|
1
|
Chen SL, Wang GP, Shi DR, Yao SH, Chen KD, Yao HP. RON in hepatobiliary and pancreatic cancers: Pathogenesis and potential therapeutic targets. World J Gastroenterol 2021; 27:2507-2520. [PMID: 34092972 PMCID: PMC8160627 DOI: 10.3748/wjg.v27.i20.2507] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 03/04/2021] [Accepted: 04/09/2021] [Indexed: 02/06/2023] Open
Abstract
The receptor protein tyrosine kinase RON belongs to the c-MET proto-oncogene family. Research has shown that RON has a role in cancer pathogenesis, which places RON on the frontline of the development of novel cancer therapeutic strategies. Hepatobiliary and pancreatic (HBP) cancers have a poor prognosis, being reported as having higher rates of cancer-related death. Therefore, to combat these malignant diseases, the mechanism underlying the aberrant expression and signaling of RON in HBP cancer pathogenesis, and the development of RON as a drug target for therapeutic intervention should be investigated. Abnormal RON expression and signaling have been identified in HBP cancers, and also act as tumorigenic determinants for HBP cancer malignant behaviors. In addition, RON is emerging as an important mediator of the clinical prognosis of HBP cancers. Thus, not only is RON significant in HBP cancers, but also RON-targeted therapeutics could be developed to treat these cancers, for example, therapeutic monoclonal antibodies and small-molecule inhibitors. Among them, antibody-drug conjugates have become increasingly popular in current research and their potential as novel anti-cancer biotherapeutics will be determined in future clinical trials.
Collapse
Affiliation(s)
- Shao-Long Chen
- Shulan International Medical College, Zhejiang Shuren University, Hangzhou 310000, Zhejiang Province, China
| | - Guo-Ping Wang
- Department of Surgical Oncology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310000, Zhejiang Province, China
| | - Dan-Rong Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Shu-Hao Yao
- Department of Stomatology, Wenzhou Medical University Renji College, Wenzhou 325035, Zhejiang Province, China
| | - Ke-Da Chen
- Shulan International Medical College, Zhejiang Shuren University, Hangzhou 310000, Zhejiang Province, China
| | - Hang-Ping Yao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| |
Collapse
|
|
2
|
Juan A, Cimas FJ, Bravo I, Pandiella A, Ocaña A, Alonso-Moreno C. Antibody Conjugation of Nanoparticles as Therapeutics for Breast Cancer Treatment. Int J Mol Sci 2020; 21:E6018. [PMID: 32825618 PMCID: PMC7504566 DOI: 10.3390/ijms21176018] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 08/13/2020] [Accepted: 08/18/2020] [Indexed: 02/08/2023] Open
Abstract
Breast cancer is the most common invasive tumor in women and the second leading cause of cancer-related death. Nanomedicine raises high expectations for millions of patients as it can provide better, more efficient, and affordable healthcare, and it has the potential to develop novel therapeutics for the treatment of solid tumors. In this regard, targeted therapies can be encapsulated into nanocarriers, and these nanovehicles are guided to the tumors through conjugation with antibodies-the so-called antibody-conjugated nanoparticles (ACNPs). ACNPs can preserve the chemical structure of drugs, deliver them in a controlled manner, and reduce toxicity. As certain breast cancer subtypes and indications have limited therapeutic options, this field provides hope for the future treatment of patients with difficult to treat breast cancers. In this review, we discuss the application of ACNPs for the treatment of this disease. Given the fact that ACNPs have shown clinical activity in this clinical setting, special emphasis on the role of the nanovehicles and their translation to the clinic is placed on the revision.
Collapse
Affiliation(s)
- Alberto Juan
- Oncología Traslacional, Unidad de Investigación del Complejo Hospitalario Universitario de Albacete, 02008 Albacete, Spain; (A.J.); (F.J.C.)
- Centro Regional de Investigaciones Biomédicas, Unidad NanoCRIB, 02008 Albacete, Spain;
| | - Francisco J. Cimas
- Oncología Traslacional, Unidad de Investigación del Complejo Hospitalario Universitario de Albacete, 02008 Albacete, Spain; (A.J.); (F.J.C.)
- Centro Regional de Investigaciones Biomédicas, Unidad Oncología Traslacional, 02071 Albacete, Spain
| | - Iván Bravo
- Centro Regional de Investigaciones Biomédicas, Unidad NanoCRIB, 02008 Albacete, Spain;
| | - Atanasio Pandiella
- Centro de Investigación del Cáncer-CSIC, IBSAL- Salamanca and CIBERONC, 37007 Salamanca, Spain;
| | - Alberto Ocaña
- Oncología Traslacional, Unidad de Investigación del Complejo Hospitalario Universitario de Albacete, 02008 Albacete, Spain; (A.J.); (F.J.C.)
- Experimental Therapeutics Unit, Hospital clínico San Carlos, IdISSC and CIBERONC, 28040 Madrid, Spain
| | - Carlos Alonso-Moreno
- Centro Regional de Investigaciones Biomédicas, Unidad NanoCRIB, 02008 Albacete, Spain;
- School of Pharmacy, University of Castilla-La Mancha, 02008 Albacete, Spain
| |
Collapse
|
|
3
|
Yao HP, Suthe SR, Tong XM, Wang MH. Targeting RON receptor tyrosine kinase for treatment of advanced solid cancers: antibody-drug conjugates as lead drug candidates for clinical trials. Ther Adv Med Oncol 2020; 12:1758835920920069. [PMID: 32426050 PMCID: PMC7222236 DOI: 10.1177/1758835920920069] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Accepted: 03/27/2020] [Indexed: 02/06/2023] Open
Abstract
The recepteur d'origine nantais (RON) receptor tyrosine kinase, belonging to the mesenchymal-to-epithelial transition proto-oncogene family, has been implicated in the pathogenesis of cancers derived from the colon, lung, breast, and pancreas. These findings lay the foundation for targeting RON for cancer treatment. However, development of RON-targeted therapeutics has not gained sufficient attention for the last decade. Although therapeutic monoclonal antibodies (TMABs) targeting RON have been validated in preclinical studies, results from clinical trials have met with limited success. This outcome diminishes pharmaceutical enthusiasm for further development of RON-targeted therapeutics. Recently, antibody-drug conjugates (ADCs) targeting RON have drawn special attention owing to their increased therapeutic activity. The rationale for developing anti-RON ADCs is based on the observation that cancer cells are not sufficiently addicted to RON signaling for survival. Thus, TMAB-mediated inhibition of RON signaling is ineffective for clinical application. In contrast, anti-RON ADCs combine a target-specific antibody with potent cytotoxins for cancer cell killing. This approach not only overcomes the shortcomings in TMAB-targeted therapies but also holds the promise for advancing anti-RON ADCs into clinical trials. In this review, we discuss the latest advancements in the development of anti-RON ADCs for targeted cancer therapy including drug conjugation profile, pharmacokinetic properties, cytotoxic effect in vitro, efficacy in tumor models, and toxicological activities in primates.
Collapse
Affiliation(s)
- Hang-Ping Yao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Clinical Research Center for Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Sreedhar Reddy Suthe
- Cancer Biology Research Center, Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA
| | - Xiang-Min Tong
- Department of Hematology, Zhejiang Provincial People’s Hospital and People’s Hospital of Hangzhou Medical College, Hangzhou, China
| | - Ming-Hai Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Biology Research Center, Texas Tech University Health Sciences Jerry H. Hodge School of Pharmacy, 1406 Coulter Street, Amarillo, TX 79106, USA
| |
Collapse
|
|
4
|
RON receptor tyrosine kinase in pancreatic ductal adenocarcinoma: Pathogenic mechanism in malignancy and pharmaceutical target for therapy. Biochim Biophys Acta Rev Cancer 2020; 1873:188360. [PMID: 32234337 DOI: 10.1016/j.bbcan.2020.188360] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 03/26/2020] [Accepted: 03/27/2020] [Indexed: 01/14/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with poor prognosis and high mortality. Molecular aberrations associated with PDAC pathogenesis and progression have been extensively investigated. Nevertheless, these findings have not been translated into clinical practice. Lack of therapeutics for PDAC treatment is another challenge. Recent application of molecularly targeted and immunoregulatory therapies appears to be disappointing. Thus, discovery of new targets and therapeutics is urgently needed to combat this malignant disease. The RON receptor tyrosine kinase is a tumorigenic determinant in PDAC malignancy, which provides the rationale to target RON for PDAC treatment. In this review, we summarize the latest evidence of RON in PDAC pathogenesis and the development of anti-RON antibody-drug conjugates for potential PDAC therapy. The finding that anti-RON antibody-drug conjugates show efficacy in preclinical animal models highlights the potential of this novel class of anti-cancer biotherapeutics in future clinical trials.
Collapse
|
|
5
|
Yao HP, Feng L, Weng TH, Hu CY, Suthe SR, Mostofa AGM, Chen LH, Wu ZG, Wang WL, Wang MH. Preclinical Efficacy of Anti-RON Antibody-Drug Conjugate Zt/g4-MMAE for Targeted Therapy of Pancreatic Cancer Overexpressing RON Receptor Tyrosine Kinase. Mol Pharm 2018; 15:3260-3271. [PMID: 29944378 DOI: 10.1021/acs.molpharmaceut.8b00298] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Aberrant expression of the RON receptor tyrosine kinase, a cell surface protein, is a pathogenic feature in pancreatic cancer, which renders it a drug target for targeted therapy. Nevertheless, development of therapeutics targeting RON for pancreatic cancer therapy is hampered due to the lack of full addiction by pancreatic cancer cells to RON signaling for growth and survival. Here we describe a novel strategy using anti-RON antibody-directed drug delivery in the form of an antibody-drug conjugate for inhibition and/or eradication of pancreatic cancers. Monoclonal antibody Zt/g4 specific to the RON Sema domain was selected as the drug carrier based on its ability to induce robust RON internalization. Conjugation of Zt/g4 with monomethyl auristatin E, designated as Zt/g4-MMAE, was achieved through a protease-sensitive dipeptide linker to reach a drug to antibody ratio of 3.29:1. Zt/g4-MMAE was stable in human plasma with a dissociation rate less than 4% within a 10 day period. In vitro, Zt/g4-MMAE rapidly induced RON internalization, resulting in cell cycle arrest followed by massive cell death. The maximal effect was seen in pancreatic cancer cells with more than 10 000 receptor molecules per cell. Zt/g4-MMAE also synergized in vitro with chemotherapeutics including gemcitabine, 5-fluorouracil, and oxaliplatin to further reduce PDAC cell viability. In vivo, Zt/g4-MMAE exerts a long-lasting activity, which not only inhibited but also eradicated pancreatic xenograft tumors. These finding indicate that Zt/g4-directed drug delivery is highly effective for eradicating pancreatic tumors. Thus, Zt/g4-MMAE is a novel biotherapeutic with potential for therapy of RON-expressing pancreatic malignancies.
Collapse
|
|
6
|
Jain SK, Tiwari A, Jain A, Verma A, Saraf S, Panda PK, Gour G. Application Potential of Polymeric Nanoconstructs for Colon-Specific Drug Delivery. ACTA ACUST UNITED AC 2018. [DOI: 10.4018/978-1-5225-4781-5.ch002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Numerous applications of colon-specific drug delivery have been found in a wide array of diseases like irritable bowel syndrome (IBS), inflammatory bowel diseases (ulcerative colitis and Crohn's disease), colorectal cancer, and diverticulitis. Drug delivery to the colon has different anatomic and pathophysiological barriers. In recent advancements, these barriers were overcome by using biodegradable polymeric nanoconstructs, which are exhibiting minimal systemic adverse effects. Various polymeric nanoconstructs (PNCs) such as nanoparticles, micelles, and dendrimers have been exploited for effective targeting to pathological sites of colon. PNCs on oral administration not only protect the bioactive from physicochemical degradation but also prevent premature leakage in the upper parts of gastrointestinal tract. The chapter summarizes various PNCs-based approaches for colon-specific drug delivery.
Collapse
|
|
7
|
Chen JF, Yu BX, Yu R, Ma L, Lv XY, Cheng Y, Ma Q. Monoclonal antibody Zt/g4 targeting RON receptor tyrosine kinase enhances chemosensitivity of bladder cancer cells to Epirubicin by promoting G1/S arrest and apoptosis. Oncol Rep 2017; 37:721-728. [PMID: 28075465 PMCID: PMC5355669 DOI: 10.3892/or.2017.5356] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Accepted: 11/21/2016] [Indexed: 02/05/2023] Open
Abstract
Epirubicin (EPI) is one of the most used intravesical chemotherapy agents after transurethral resection to non-muscle invasive bladder tumors (NMIBC) to prevent cancer recurrence and progression. However, even after resection of bladder tumors and intravesical chemotherapy, half of them will recur and progress. RON is a membrane tyrosine kinase receptor usually overexpressed in bladder cancer cells and associated with poor pathological features. This study aims to investigate the effects of anti-RON monoclonal antibody Zt/g4 on the chemosensitivity of bladder cells to EPI. After Zt/g4 treatment, cell cytotoxicity was significantly increased and cell invasion was markedly suppressed in EPI-treated bladder cancer cells. Further investigation indicated that combing Zt/g4 with EPI promoted cell G1/S-phase arrest and apoptosis, which are the potential mechanisms that RON signaling inhibition enhances chemosensitivity of EPI. Thus, combing antibody-based RON targeted therapy enhances the therapeutic effects of intravesical chemotherapy, which provides new strategy for further improvement of NMIBC patient outcomes.
Collapse
Affiliation(s)
- Jun-Feng Chen
- Translational Research Laboratory for Urology, Ningbo First Hospital, The Affiliated Hospital of Ningbo University, Ningbo, Zhejiang 315010, P.R. China
| | - Bi-Xia Yu
- Translational Research Laboratory for Urology, Ningbo First Hospital, The Affiliated Hospital of Ningbo University, Ningbo, Zhejiang 315010, P.R. China
| | - Rui Yu
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, Zhejiang 315212, P.R. China
| | - Liang Ma
- Translational Research Laboratory for Urology, Ningbo First Hospital, The Affiliated Hospital of Ningbo University, Ningbo, Zhejiang 315010, P.R. China
| | - Xiu-Yi Lv
- Translational Research Laboratory for Urology, Ningbo First Hospital, The Affiliated Hospital of Ningbo University, Ningbo, Zhejiang 315010, P.R. China
| | - Yue Cheng
- Translational Research Laboratory for Urology, Ningbo First Hospital, The Affiliated Hospital of Ningbo University, Ningbo, Zhejiang 315010, P.R. China
| | - Qi Ma
- Translational Research Laboratory for Urology, Ningbo First Hospital, The Affiliated Hospital of Ningbo University, Ningbo, Zhejiang 315010, P.R. China
| |
Collapse
|
|
8
|
Zarei O, Benvenuti S, Ustun-Alkan F, Hamzeh-Mivehroud M, Dastmalchi S. Strategies of targeting the extracellular domain of RON tyrosine kinase receptor for cancer therapy and drug delivery. J Cancer Res Clin Oncol 2016; 142:2429-2446. [PMID: 27503093 DOI: 10.1007/s00432-016-2214-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Accepted: 08/01/2016] [Indexed: 01/22/2023]
Abstract
PURPOSE Cancer is one of the most important life-threatening diseases in the world. The current efforts to combat cancer are being focused on molecular-targeted therapies. The main purpose of such approaches is based on targeting cancer cell-specific molecules to minimize toxicity for the normal cells. RON (Recepteur d'Origine Nantais) tyrosine kinase receptor is one of the promising targets in cancer-targeted therapy and drug delivery. METHODS In this review, we will summarize the available agents against extracellular domain of RON with potential antitumor activities. RESULTS The presented antibodies and antibody drug conjugates against RON in this review showed wide spectrum of in vitro and in vivo antitumor activities promising the hope for them entering the clinical trials. CONCLUSION Due to critical role of extracellular domain of RON in receptor activation, the development of therapeutic agents against this region could lead to fruitful outcome in cancer therapy.
Collapse
Affiliation(s)
- Omid Zarei
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
- Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Students Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Silvia Benvenuti
- Molecular Therapeutics and Exploratory Research Laboratory, Candiolo Cancer Institute-FPO-IRCCS, Candiolo, Turin, Italy
| | - Fulya Ustun-Alkan
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Istanbul University, Istanbul, Turkey
| | - Maryam Hamzeh-Mivehroud
- Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Medicinal Chemistry, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Siavoush Dastmalchi
- Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Medicinal Chemistry, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
| |
Collapse
|
|
9
|
Feng L, Yao HP, Zhou YQ, Zhou J, Zhang R, Wang MH. Biological evaluation of antibody-maytansinoid conjugates as a strategy of RON targeted drug delivery for treatment of non-small cell lung cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2016; 35:70. [PMID: 27102688 PMCID: PMC4840490 DOI: 10.1186/s13046-016-0347-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Accepted: 04/13/2016] [Indexed: 11/18/2022]
Abstract
Background Aberrant expression of the RON receptor tyrosine kinase, a member of the MET proto-oncogene family, in breast cancer and non-small cell lung cancer (NSCLC) has therapeutic implication. Here we evaluated the efficacy of a novel anti-RON antibody-drug maytansinoid conjugate Zt/g4-DM1 for treatment of breast and NSCLC xenograft tumors in mouse models and explored a treatment strategy by combination of Zt/g4-DM1 with chemotherapeutics to achieve the maximal therapeutic activity. Methods Mouse monoclonal antibody Zt/g4 (IgG1a/κ) specific to human RON was conjugated to DM1 via thioether linkage to form Zt/g4-DM1 with a drug-antibody ratio of 4:1. Several breast cancer and NSCLC cell lines, expressing different levels of RON, were used as the model. Immunofluorescence was used to determine Zt/g4-induced RON internalization. Flow cytometric analysis and cell viability assay were used to determine the effect of Zt-g4-DM1 on cell cycle and death. Mouse xenograft NSCLC models were used in vivo to determine the therapeutic efficacy of Zt/g4-DM1 alone or in combination with chemotherapeutics. Results In vitro, Zt/g4 treatment of breast cancer and NSCLC cells rapidly induced cell surface RON internalization, which results in intracellular delivery of DM1 sufficient to arrest cell cycle at G2/M phase, reduce cell viability, and cause massive cell death. In mouse tumor xenograft models, Zt/g4-DM1 at 20 mg/kg in a Q12 × 2 regimen effectively blocked breast cancer and NSCLC cell- mediated tumor growth. More than 95 % inhibition of tumor growth among three tumor xenograft models tested was achieved according to the measured tumor volume. The minimal dose to balance the tumor growth and inhibition (tumoristatic concentration) was established at 2.02 mg/kg for H2228, 1.94 mg/kg for H358 cell, and 6.25 mg/kg for T-47D cell-mediated xenograft tumors. Conclusion Zt/g4 is highly effective in RON-directed drug delivery for targeted inhibition of NSCLC cell-derived tumor growth in mouse xenograft models. This work provides the basis for clinical development of humanized Zt/g4-DM1 for potential cancer therapy in the future.
Collapse
Affiliation(s)
- Liang Feng
- State Key Laboratory for Diagnosis & Treatment of Infectious Diseases and Collaborative Innovation Center for Diagnosis & Treatment of Infectious Diseases, First Hospital of Zhejiang University School of Medicine, Zhejiang, China.,Department of Biomedical Sciences, Texas Tech University Health Sciences Center School of Pharmacy, 1406 Coulter Street, Suite 1117, Amarillo, TX, 79106, USA
| | - Hang-Ping Yao
- State Key Laboratory for Diagnosis & Treatment of Infectious Diseases and Collaborative Innovation Center for Diagnosis & Treatment of Infectious Diseases, First Hospital of Zhejiang University School of Medicine, Zhejiang, China.,Department of Biomedical Sciences, Texas Tech University Health Sciences Center School of Pharmacy, 1406 Coulter Street, Suite 1117, Amarillo, TX, 79106, USA
| | - Yong-Qing Zhou
- Department of Neurosurgery, First Hospital of Zhejiang University School of Medicine, Zhejiang, China
| | - Jianwei Zhou
- Department of Molecular Cell Biology & Toxicology, Nanjing Medical University School of Public Health, Jiangsu, China
| | - Ruiwen Zhang
- Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center School of Pharmacy, Amarillo, TX, USA
| | - Ming-Hai Wang
- State Key Laboratory for Diagnosis & Treatment of Infectious Diseases and Collaborative Innovation Center for Diagnosis & Treatment of Infectious Diseases, First Hospital of Zhejiang University School of Medicine, Zhejiang, China. .,Department of Biomedical Sciences, Texas Tech University Health Sciences Center School of Pharmacy, 1406 Coulter Street, Suite 1117, Amarillo, TX, 79106, USA.
| |
Collapse
|
|
10
|
|
|
11
|
Feng L, Yao HP, Wang W, Zhou YQ, Zhou J, Zhang R, Wang MH. Efficacy of anti-RON antibody Zt/g4-drug maytansinoid conjugation (Anti-RON ADC) as a novel therapeutics for targeted colorectal cancer therapy. Clin Cancer Res 2014; 20:6045-58. [PMID: 25294907 DOI: 10.1158/1078-0432.ccr-14-0898] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
PURPOSE The receptor tyrosine kinase RON is critical in epithelial tumorigenesis and a drug target for cancer therapy. Here, we report the development and therapeutic efficacy of a novel anti-RON antibody Zt/g4-maytansinoid (DM1) conjugates for targeted colorectal cancer (CRC) therapy. EXPERIMENTAL DESIGN Zt/g4 (IgG1a/κ) was conjugated to DM1 via thioether linkage to form Zt/g4-DM1 with a drug-antibody ratio of 4:1. CRC cell lines expressing different levels of RON were tested in vitro to determine Zt/g4-DM1-induced RON endocytosis, cell-cycle arrest, and cytotoxicity. Efficacy of Zt/g4-DM1 in vivo was evaluated in mouse xenograft CRC tumor model. RESULTS Zt/g4-DM1 rapidly induced RON endocytosis, arrested cell cycle at G2-M phase, reduced cell viability, and caused massive cell death within 72 hours. In mouse xenograft CRC models, Zt/g4-DM1 at a single dose of 20 mg/kg body weight effectively delayed CRC cell-mediated tumor growth up to 20 days. In a multiple dose-ranging study with a five injection regimen, Zt/g4-DM1 inhibited more than 90% tumor growth at doses of 7, 10, and 15 mg/kg body weight. The minimal dose achieving 50% of tumor inhibition was approximately 5.0 mg/kg. The prepared Zt/g4-DM1 is stable at 37°C for up to 30 days. At 60 mg/kg, Zt/g4-DM1 had a moderate toxicity in vivo with an average of 12% reduction in mouse body weight. CONCLUSION Zt/g4-DM1 is highly effective in targeted inhibition of CRC cell-derived tumor growth in mouse xenograft models. This work provides the basis for development of humanized Zt/g4-DM1 for RON-targeted CRC therapy in the future.
Collapse
Affiliation(s)
- Liang Feng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Hospital of Zhejiang University School of Medicine, Zhejiang, China. Department of Biomedical Sciences, Texas Tech University Health Sciences Center School of Pharmacy, Amarillo, Texas
| | - Hang-Ping Yao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Hospital of Zhejiang University School of Medicine, Zhejiang, China
| | - Wei Wang
- Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center School of Pharmacy, Amarillo, Texas
| | - Yong-Qing Zhou
- Department of Neurosurgery, First Hospital of Zhejiang University School of Medicine, Zhejiang, China
| | - Jianwei Zhou
- Department of Molecular Cell Biology and Toxicology, Nanjing Medical University School of Public Health, Jiangsu, China
| | - Ruiwen Zhang
- Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center School of Pharmacy, Amarillo, Texas
| | - Ming-Hai Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Hospital of Zhejiang University School of Medicine, Zhejiang, China. Department of Biomedical Sciences, Texas Tech University Health Sciences Center School of Pharmacy, Amarillo, Texas.
| |
Collapse
|
|
12
|
Hua S. Orally administered liposomal formulations for colon targeted drug delivery. Front Pharmacol 2014; 5:138. [PMID: 24959147 PMCID: PMC4050429 DOI: 10.3389/fphar.2014.00138] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2014] [Accepted: 05/22/2014] [Indexed: 01/05/2023] Open
Affiliation(s)
- Susan Hua
- School of Biomedical Sciences and Pharmacy, The University of Newcastle Callaghan, NSW, Australia
| |
Collapse
|
|
13
|
Minn I, Menezes ME, Sarkar S, Yarlagadda K, Das SK, Emdad L, Sarkar D, Fisher PB, Pomper MG. Molecular-genetic imaging of cancer. Adv Cancer Res 2014; 124:131-69. [PMID: 25287688 PMCID: PMC4339000 DOI: 10.1016/b978-0-12-411638-2.00004-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Molecular-genetic imaging of cancer using nonviral delivery systems has great potential for clinical application as a safe, efficient, noninvasive tool for visualization of various cellular processes including detection of cancer, and its attendant metastases. In recent years, significant effort has been expended in overcoming technical hurdles to enable clinical adoption of molecular-genetic imaging. This chapter will provide an introduction to the components of molecular-genetic imaging and recent advances on each component leading to safe, efficient clinical applications for detecting cancer. Combination with therapy, namely, generating molecular-genetic theranostic constructs, will provide further impetus for clinical translation of this promising technology.
Collapse
Affiliation(s)
- Il Minn
- Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland, USA
| | | | - Siddik Sarkar
- Department of Human and Molecular Genetics, Richmond, Virginia, USA
| | - Keerthi Yarlagadda
- Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland, USA
| | - Swadesh K Das
- Department of Human and Molecular Genetics, Richmond, Virginia, USA; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
| | - Luni Emdad
- Department of Human and Molecular Genetics, Richmond, Virginia, USA; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
| | - Devanand Sarkar
- Department of Human and Molecular Genetics, Richmond, Virginia, USA; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
| | - Paul B Fisher
- Department of Human and Molecular Genetics, Richmond, Virginia, USA; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
| | - Martin G Pomper
- Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.
| |
Collapse
|
|
14
|
Abstract
Since the discovery of MSP (macrophage-stimulating protein; also known as MST1 and hepatocyte growth factor-like (HGFL)) as the ligand for the receptor tyrosine kinase RON (also known as MST1R) in the early 1990s, the roles of this signalling axis in cancer pathogenesis has been extensively studied in various model systems. Both in vitro and in vivo evidence has revealed that MSP-RON signalling is important for the invasive growth of different types of cancers. Currently, small-molecule inhibitors and antibodies blocking RON signalling are under investigation. Substantial responses have been achieved in human tumour xenograft models, laying the foundation for clinical validation. In this Review, we discuss recent advances that demonstrate the importance of MSP-RON signalling in cancer and its potential as a therapeutic target.
Collapse
Affiliation(s)
- Hang-Ping Yao
- Viral Oncogenesis Section in State Key Laboratory for Diagnosis & Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P. R. China
| | | | | | | |
Collapse
|
|
15
|
Trad A, Hansen HP, Shomali M, Peipp M, Klausz K, Hedemann N, Yamamoto K, Mauermann A, Desel C, Lorenzen I, Lemke H, Rose-John S, Grötzinger J. ADAM17-overexpressing breast cancer cells selectively targeted by antibody-toxin conjugates. Cancer Immunol Immunother 2013; 62:411-21. [PMID: 22940887 PMCID: PMC11028912 DOI: 10.1007/s00262-012-1346-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2012] [Accepted: 08/17/2012] [Indexed: 11/25/2022]
Abstract
A disintegrin and metalloproteinase 17 (ADAM17) is significantly upregulated not only in malignant cells but also in the pro-inflammatory microenvironment of breast cancer. There, ADAM17 is critically involved in the processing of tumor-promoting proteins. Therefore, ADAM17 appears to be an attractive therapeutic target to address not only tumor cells but also the tumor-promoting environment. In a previous study, we generated a monoclonal anti-ADAM17 antibody (A300E). Although showing no complement-dependent cytotoxicity or antibody-dependent cellular cytotoxicity, the antibody was rapidly internalized by ADAM17-expressing cells and was able to transport a conjugated toxin into target cells. As a result, doxorubicin-coupled A300E or Pseudomonas exotoxin A-loaded A300E was able to kill ADAM17-expressing cells. This effect was strictly dependent on the presence of ADAM17 on the surface of target cells. As a proof of principle, both immunotoxins killed MDA-MB-231 breast cancer cells in an ADAM17-dependent manner. These data suggest that the use of anti-ADAM17 monoclonal antibodies as a carrier might be a promising new strategy for selective anti-cancer drug delivery.
Collapse
Affiliation(s)
- Ahmad Trad
- Institute of Biochemistry, Christian-Albrechts-University of Kiel, Olshausenstr. 40, 24098 Kiel, Germany
| | - Hinrich P. Hansen
- Laboratory of Immunotherapy, Department I of Internal Medicine, University Clinic of Cologne, Cologne, Germany
| | - Mohammad Shomali
- Institute of Biochemistry, Christian-Albrechts-University of Kiel, Olshausenstr. 40, 24098 Kiel, Germany
| | - Matthias Peipp
- Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University, Kiel, Germany
| | - Katja Klausz
- Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University, Kiel, Germany
| | - Nina Hedemann
- Institute of Biochemistry, Christian-Albrechts-University of Kiel, Olshausenstr. 40, 24098 Kiel, Germany
| | - Kosuke Yamamoto
- Institute of Biochemistry, Christian-Albrechts-University of Kiel, Olshausenstr. 40, 24098 Kiel, Germany
| | - André Mauermann
- Institute of Biochemistry, Christian-Albrechts-University of Kiel, Olshausenstr. 40, 24098 Kiel, Germany
| | - Christine Desel
- Institute of Biochemistry, Christian-Albrechts-University of Kiel, Olshausenstr. 40, 24098 Kiel, Germany
| | - Inken Lorenzen
- Institute of Biochemistry, Christian-Albrechts-University of Kiel, Olshausenstr. 40, 24098 Kiel, Germany
| | - Hilmar Lemke
- Institute of Biochemistry, Christian-Albrechts-University of Kiel, Olshausenstr. 40, 24098 Kiel, Germany
| | - Stefan Rose-John
- Institute of Biochemistry, Christian-Albrechts-University of Kiel, Olshausenstr. 40, 24098 Kiel, Germany
| | - Joachim Grötzinger
- Institute of Biochemistry, Christian-Albrechts-University of Kiel, Olshausenstr. 40, 24098 Kiel, Germany
| |
Collapse
|
|
16
|
Ma Q, Zhang K, Guin S, Zhou YQ, Wang MH. Deletion or insertion in the first immunoglobulin-plexin-transcription (IPT) domain differentially regulates expression and tumorigenic activities of RON receptor Tyrosine Kinase. Mol Cancer 2010; 9:307. [PMID: 21114864 PMCID: PMC3001714 DOI: 10.1186/1476-4598-9-307] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2010] [Accepted: 11/29/2010] [Indexed: 12/28/2022] Open
Abstract
Background Activation of the RON receptor tyrosine kinase, a member of the c-MET family, regulates tumorigenic phenotypes. The RON extracellular domains are critical in regulating these activities. The objective of this study was to determine the role of the first IPT domain in regulating RON-mediated tumorigenic activities and the underlying mechanisms. Results Two RON variants, RON160 and RONE5/6in with deletion and insertion in the first IPT domain, respectively, were molecularly cloned. RON160 was a splicing variant generated by deletion of 109 amino acids encoded by exons 5 and 6. In contrast, RONE5/6in was derived from a transcript with an insertion of 20 amino acids between exons 5 and 6. Both RON160 and RONE5/6in were proteolytically matured into two-chain receptor and expressed on the cell surface. RON160 was constitutively active with tyrosine phosphorylation. However, activation of RONE5/6in required ligand stimulation. Deletion resulted in the resistance of RON160 to proteolytic digestion by cell associated trypsin-like enzymes. RON160 also resisted anti-RON antibody-induced receptor internalization. These features contributed to sustained intracellular signaling cascades. On the other hand, RONE5/6in was highly susceptible to protease digestion, which led to formation of a truncated variant known as RONp110. RONE5/6in also underwent rapid internalization upon anti-RON antibody treatment, which led to signaling attenuation. Although ligand-induced activation of RONE5/6in partially caused epithelial to mesenchymal transition (EMT), it was RON160 that showed cell-transforming activities in cell focus formation and anchorage-independent growth. RON160-mediated EMT is also associated with increased motile/invasive activity. Conclusions Alterations in the first IPT domain in extracellular region differentially regulate RON mediated tumorigenic activities. Deletion of the first IPT results in formation of oncogenic variant RON160. Enhanced degradation and internalization with attenuated signaling cascades could be the mechanisms underlying non-tumorigenic features of RONE5/6in.
Collapse
Affiliation(s)
- Qi Ma
- Laboratory of Cancer Biology in State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P, R, China
| | | | | | | | | |
Collapse
|