through inhibition of the epithelial-to-mesenchymal transition (EMT) markers ZEB1, Snail and N-cadherin. In contrast, we found that the anti-tumor activity of single-targeted ERBB agents including cetuximab (anti-EGFR mAb), trastuzumab (anti-HER2 mAb), H3.105.5 (anti-HER3 mAb) and erlotinib (EGFR small molecule inhibitor) were marginal. CONCLUSIONS Our findings indicate that dacomitinib-mediated blockade of the ERBB receptors yields advantages over single-targeted ERBB inhibition and provide a rationale for further investigation of the therapeutic potential of dacomitinib in the treatment of ERBB-driven PDAC.
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Affiliation(s)
- Majid Momeny
- Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
| | - Fatemeh Esmaeili
- Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Sepideh Hamzehlou
- Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hassan Yousefi
- Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Sepehr Javadikooshesh
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Vasimeh Vahdatirad
- Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Zivar Alishahi
- Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyedeh H Mousavipak
- Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ahmad R Dehpour
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyyed M Tavangar
- Department of Pathology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Javad Tavakkoly-Bazzaz
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Peiman Haddad
- Radiation Oncology Research Center, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Farzaneh Kordbacheh
- Cancer and Vascular Biology Group, ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, Australia
| | - Kamran Alimoghaddam
- Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Ardeshir Ghavamzadeh
- Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed H Ghaffari
- Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran.
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Ku A, Chan C, Aghevlian S, Cai Z, Cescon D, Bratman SV, Ailles L, Hedley DW, Reilly RM. MicroSPECT/CT Imaging of Cell-Line and Patient-Derived EGFR-Positive Tumor Xenografts in Mice with Panitumumab Fab Modified with Hexahistidine Peptides To Enable Labeling with 99mTc(I) Tricarbonyl Complex. Mol Pharm 2019; 16:3559-3568. [PMID: 31242384 DOI: 10.1021/acs.molpharmaceut.9b00422] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
We aimed to investigate the feasibility of conjugating synthetic hexahistidine peptides (His6) peptides to panitumumab Fab (PmFab) to enable labeling with [99mTc(H2O)3(CO)3]+ complex and study these radioimmunoconjugates for imaging EGFR-overexpressing tumor xenografts in mice by microSPECT/CT. Fab were reacted with a 10-fold excess of sulfo-SMCC to introduce maleimide functional groups for reaction with the terminal thiol on peptides [CGYGGHHHHHH] that harbored the His6 motif. Modification of Fab with His6 peptides was assessed by SDS-PAGE/Western blot, and the number of His6 peptides introduced was quantified by a radiometric assay incorporating 123I-labeled peptides into the conjugation reaction. Radiolabeling was achieved by incubation of PmFab-His6 in PBS, pH 7.0, with [99mTc(H2O)3(CO)3]+ in a 1.4 MBq/μg ratio. The complex was prepared by adding [99mTcO4]- to an Isolink kit (Paul Scherrer Institute). Immunoreactivity was assessed in a direct (saturation) binding assay using MDA-MB-468 human triple-negative breast cancer (TNBC) cells. Tumor and normal tissue uptake and imaging properties of 99mTc-PmFab-His6 (70 μg; 35-40 MBq) injected i.v. (tail vein) were compared to irrelevant 99mTc-Fab 3913 in NOD/SCID mice engrafted subcutaneously (s.c.) with EGFR-overexpressing MDA-MB-468 or PANC-1 human pancreatic ductal carcinoma (PDCa) cell-line derived xenografts (CLX) at 4 and 24 h post injection (p.i.). In addition, tumor imaging studies were performed with 99mTc-PmFab-His6 in mice with patient-derived tumor xenografts (PDX) of TNBC, PDCa, and head and neck squamous cell carcinoma (HNSCC). Biodistribution studies in nontumor bearing Balb/c mice were performed to project the radiation absorbed doses for imaging studies in humans with 99mTc-PmFab-His6. PmFab was derivatized with 0.80 ± 0.03 His6 peptides. Western blot and SDS-PAGE confirmed the presence of His6 peptides. 99mTc-PmFab-His6 was labeled to high radiochemical purity (≥95%), and the Kd for binding to EGFR on MDA-MB-468 cells was 5.5 ± 0.4 × 10-8 mol/L. Tumor uptake of 99mTc-PmFab-His6 at 24 h p.i. was significantly (P < 0.05) higher than irrelevant 99mTc-Fab 3913 in mice with MDA-MB-468 tumors (14.9 ± 3.1%ID/g vs 3.0 ± 0.9%ID/g) and in mice with PANC-1 tumors (5.6 ± 0.6 vs 0.5 ± 0.1%ID/g). In mice implanted orthotopically in the pancreas with the same PDCa PDX, tumor uptake at 24 h p.i. was 4.2 ± 0.2%ID/g. Locoregional metastases of these PDCa tumors in the peritoneum exhibited slightly and significantly lower uptake than the primary tumors (3.1 ± 0.3 vs 4.2 ± 0.3%ID/g; P = 0.02). In mice implanted with different TNBC or HNSCC PDX, tumor uptake at 24 h p.i. was variable and ranged from 3.7 to 11.4%ID/g and 3.8-14.5%ID/g, respectively. MicroSPECT/CT visualized all CLX and PDX tumor xenografts at 4 and 24 h p.i. Dosimetry estimates revealed that in humans, the whole body dose from administration of 740-1110 MBq of 99mTc-PmFab-His6 would be 2-3 mSv, which is less than for a 99mTc-medronate bone scan (4 mSv).
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Affiliation(s)
- Anthony Ku
- Department of Pharmaceutical Sciences , University of Toronto , 144 College Street , Toronto , ON M5S 3M2 , Canada
| | - Conrad Chan
- Department of Pharmaceutical Sciences , University of Toronto , 144 College Street , Toronto , ON M5S 3M2 , Canada
| | - Sadaf Aghevlian
- Department of Pharmaceutical Sciences , University of Toronto , 144 College Street , Toronto , ON M5S 3M2 , Canada
| | - Zhongli Cai
- Department of Pharmaceutical Sciences , University of Toronto , 144 College Street , Toronto , ON M5S 3M2 , Canada
| | | | | | | | | | - Raymond M Reilly
- Department of Pharmaceutical Sciences , University of Toronto , 144 College Street , Toronto , ON M5S 3M2 , Canada.,Department of Medical Imaging , University of Toronto , 263 McCaul Street , Toronto , ON M5T 1W7 , Canada.,Toronto General Research Institute and Joint Department of Medical Imaging , University Health Network , 200 Elizabeth Street , Toronto , ON M5G 2C4 , Canada
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Takakura K, Kawamura A, Torisu Y, Koido S, Yahagi N, Saruta M. The Clinical Potential of Oligonucleotide Therapeutics against Pancreatic Cancer. Int J Mol Sci 2019; 20:ijms20133331. [PMID: 31284594 PMCID: PMC6651255 DOI: 10.3390/ijms20133331] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2019] [Revised: 07/03/2019] [Accepted: 07/03/2019] [Indexed: 02/07/2023] Open
Abstract
Although many diagnostic and therapeutic modalities for pancreatic cancer have been proposed, an urgent need for improved therapeutic strategies remains. Oligonucleotide therapeutics, such as those based on antisense RNAs, small interfering RNA (siRNA), microRNA (miRNA), aptamers, and decoys, are promising agents against pancreatic cancer, because they can identify a specific mRNA fragment of a given sequence or protein, and interfere with gene expression as molecular-targeted agents. Within the past 25 years, the diversity and feasibility of these drugs as diagnostic or therapeutic tools have dramatically increased. Several clinical and preclinical studies of oligonucleotides have been conducted for patients with pancreatic cancer. To support the discovery of effective diagnostic or therapeutic options using oligonucleotide-based strategies, in the absence of satisfactory therapies for long-term survival and the increasing trend of diseases, we summarize the current clinical trials of oligonucleotide therapeutics for pancreatic cancer patients, with underlying preclinical and scientific data, and focus on the possibility of oligonucleotides for targeting pancreatic cancer in clinical implications.
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Affiliation(s)
- Kazuki Takakura
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 105-8461, Japan.
| | - Atsushi Kawamura
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 105-8461, Japan
| | - Yuichi Torisu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 105-8461, Japan
| | - Shigeo Koido
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 105-8461, Japan
| | - Naohisa Yahagi
- Division of Research and Development for Minimally Invasive Treatment, Cancer Center, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Masayuki Saruta
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 105-8461, Japan
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Halfdanarson TR, Foster NR, Kim GP, Meyers JP, Smyrk TC, McCullough AE, Ames MM, Jaffe JP, Alberts SR. A Phase II Randomized Trial of Panitumumab, Erlotinib, and Gemcitabine Versus Erlotinib and Gemcitabine in Patients with Untreated, Metastatic Pancreatic Adenocarcinoma: North Central Cancer Treatment Group Trial N064B (Alliance). Oncologist 2019; 24:589-e160. [PMID: 30679315 PMCID: PMC6516109 DOI: 10.1634/theoncologist.2018-0878] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Accepted: 12/13/2018] [Indexed: 01/05/2023] Open
Abstract
LESSONS LEARNED Dual epidermal growth factor receptor (EGFR)-directed therapy with erlotinib and panitumumab in combination with gemcitabine was superior to gemcitabine and erlotinib, but the clinical relevance is uncertain given the limited role of gemcitabine monotherapy.A significantly longer overall survival was observed in patients receiving the dual EGFR-directed therapy.The dual EGFR-directed therapy resulted in increased toxicity. BACKGROUND Gemcitabine is active in patients with advanced pancreatic adenocarcinoma. The combination of erlotinib, an oral epidermal growth factor receptor (EGFR) inhibitor, and gemcitabine was shown to modestly prolong overall survival when compared with gemcitabine alone. The North Central Cancer Treatment Group (now part of Alliance for Clinical Trials in Oncology) trial N064B compared gemcitabine plus erlotinib versus gemcitabine plus combined EGFR inhibition with erlotinib and panitumumab. METHODS Eligible patients with metastatic adenocarcinoma of the pancreas were randomized to either gemcitabine 1,000 mg/m2 on days 1, 8, and 15 of a 28-day cycle with erlotinib 100 mg p.o. daily (Arm A) or the same combination with the addition of panitumumab 4 mg/kg on days 1 and 15 of a 28-day cycle (Arm B). The primary endpoint of the trial was overall survival. Secondary endpoints included progression-free survival, the confirmed response rate, and toxicity. Comparison between arms for the primary endpoint was done with a one-sided log-rank test, and a p value less than .20 was considered statistically significant. Response rate comparison was done with Fisher's exact test. All other reported p values are two-sided. RESULTS A total of 92 patients were randomized, 46 to each arm. The median overall survival was 4.2 months in Arm A and 8.3 months in Arm B (hazard ratio, 0.817; 95% confidence interval [CI], 0.530-1.260; p = .1792). The progression-free survival was 2.0 months in Arm A and 3.6 months in Arm B (hazard ratio, 0.843; 95% CI, 0.555-1.280; p = .4190). A partial confirmed response was seen in 8.7% of patients on Arm A and 6.5% on Arm B (p = .9999). No patients had a complete response. Grade 3 and higher nonhematologic toxicities were more common in patients on Arm B compared with those on Arm A (82.6% vs. 52.2%; p = .0018). CONCLUSION Dual EGFR-directed therapy resulted in a significant prolongation of overall survival in patients with advanced adenocarcinoma of the pancreas but was associated with substantially increased toxicities. Dual EGFR-directed therapy in combination with gemcitabine alone cannot be recommended for further study, as single-agent gemcitabine is no longer considered an appropriate therapy for otherwise fit patients with metastatic pancreatic cancer.
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Affiliation(s)
| | - Nathan R Foster
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA
- Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Jeffrey P Meyers
- Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota, USA
| | - Thomas C Smyrk
- Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Ann E McCullough
- Department of Pathology and Laboratory Medicine, Mayo Clinic, Scottsdale, Arizona, USA
| | - Matthew M Ames
- Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA
| | - Jeffrry P Jaffe
- Metro-Minnesota Community Oncology Research Consortium, Saint Louis Park, Minnesota, USA
| | - Steven R Alberts
- Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA
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Hanck-Silva G, Fatori Trevizan LN, Petrilli R, de Lima FT, Eloy JO, Chorilli M. A Critical Review of Properties and Analytical/Bioanalytical Methods for Characterization of Cetuximab. Crit Rev Anal Chem 2019; 50:125-135. [DOI: 10.1080/10408347.2019.1581984] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Affiliation(s)
- Gilmar Hanck-Silva
- School of Pharmaceutical Sciences, São Paulo State University (UNESP), Araraquara, São Paulo, Brazil
| | | | - Raquel Petrilli
- School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
| | - Felipe Tita de Lima
- School of Pharmaceutical Sciences, São Paulo State University (UNESP), Araraquara, São Paulo, Brazil
| | - Josimar O. Eloy
- College of Pharmacy, Dentistry and Nursing, Federal University of Ceará (UFC), Fortaleza, Ceará, Brazil
| | - Marlus Chorilli
- School of Pharmaceutical Sciences, São Paulo State University (UNESP), Araraquara, São Paulo, Brazil
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Abendroth A, Noureddine R, Abramczyk M, Paul A, Gerken G, Schmid KW, Markus P, Schumacher B, Wiesweg M, Köhler J, Markus M, Mende B, Dechêne A, Schuler M, Kasper S. Long-term outcome of patients with advanced pancreatic cancer treated with sequential chemotherapies before the era of modern combination therapy protocols. J Cancer Res Clin Oncol 2019; 145:445-455. [PMID: 30430229 DOI: 10.1007/s00432-018-2789-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Accepted: 11/08/2018] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Patients (pts) with locally advanced (LAPC) or metastatic pancreatic ductal adenocarcinoma (mPDAC) have a dismal prognosis. Recently, new combination chemotherapies such as FOLFIRINOX and nab-paclitaxel/gemcitabine have demonstrated superiority over gemcitabine monotherapy. However, a substantial proportion of pts cannot tolerate these intensive front-line protocols. Moreover, the long-term superiority of multiagent protocols over less intensive strategies remains to be shown. To provide a benchmark for future studies, we analyzed the outcome of patients with LAPC or mPDAC treated at the West German Cancer Center before the FOLFIRINOX/nab-paclitaxel + gemcitabine era. METHODS This retrospective analysis included 201 consecutive pts with LAPC and mPDAC treated between 2007 and 2011. Efficacy parameters were correlated with type of chemotherapy, number of treatment lines and clinicopathological parameters. RESULTS Gemcitabine monotherapy was given as first-line therapy in 51.1%, whereas 48.9% received combination chemotherapies such as gemcitabine/oxaliplatin or FOLFOX. Patients received a median of two lines of treatment, with 54.8% receiving second-line and 37.9% receiving third- and further-line therapies. There was no significant difference between gemcitabine monotherapy and combination therapies. Despite moderate activity of first-line treatment, median overall survival for LAPC was 11.3 months and 8.7 months for mPDAC. Multivariate analysis identified age and number of treatment lines as prognostic markers. CONCLUSION The long-term outcome of unselected pts with LAPC and mPDAC treated before the introduction of aggressive multiagent chemotherapy protocols compares favorably with the results of contemporary benchmark trials. This suggests a multifactorial benefit from interdisciplinary care provided over sequential treatment lines at high volume expert centers.
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Affiliation(s)
- A Abendroth
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany
- Medical Faculty, University Duisburg-Essen, Essen, Germany
| | - R Noureddine
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany
| | - M Abramczyk
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany
| | - A Paul
- Department of General, Visceral and Transplant Surgery, West German Cancer Center, University Hospital Essen, Essen, Germany
- German Cancer Consortium (DKTK), Partner site University Hospital Essen, Essen, Germany
- Medical Faculty, University Duisburg-Essen, Essen, Germany
| | - G Gerken
- Department of Gastroenterology and Hepatology, West German Cancer Center, University Hospital Essen, Essen, Germany
- Medical Faculty, University Duisburg-Essen, Essen, Germany
| | - K W Schmid
- West German Cancer Center, Institute of Pathology Essen, University Hospital Essen, Essen, Germany
- German Cancer Consortium (DKTK), Partner site University Hospital Essen, Essen, Germany
- Medical Faculty, University Duisburg-Essen, Essen, Germany
| | - P Markus
- Department of General Surgery and Traumatology, Elisabeth Hospital Essen, Essen, Germany
- Medical Faculty, University Duisburg-Essen, Essen, Germany
| | - B Schumacher
- Department of Gastroenterology, Elisabeth Hospital Essen, Essen, Germany
| | - M Wiesweg
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany
- Medical Faculty, University Duisburg-Essen, Essen, Germany
| | - J Köhler
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany
- Medical Faculty, University Duisburg-Essen, Essen, Germany
| | - M Markus
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany
| | - B Mende
- Central Pharmacy, University Hospital Essen, Essen, Germany
| | - A Dechêne
- Department of Gastroenterology and Hepatology, West German Cancer Center, University Hospital Essen, Essen, Germany
- Medical Faculty, University Duisburg-Essen, Essen, Germany
| | - M Schuler
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany
- German Cancer Consortium (DKTK), Partner site University Hospital Essen, Essen, Germany
- Medical Faculty, University Duisburg-Essen, Essen, Germany
| | - S Kasper
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.
- Medical Faculty, University Duisburg-Essen, Essen, Germany.
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Aghevlian S, Cai Z, Lu Y, Hedley DW, Winnik MA, Reilly RM. Radioimmunotherapy of PANC-1 Human Pancreatic Cancer Xenografts in NRG Mice with Panitumumab Modified with Metal-Chelating Polymers Complexed to 177Lu. Mol Pharm 2019; 16:768-778. [PMID: 30589553 DOI: 10.1021/acs.molpharmaceut.8b01040] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Our aim was to evaluate the effectiveness and normal tissue toxicity of radioimmunotherapy (RIT) of s.c. PANC-1 human pancreatic cancer (PnCa) xenografts in NRG mice using anti-EGFR panitumumab linked to metal-chelating polymers (MCPs) that present 13 DOTA chelators to complex the β-emitter, 177Lu. The clonogenic survival (CS) of PANC-1 cells treated in vitro with panitumumab-MCP-177Lu (0.3-1.2 MBq) and DNA double-strand breaks (DSBs) in the nucleus of these cells were measured by confocal immunofluorescence microscopy for γ-H2AX. Subcellular distribution of radioactivity for panitumumab-MCP-177Lu was measured, and absorbed doses to the cell nucleus were calculated. Normal tissue toxicity was assessed in non tumor-bearing NRG mice by monitoring body weight, complete blood cell counts (CBC), serum alanine aminotransferase (ALT), and creatinine (Cr) after i.v. injection of 6 MBq (10 μg) of panitumumab-MCP-177Lu. RIT was performed in NRG mice with s.c. PANC-1 tumors injected i.v. with 6 MBq (10 μg) of panitumumab-MCP-177Lu. Control mice received nonspecific human IgG-MCP-177Lu (6 MBq; 10 μg), unlabeled panitumumab (10 μg), or normal saline. The tumor growth index (TGI) was compared. Tumor and normal organ doses were estimated based on biodistribution studies. Panitumumab-MCP-177Lu reduced the CS of PANC-1 cells in vitro by 7.7-fold at the highest amount tested (1.2 MBq). Unlabeled panitumumab had no effect on the CS of PANC-1 cells. γ-H2AX foci were increased by 3.8-fold by panitumumab-MCP-177Lu. Panitumumab-MCP-177Lu deposited 3.84 Gy in the nucleus of PANC-1 cells. Administration of panitumumab-MCP-177Lu (6 MBq; 10 μg) to NRG mice caused no change in body weight, CBC, or ALT and only a slight increase in Cr compared to NRG mice treated with normal saline. Panitumumab-MCP-177Lu strongly inhibited tumor growth in NRG mice (TGI = 2.3 ± 0.2) compared to normal saline-treated mice (TGI = 5.8 ± 0.5; P < 0.01). Unlabeled panitumumab had no effect on tumor growth (TGI = 6.0 ± 1.6; P > 0.05). The absorbed dose of PANC-1 tumors was 12.3 Gy. The highest normal organ doses were absorbed by the pancreas, liver, spleen, and kidneys. We conclude that EGFR-targeted RIT with panitumumab-MCP-177Lu was able to overcome resistance to panitumumab in KRAS mutant PANC-1 tumors in NRG mice and may be a promising approach to treatment of PnCa in humans.
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Affiliation(s)
- Sadaf Aghevlian
- Department of Pharmaceutical Sciences , University of Toronto , 144 College Street , Toronto , Ontario M5S 3M2 , Canada
| | - Zhongli Cai
- Department of Pharmaceutical Sciences , University of Toronto , 144 College Street , Toronto , Ontario M5S 3M2 , Canada
| | - Yijie Lu
- Department of Chemistry , University of Toronto , 80 St. George Street , Toronto , Ontario M5S 3H6 , Canada
| | - David W Hedley
- Department of Medical Oncology , Princess Margaret Cancer Centre , 610 University Avenue , Toronto , Ontario M5G 2M9 , Canada
| | - Mitchell A Winnik
- Department of Chemistry , University of Toronto , 80 St. George Street , Toronto , Ontario M5S 3H6 , Canada
| | - Raymond M Reilly
- Department of Pharmaceutical Sciences , University of Toronto , 144 College Street , Toronto , Ontario M5S 3M2 , Canada.,Department of Medical Imaging , University of Toronto , 263 McCaul Street , Toronto , Ontario M5T 1W7 , Canada.,Toronto General Research Institute and Joint Department of Medical Imaging , University Health Network , 200 Elizabeth Street , Toronto , Ontario M5G 2C4 , Canada
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Verma HK, Kampalli PK, Lakkakula S, Chalikonda G, Bhaskar LVKS, Pattnaik S. A Retrospective Look at Anti-EGFR Agents in Pancreatic Cancer Therapy. Curr Drug Metab 2019; 20:958-966. [PMID: 31755384 DOI: 10.2174/1389200220666191122104955] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 09/30/2019] [Accepted: 10/04/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND The introduction of Monoclonal Antibodies (mAbs) and small-molecule Tyrosine Kinase Inhibitors (TKIs) that target the Epidermal Growth Factor Receptor (EGFR), marks a huge step forward in the Pancreatic Cancer (PC) therapy. However, anti-EGFR therapy is found to be successful only in a fraction of patients. Although anti-EGFR agents have shown considerable clinical promise, a serious adverse event associated with anti- EGFR therapy has been challenging. At this juncture, there is still more to be done in the search for effective predictive markers with therapeutic applicability. METHODS A focused literature search was conducted to summarize the existing evidence on anti-EGFR agents in pancreatic cancer therapy. RESULTS This review discusses various anti-EGFR agents currently in use for PC therapy and potential adverse effects associated with it. Existing evidence on EGFR TKIs demonstrated better tolerant effects and outcomes with multiple toxic regimens. Anti-EGFR therapy in combination with chemotherapy is necessary to achieve the best clinical outcomes. CONCLUSION Future prospective studies on the identification of additional biological agents and novel anti-EGFR agents are warranted.
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Affiliation(s)
- Henu K Verma
- Stem Cell Laboratory, Institute of Endocrinology and Oncology, Naples, Italy
| | | | | | - Gayathri Chalikonda
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta GA-30322, United States
| | | | - Smaranika Pattnaik
- Department of Biotechnology and Bioinformatics, Sambalpur University, Sambalpur, India
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Hu XY, Wang R, Jin J, Liu XJ, Cui AL, Sun LQ, Li YP, Li Y, Wang YC, Zhen YS, Miao QF, Li ZR. An EGFR-targeting antibody-drug conjugate LR004-VC-MMAE: potential in esophageal squamous cell carcinoma and other malignancies. Mol Oncol 2018; 13:246-263. [PMID: 30372581 PMCID: PMC6360372 DOI: 10.1002/1878-0261.12400] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 09/27/2018] [Accepted: 10/16/2018] [Indexed: 12/18/2022] Open
Abstract
Epidermal growth factor receptor (EGFR) is a rational target for cancer therapy, because its overexpression plays an important oncogenic role in a variety of solid tumors; however, EGFR‐targeted antibody–drug conjugate (ADC) therapy for esophageal squamous cell carcinoma (ESCC) is exceedingly rare. LR004 is a novel anti‐EGFR antibody with the advantages of improved safety and fewer hypersensitivity reactions. It may be of great value as a carrier in ADCs with high binding affinity and internalization ability. Here, we prepared an EGFR‐targeting ADC, LR004‐VC‐MMAE, and evaluated its antitumor activities against ESCC and EGFR‐positive cells. LR004 was covalently conjugated with monomethyl auristatin E (MMAE) via a VC linker by antibody interchain disulfide bond reduction. VC‐MMAE was conjugated with LR004 with approximately 4.0 MMAE molecules per ADC. LR004‐VC‐MMAE showed a potent antitumor effect against ESCC and other EGFR‐positive cells with IC50 values of nM concentrations in vitro. The in vivo antitumor effects of LR004‐VC‐MMAE were investigated in ESCC KYSE520 and A431 xenograft nude mice models. Significant activity was seen at 5 mg·kg−1, and complete tumor regression was observed at 15 mg·kg−1 in the KYSE520 xenograft nude mice after four injections, while the naked antibody LR004 had little effect on inhibiting tumor growth. Similar promising results were obtained in the A431 models. In addition, the tumors also remained responsive to LR004‐VC‐MMAE for large tumor experiments (tumor volume 400–500 mm3). The study results demonstrated that LR004‐VC‐MMAE could be a potential therapeutic agent for ESCC and other EGFR‐expressing malignancies. We also evaluated PK profile of LR004‐VC‐MMAE ADC in the mice model, which would provide qualitative guiding significance for the further research.
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Affiliation(s)
- Xin-Yue Hu
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Rong Wang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Jie Jin
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Xiu-Jun Liu
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - A-Long Cui
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Lian-Qi Sun
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Yan-Ping Li
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Yi Li
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Yu-Cheng Wang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Yong-Su Zhen
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Qing-Fang Miao
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Zhuo-Rong Li
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
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Bruera G, Massacese S, Candria S, Galvano A, Manetta R, Giordano AV, Carducci S, Di Sibio A, Ciacco E, Russo A, Ricevuto E. Real life triplet FIr/FOx chemotherapy in first-line metastatic pancreatic ductal adenocarcinoma patients: recommended schedule for expected activity and safety and phase II study. Oncotarget 2018; 9:31861-31876. [PMID: 30159128 PMCID: PMC6112758 DOI: 10.18632/oncotarget.25870] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Accepted: 07/18/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Gemcitabine/nab-paclitaxel and FOLFIRINOX demonstrated significantly increased survival compared with gemcitabine in metastatic pancreatic ductal adenocarcinoma (PDAC): objective response rate (ORR) 23 and 31.6%, progression-free survival (PFS) 5.5 and 6.4 months, overall survival (OS) 8.7 and 11.1 months. Present phase II study evaluated recommended first-line triplet FIr/FOx schedule. METHODS Simon two-step design: p010%, p130%, power 80%, α5%, β20%. Projected ORR: I step, 1/10; II 5/29. Schedule: 12h-timed-flat-infusion/5-fluorouracil 750-800-900 mg/m2 d1-2,8-9,15-16,22-23; irinotecan 120-140-160 mg/m2 d1,15; oxaliplatin 70-80 mg/m2 d8,22; every 4 weeks, according to clinical parameters (age, comorbidities, performance status (PS), liver function). Activity and efficacy were evaluated, and compared using log-rank; limiting toxicity syndromes (LTS), using chi-square. RESULTS Twenty-nine consecutive patients were enrolled, according to primary/intermediate/secondary Cumulative Illness Rating Scale (CIRS). Median age 62; elderly 13 (44.7%); PS2 3 (10.4%), secondary CIRS 5 (17.2%). Primary endpoint was met: ORR 53% (7/13 patients) as-treated, 50% intent-to-treat. Cumulative G3-4 toxicities: diarrhea 17%, asthenia 14%, hypertransaminasemy 7%, mucositis 7%, vomiting 3%, anemia 3%, thrombocytopenia 3%. LTS were 27.5% overall, 38.4% in elderly. At 3 months median follow-up, PFS 4 months, OS 11 months. PS2 patients showed significantly worse OS (P 0.022). CONCLUSION Intensive first-line triplet FIr/FOx is tolerable at modulated doses, and confirms high activity/efficacy in metastatic PDAC. Patients' careful selection, and exclusion of PS2, can maintain safety profile and efficient dose intensity.
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Affiliation(s)
- Gemma Bruera
- Oncology Territorial Care Unit, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L’Aquila, L’Aquila, Italy
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
| | - Silvia Massacese
- Pharmacy Unit, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, L’Aquila, Italy
| | - Stefania Candria
- Oncology Territorial Care Unit, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L’Aquila, L’Aquila, Italy
| | - Antonio Galvano
- Medical Oncology Unit, Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy
| | - Rosa Manetta
- Radiology Unit, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, L’Aquila, Italy
| | - Aldo Victor Giordano
- Radiology Unit, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, L’Aquila, Italy
| | - Sergio Carducci
- Radiology Unit, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, L’Aquila, Italy
| | - Alessandra Di Sibio
- Radiology Unit, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, L’Aquila, Italy
| | - Eugenio Ciacco
- Pharmacy Unit, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, L’Aquila, Italy
| | - Antonio Russo
- Medical Oncology Unit, Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy
| | - Enrico Ricevuto
- Oncology Territorial Care Unit, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L’Aquila, L’Aquila, Italy
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
| | - on behalf of Oncology Network ASL1 Abruzzo, Italy
- Oncology Territorial Care Unit, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L’Aquila, L’Aquila, Italy
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
- Pharmacy Unit, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, L’Aquila, Italy
- Medical Oncology Unit, Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy
- Radiology Unit, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, L’Aquila, Italy
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Abstract
Gold nanoparticles (Au NPs) are very attractive and versatile nanoparticles since they have a remarkable capacity to absorb and scatter light, convert optical energy into heat via nonradiative electron relaxation dynamics, and surface chemistries that can be capitalized upon so that the nanoparticles act as drug carriers. Au NPs have excellent stability and biocompatibility, tailorable shapes and sizes, an easily functionalized surface, high drug-loading capacity, and low toxicity. The properties of Au NPs can be leveraged to develop more precisely targeted and effective cancer therapeutics. Au NPs have been used to target delivery of chemotherapeutic agents, complement radiation and thermal therapy, and enhance contrast for in vivo imaging of the tumor in a variety of cancer types and diseased organs.
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Affiliation(s)
- Dean M Connor
- Department of Cell and Molecular Pharmacology & Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, United States; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States
| | - Ann-Marie Broome
- Department of Cell and Molecular Pharmacology & Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, United States; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States; Department of Neurosciences, Medical University of South Carolina, Charleston, SC, United States.
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Xing M, Wang X, Chi Y, Zhou D. Gene therapy for colorectal cancer using adenovirus-mediated full-length antibody, cetuximab. Oncotarget 2017; 7:28262-72. [PMID: 27058423 PMCID: PMC5053725 DOI: 10.18632/oncotarget.8596] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2015] [Accepted: 03/28/2016] [Indexed: 11/25/2022] Open
Abstract
Cetuximab is a chimeric monoclonal antibody, approved to treat patients with metastatic colorectal cancer (mCRC), head and neck squamous cell carcinoma (HNSCC), non-small-cell lung cancer (NSCLC) for years. It functions by blocking the epidermal growth factor receptor (EGFR) from receiving signals or interacting with other proteins. Although the demand for cetuximab for the treatment of cancer patients in clinics is increasing, the complicated techniques involved and its high cost limit its wide applications. Here, a new, cheaper form of cetuximab was generated for cancer gene therapy. This was achieved by cloning the full-length cetuximab antibody into two serotypes of adenoviral vectors, termed as AdC68-CTB and Hu5-CTB. In vivo studies showed that a single dose of AdC68-CTB or Hu5-CTB induced sustained cetuximab expression and dramatically suppressed tumor growth in NCI-H508– or DiFi-inoculated nude mice. In conclusion, gene therapy using adenovirus expressing full-length cetuximab could be a novel alternative method for the effective treatment of colorectal cancer.
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Affiliation(s)
- Man Xing
- Vaccine Research Center, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Science, Shanghai, China
| | - Xiang Wang
- Vaccine Research Center, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Science, Shanghai, China
| | - Yudan Chi
- Vaccine Research Center, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Science, Shanghai, China
| | - Dongming Zhou
- Vaccine Research Center, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Science, Shanghai, China
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Berlin JD, Feng Y, Catalano P, Abbruzzese JL, Philip PA, McWilliams RR, Lowy AM, Benson AB, Blackstock AW. An Intergroup Randomized Phase II Study of Bevacizumab or Cetuximab in Combination with Gemcitabine and in Combination with Chemoradiation in Patients with Resected Pancreatic Carcinoma: A Trial of the ECOG-ACRIN Cancer Research Group (E2204). Oncology 2017; 94:39-46. [PMID: 29040974 PMCID: PMC5828967 DOI: 10.1159/000480295] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Accepted: 08/14/2017] [Indexed: 12/18/2022]
Abstract
OBJECTIVES Evaluate toxicity of two treatment arms, A (cetuximab) and B (bevacizumab), when combined with gemcitabine, and chemoradiation in patients with completely resected pancreatic carcinoma. Secondary objectives included overall survival (OS) and disease-free survival (DFS). METHODS Patients with R0/R1 resection were randomized 1:1 to cetuximab or bevacizumab administered in combination with gemcitabine for two treatment cycles. Next three cycles included concurrent cetuximab/bevacizumab plus chemoradiation, followed by one cycle of cetuximab/bevacizumab. Cycles 7-12 included cetuximab/bevacizumab with gemcitabine. Cycles were 2 weeks. Frequency of specific toxicities was summarized for each treatment arm at two times during the study, after chemotherapy but prior to chemoradiation and after all therapy. RESULTS A total of 127 patients were randomized (A, n = 65; B, n = 62). Prior to chemoradiation, the overall rate for toxicities of interest was 10% for arm A and 2% for arm B. After all therapy, the overall rates for toxicities of interest were 30 and 25% for arms A and B, respectively. Overall median OS and DFS were 17 and 11 months, respectively, which is not a significant improvement over expected survival rates for historical controls. CONCLUSIONS Both treatments were tolerable with manageable toxicities, and were safe enough for a phase III trial had this been indicated.
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Affiliation(s)
| | - Yang Feng
- Dana Farber Cancer Institute, Boston, Massachusetts
| | | | | | - Philip A. Philip
- Karmanos Cancer Center, Wayne State University, Detroit, Michigan
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Abstract
The management of pancreatic cancer has grown rapidly in the last decade. The Gastrointestinal Tumor Study Group trial in 1985 supported postoperative chemoradiation, and a more recent study recommended 6 months of adjuvant gemcitabine and capecitabine or monotherapy with gemcitabine or fluorouracil plus folinic acid, in the absence of neoadjuvant therapy. Clinicians are now studying the role of targeted therapy in pancreatic cancer and neoadjuvant chemotherapy in resectable, borderline resectable, and locally advanced pancreatic cancer. This article critically evaluates the evolution of pancreatic cancer management, focussing on level 1a, prospective randomized control trials from 2007 to 2017.
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Affiliation(s)
- Neha Goel
- Department of Surgical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA
| | - Sanjay S Reddy
- Department of Surgical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
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Randomized Phase II Trial of Irinotecan/Docetaxel or Irinotecan/Docetaxel Plus Cetuximab for Metastatic Pancreatic Cancer: An Eastern Cooperative Oncology Group Study. Am J Clin Oncol 2017; 39:340-5. [PMID: 24685886 PMCID: PMC4177955 DOI: 10.1097/coc.0000000000000068] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Objectives: The primary objective was to determine the response rate in patients with metastatic pancreatic cancer treated in first line with irinotecan/docetaxel combination (Arm A) or with irinotecan/docetaxel/cetuximab combination (Arm B). Secondary endpoints were progression-free survival (PFS), overall survival (OS), toxicity, and the rate of thromboembolic events with prophylactic enoxaparin sodium. Patients and Methods: Patients were eligible who had measurable, metastatic adenocarcinoma of the pancreas, and normal bilirubin. All patients received anticoagulation. Docetaxel (35 mg/m2) and irinotecan (50 mg/m2) were administered once a week for 4 weeks followed by 2 weeks rest (Arm A) alone or with the addition of cetuximab (Arm B). The primary endpoint was response rate. Results: A total of 87 eligible patients were enrolled and treated. Grade 3/4 toxicity was observed in 74% of patients in Arm A and 76% in Arm B. The principal grade 3/4 toxicity was diarrhea. Response rates were 4.5% in Arm A and 7% in Arm B. Median PFS and OS were 3.9 and 6.5 months in Arm A and 4.5 and 5.4 months in Arm B. Conclusions: Docetaxel/irinotecan combination is associated with considerable toxicity. Objective responses were infrequent and addition of cetuximab in an unselected population was not beneficial, but PFS and OS were comparable with those achieved with other regimens. Docetaxel/irinotecan therapy is active in metastatic pancreatic cancer.
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Tandel R, Teradal N, Satpati A, Jaldappagari S. Fabrication of the electrochemically reduced graphene oxide-bismuth nanoparticles composite and its analytical application for an anticancer drug gemcitabine. CHINESE CHEM LETT 2017. [DOI: 10.1016/j.cclet.2016.11.028] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Chiramel J, Backen AC, Pihlak R, Lamarca A, Frizziero M, Tariq NUA, Hubner RA, Valle JW, Amir E, McNamara MG. Targeting the Epidermal Growth Factor Receptor in Addition to Chemotherapy in Patients with Advanced Pancreatic Cancer: A Systematic Review and Meta-Analysis. Int J Mol Sci 2017; 18:E909. [PMID: 28445400 PMCID: PMC5454822 DOI: 10.3390/ijms18050909] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 04/12/2017] [Accepted: 04/18/2017] [Indexed: 12/28/2022] Open
Abstract
Overexpression of epidermal growth factor receptors (EGFR) occurs in >90% of pancreatic ductal adenocarcinomas (PDACs) and is associated with a poorer prognosis. A systematic review of electronic databases identified studies exploring the addition of EGFR-targeted treatment to chemotherapy in patients with locally advanced (LA)/metastatic PDAC. Efficacy, safety and tolerability of EGFR-targeted therapy were explored using meta-analysis of randomised controlled trials (RCTs). Meta-regression was utilised to explore factors associated with improved prognosis (all studies) and benefit from EGFR-targeted therapy (RCTs). Twenty-eight studies (7 RCTs and 21 cohort studies) comprising 3718 patients were included. The addition of EGFR-targeted treatment to chemotherapy did not improve progression-free (pooled hazard ratio (HR): 0.90, p = 0.15) or overall survival (HR: 0.94, p = 0.18). EGFR-targeted therapy was associated with increased treatment-related deaths (pooled odds ratio (OR): 5.18, p = 0.007), and grade (G)3/4 rash (OR: 4.82, p = 0.03). There was a borderline significant increase in G3/4 diarrhoea (OR: 1.75, p = 0.06), but no effect on treatment discontinuation without progression (OR: 0.87, p = 0.25). Neither G3/4 rash nor diarrhoea were associated with increased survival benefit from EGFR-targeted therapy. The effect of EGFR-targeted therapy on overall survival (OS) appeared greater in studies with a greater proportion of LA rather than metastatic patients (R = -0.69, p < 0.001). Further studies in unselected patients with advanced PDAC are not warranted. The benefit from EGFR inhibitors may be limited to patient subgroups not yet clearly defined.
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Affiliation(s)
- Jaseela Chiramel
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK.
| | - Alison C Backen
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK.
| | - Rille Pihlak
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK.
- Division of Molecular & Clinical Cancer Sciences, University of Manchester, Manchester M20 4BX, UK.
| | - Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK.
| | - Melissa Frizziero
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK.
| | - Noor-Ul-Ain Tariq
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK.
- Division of Molecular & Clinical Cancer Sciences, University of Manchester, Manchester M20 4BX, UK.
| | - Richard A Hubner
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK.
| | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK.
- Division of Molecular & Clinical Cancer Sciences, University of Manchester, Manchester M20 4BX, UK.
| | - Eitan Amir
- Department of Medical Oncology, Princess Margaret Cancer Centre/University of Toronto, 610 University Avenue, Toronto, ON M5G 2M9, Canada.
| | - Mairéad G McNamara
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK.
- Division of Molecular & Clinical Cancer Sciences, University of Manchester, Manchester M20 4BX, UK.
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Zhu L, Staley C, Kooby D, El-Rays B, Mao H, Yang L. Current status of biomarker and targeted nanoparticle development: The precision oncology approach for pancreatic cancer therapy. Cancer Lett 2017; 388:139-148. [PMID: 27916607 PMCID: PMC5318282 DOI: 10.1016/j.canlet.2016.11.030] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Revised: 11/15/2016] [Accepted: 11/24/2016] [Indexed: 12/13/2022]
Abstract
Pancreatic cancer remains one of the major causes of cancer-related mortality. The majority of pancreatic cancer patients are diagnosed at the advanced stage with unresectable and drug resistant tumors. The new treatments with the combination of chemotherapy, molecular targeted therapy, and immunotherapy have shown modest effects on therapeutic efficacy and survival of the patients. Therefore, there is an urgent need to develop effective therapeutic approaches targeting highly heterogeneous pancreatic cancer cells and tumor microenvironments. Recent advances in biomarker targeted cancer therapy and image-guided drug delivery and monitoring treatment response using multifunctional nanoparticles, also referred to as theranostic nanoparticles, offer a new opportunity of effective detection and treatment of pancreatic cancer. Increasing evidence from preclinical studies has shown the potential of applications of theranostic nanoparticles for designing precision oncology approaches for pancreatic cancer therapy. In this review, we provide an update on the current understanding and strategies for the development of targeted therapy for pancreatic cancer using nanoparticle drug carriers. We address issues concerning drug delivery barriers in stroma rich pancreatic cancer and the potential approaches to improve drug delivery efficiency, therapeutic responses and tumor imaging. Research results presented in this review suggest the development of an integrated therapy protocol through image-guided and targeted drug delivery and therapeutic effect monitoring as a promising precision oncology strategy for pancreatic cancer treatment.
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Affiliation(s)
- Lei Zhu
- Department of Surgery, Emory University School of Medicine, Atlanta, GA 30322, United States
| | - Charles Staley
- Department of Surgery, Emory University School of Medicine, Atlanta, GA 30322, United States
| | - David Kooby
- Department of Surgery, Emory University School of Medicine, Atlanta, GA 30322, United States
| | - Bassel El-Rays
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, United States
| | - Hui Mao
- Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, GA 30322, United States
| | - Lily Yang
- Department of Surgery, Emory University School of Medicine, Atlanta, GA 30322, United States; Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, GA 30322, United States.
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Andrikou K, Peterle C, Pipitone S, Salati M, Cascinu S. Emerging antibodies for the treatment of pancreatic cancer. Expert Opin Emerg Drugs 2017; 22:39-51. [DOI: 10.1080/14728214.2017.1293649] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Kalliopi Andrikou
- Division of Medical Oncology, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, Modena, Italy
| | - Chiara Peterle
- Division of Medical Oncology, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, Modena, Italy
| | - Stefania Pipitone
- Division of Medical Oncology, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, Modena, Italy
| | - Massimiliano Salati
- Division of Medical Oncology, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, Modena, Italy
| | - Stefano Cascinu
- Division of Medical Oncology, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, Modena, Italy
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Preclinical Rationale for the Phase III Trials in Metastatic Pancreatic Cancer: Is Wishful Thinking Clouding Successful Drug Development for Pancreatic Cancer? Pancreas 2017; 46:143-150. [PMID: 28085753 PMCID: PMC5242389 DOI: 10.1097/mpa.0000000000000753] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Prior phase III trials in advanced pancreatic cancer have been predominantly unsuccessful. In this review, we attempt to understand how past preclinical data were translated into phase III clinical trials in metastatic pancreatic cancer as described in the article. A systematic literature review conducted through the MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases, from January 1997 to June 2015 using key words-phase III clinical trials, metastatic/advanced pancreatic adenocarcinoma or pancreatic cancer identified 30 randomized controlled trials (RCTs) that met criteria. The trials were limited to RCTs in the first-line treatment of patients with metastatic pancreatic cancer. The success rate of first-line phase III studies in advanced pancreatic cancer was only 13%. In 60% of the RCTs, no preclinical experiments were referenced in biologically cognate pancreatic models. Nine (30%) of the RCTs were designed based on preclinical evidence from in vitro cell lines alone without additional in vivo validation in xenograft models. It remains uncertain how strongly the preclinical data influence the development of clinical regimens but so far the studies developed based on more solid preclinical evidence have been successful.
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Frieze DA, McCune JS. Current Status of Cetuximab for the Treatment of Patients with Solid Tumors. Ann Pharmacother 2016; 40:241-50. [PMID: 16403849 DOI: 10.1345/aph.1g191] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Objective: To review the pharmacology, pharmacokinetics, clinical evidence, and safety, as well as the potential directions for use, of the epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab. Data Sources: A MEDLINE search (1966–December 2005) was conducted using the following terms: cetuximab, Erbitux, C225, epidermal growth factor receptor, and EGFR. Additional information was obtained via meeting abstracts, bibliographies from relevant articles, national guidelines, and the manufacturer. Study Selection and Data Extraction: Preclinical and clinical trials utilizing cetuximab in the treatment of solid tumors were selected from the data sources. All published, randomized clinical trials involving cetuximab in treatment of metastatic colorectal cancer and studies providing a description of the pharmacology, pharmacokinetics, safety, or efficacy were included in this review. Data Synthesis: Many solid tumors overexpress EGFR, making it an ideal target for anticancer agents. Cetuximab is the only EGFR monoclonal antibody commercially available and is approved for the treatment of EGFR-expressing, metastatic colorectal cancer in patients refractory or intolerant to irinotecan. Data on patients with other solid tumors are encouraging with cetuximab used as monotherapy or in combination with chemotherapy, radiation, or other targeted agents. Common adverse effects include dermatologic and hypersensitivity reactions. Conclusions: Further clinical data are necessary to clearly define the role of cetuximab in the treatment of patients with solid malignancies, with emphasis on survival and quality-of-life benefits relative to its cost.
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