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1
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Xu Z, Jia H, Yin X. Delayed cardiotoxicity following osimertinib therapy in non-small cell lung cancer: a unique case report. Anticancer Drugs 2024; 35:556-558. [PMID: 38453155 DOI: 10.1097/cad.0000000000001595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/09/2024]
Abstract
This case report features a 62-year-old male with stage IB lung adenocarcinoma harboring an epidermal growth factor receptor exon 19 deletion, who underwent treatment with osimertinib following a left upper lobectomy and lymph node dissection. Despite a history of smoking and well-managed type 2 diabetes, the patient developed heart failure 18 months post-initiation of osimertinib therapy, marking one of the latest occurrences of heart failure following osimertinib treatment documented in limited literature. Cardiac MRI revealed significant left ventricular enlargement, lateral wall myocardial thinning, and localized myocardial fibrosis without perfusion defects, a finding not previously reported in literature. This case underscores the severe and unusual cardiac effects of osimertinib in patients with latent risk factors, highlighting the importance of vigilant cardiac monitoring and a multidisciplinary management approach.
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Affiliation(s)
| | | | - Xiaoping Yin
- Department of Radiology, Affiliated Hospital of Hebei University, Baoding, China
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2
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Green JR, Mahalingaiah PKS, Gopalakrishnan SM, Liguori MJ, Mittelstadt SW, Blomme EAG, Van Vleet TR. Off-target pharmacological activity at various kinases: Potential functional and pathological side effects. J Pharmacol Toxicol Methods 2023; 123:107468. [PMID: 37553032 DOI: 10.1016/j.vascn.2023.107468] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 06/16/2023] [Accepted: 08/01/2023] [Indexed: 08/10/2023]
Abstract
In drug discovery, during the lead optimization and candidate characterization stages, novel small molecules are frequently evaluated in a battery of in vitro pharmacology assays to identify potential unintended, off-target interactions with various receptors, transporters, ion channels, and enzymes, including kinases. Furthermore, these screening panels may also provide utility at later stages of development to provide a mechanistic understanding of unexpected safety findings. Here, we present a compendium of the most likely functional and pathological outcomes associated with interaction(s) to a panel of 95 kinases based on an extensive curation of the scientific literature. This panel of kinases was designed by AbbVie based on safety-related data extracted from the literature, as well as from over 20 years of institutional knowledge generated from discovery efforts. For each kinase, the scientific literature was reviewed using online databases and the most often reported functional and pathological effects were summarized. This work should serve as a practical guide for small molecule drug discovery scientists and clinical investigators to predict and/or interpret adverse effects related to pharmacological interactions with these kinases.
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Affiliation(s)
- Jonathon R Green
- Departments of Preclinical Safety, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, United States.
| | | | - Sujatha M Gopalakrishnan
- Drug Discovery Science and Technology, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, United States
| | - Michael J Liguori
- Departments of Preclinical Safety, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, United States
| | - Scott W Mittelstadt
- Departments of Preclinical Safety, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, United States
| | - Eric A G Blomme
- Departments of Preclinical Safety, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, United States
| | - Terry R Van Vleet
- Departments of Preclinical Safety, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, United States
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3
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Bikomeye JC, Terwoord JD, Santos JH, Beyer AM. Emerging mitochondrial signaling mechanisms in cardio-oncology: beyond oxidative stress. Am J Physiol Heart Circ Physiol 2022; 323:H702-H720. [PMID: 35930448 PMCID: PMC9529263 DOI: 10.1152/ajpheart.00231.2022] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 07/29/2022] [Accepted: 07/29/2022] [Indexed: 12/27/2022]
Abstract
Many anticancer therapies (CTx) have cardiotoxic side effects that limit their therapeutic potential and cause long-term cardiovascular complications in cancer survivors. This has given rise to the field of cardio-oncology, which recognizes the need for basic, translational, and clinical research focused on understanding the complex signaling events that drive CTx-induced cardiovascular toxicity. Several CTx agents cause mitochondrial damage in the form of mitochondrial DNA deletions, mutations, and suppression of respiratory function and ATP production. In this review, we provide a brief overview of the cardiovascular complications of clinically used CTx agents and discuss current knowledge of local and systemic secondary signaling events that arise in response to mitochondrial stress/damage. Mitochondrial oxidative stress has long been recognized as a contributor to CTx-induced cardiotoxicity; thus, we focus on emerging roles for mitochondria in epigenetic regulation, innate immunity, and signaling via noncoding RNAs and mitochondrial hormones. Because data exploring mitochondrial secondary signaling in the context of cardio-oncology are limited, we also draw upon clinical and preclinical studies, which have examined these pathways in other relevant pathologies.
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Affiliation(s)
- Jean C Bikomeye
- Doctorate Program in Public and Community Health, Division of Epidemiology and Social Sciences, Institute for Health and Equity, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Janée D Terwoord
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin
- Biomedical Sciences Department, Rocky Vista University, Ivins, Utah
| | - Janine H Santos
- Mechanistic Toxicology Branch, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina
| | - Andreas M Beyer
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin
- Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
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4
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Veeder JA, Hothem LN, Cipriani AE, Jensen BC, Rodgers JE. Chemotherapy-associated cardiomyopathy: Mechanisms of toxicity and cardioprotective strategies. Pharmacotherapy 2021; 41:1066-1080. [PMID: 34806206 DOI: 10.1002/phar.2638] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 10/07/2021] [Accepted: 10/15/2021] [Indexed: 01/01/2023]
Abstract
OBJECTIVE To describe the proposed mechanisms of chemotherapy-associated cardiomyopathy (CAC) and potential cardioprotective therapies for CAC including a comprehensive review of existing systematic analyses, guideline recommendations, and ongoing clinical trials. DATA SOURCES A literature search of MEDLINE was performed (from 1990 to June 2020) using the following search terms: anthracycline, trastuzumab, cardiomyopathy, cardiotoxicity, primary prevention, angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), beta blocker, dexrazoxane (DEX) as well as using individual names from select therapeutic categories. STUDY SELECTION AND DATA EXTRACTION Existing English language systematic analyses and guidelines were considered. DATA SYNTHESIS The mechanisms of CAC are multifaceted, but various cardioprotective therapies target many of these pathways. To date, anthracyclines and HER-2 targeted therapies have been the focus of cardioprotective trials to date as they are the most commonly implicated therapies in CAC. While traditional neurohormonal antagonists (ACEIs, ARBs, and beta blockers) and DEX performed favorably in many small clinical trials, the quality of available evidence remains limited. Hence, major guidelines lack consensus on an approach to primary prevention of CAC. Given the uncertain role of preventive therapy, monitoring for a symptomatic or asymptomatic decline in LV function is imperative with prompt evaluation should this occur. Numerous ongoing randomized controlled trials seek to either confirm the findings of these previous studies or identify new therapeutic agents to prevent CAC. Clinical implications are derived from the available literature as well as current guideline recommendations for CAC cardioprotection. CONCLUSION At this time, no single therapy has a clear cardioprotective benefit in preventing CAC nor is any therapy strongly recommended by current guidelines. Additional studies are needed to determine the optimal preventative regimens.
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Affiliation(s)
- Justin A Veeder
- UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina, USA
- AstraZeneca, Nashville, Tennessee, USA
| | - Lauren N Hothem
- UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina, USA
- GlaxoSmithKline, Research Triangle, North Carolina, USA
| | - Amber E Cipriani
- UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina, USA
- Department of Pharmacy, University of North Carolina Medical Center, Chapel Hill, North Carolina, USA
| | - Brian C Jensen
- Department of Medicine, University of North Carolina Medical Center, Chapel Hill, North Carolina, USA
| | - Jo E Rodgers
- UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina, USA
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5
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Cai JH, Zheng JH, Lin XQ, Lin WX, Zou J, Chen YK, Li ZY, Chen YX. Individualized treatment of breast cancer with chronic renal failure: A case report and review of literature. World J Clin Cases 2021; 9:10345-10354. [PMID: 34904109 PMCID: PMC8638037 DOI: 10.12998/wjcc.v9.i33.10345] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 09/05/2021] [Accepted: 09/23/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Studies have shown that patients with chronic renal failure (CRF) are more likely to suffer from breast cancer and other malignant tumors. To our knowledge, CRF can reduce drug excretion, thereby increase drug exposure and lead to increased toxicity, which will limit drug treatment and lead to tumor progression. Currently, there are few successful reports on the combination of docetaxel, trastuzumab, and pertuzumab (THP) as a neoadjuvant treatment regimen for breast cancer patients with CRF.
CASE SUMMARY We report a breast cancer (cT2N2M0, Her-2+/HR-) patient with CRF. It was a clinical stage IIIA tumor on the left breast. The patient had suffered from uremia for 2 years, and her heart function was normal. Based on the pathological type, molecular type, and clinical stage of breast cancer, and the patient’s renal function, the clinician analyzed the pharmacological and pharmacokinetic characteristics of the antitumor drugs after consulting the relevant literature, and prescribed the neoadjuvant regimen of THP (docetaxel 80 mg/m², trastuzumab 8 mg/kg for the first dose, and 6 mg/kg for the maintenance dose with pertuzumab 840 mg for the first dose and 420 mg for the maintenance dose), once every 3 wk, for a total of 6 courses. The neoadjuvant treatment had a good effect, and the patient then underwent surgery which was uneventful.
CONCLUSION CRF is not a contraindication for systemic treatment and surgery of breast cancer. The THP regimen without dose adjustment may be a safe and effective neoadjuvant treatment for HER-2 positive breast cancer patients with CRF.
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Affiliation(s)
- Jie-Hui Cai
- Department of General Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Jie-Hua Zheng
- Department of General Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Xiao-Qi Lin
- Department of General Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
- Breast Disease Research Center, The Medical Research Institute of Shantou Doctoral Association, Shantou 515041, Guangdong Province, China
| | - Wei-Xun Lin
- Department of General Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
- Breast Disease Research Center, The Medical Research Institute of Shantou Doctoral Association, Shantou 515041, Guangdong Province, China
| | - Juan Zou
- Department of General Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
- Breast Disease Research Center, The Medical Research Institute of Shantou Doctoral Association, Shantou 515041, Guangdong Province, China
| | - Yao-Kun Chen
- Department of General Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
- Breast Disease Research Center, The Medical Research Institute of Shantou Doctoral Association, Shantou 515041, Guangdong Province, China
| | - Zhi-Yang Li
- Department of General Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Ye-Xi Chen
- Department of General Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
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6
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Ikebe S, Amiya R, Minami S, Ihara S, Higuchi Y, Komuta K. Osimertinib-induced cardiac failure with QT prolongation and torsade de pointes in a patient with advanced pulmonary adenocarcinoma. Int Cancer Conf J 2021; 10:68-71. [PMID: 33489705 PMCID: PMC7797397 DOI: 10.1007/s13691-020-00450-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Accepted: 09/26/2020] [Indexed: 12/14/2022] Open
Abstract
Osimertinib-induced cardiotoxicity is a well-known but rare disorder. An 84-year-old woman was diagnosed with recurrence of lung adenocarcinoma showing an epidermal growth factor receptor mutation of exon 19 deletion, which was initially treated by curative-intent thoracic radiotherapy 4 years prior. She started taking osimertinib (80 mg/day). She had no history of heart disease and showed no signs of cardiac problems. However, 2 months later she presented with symptoms of cardiac failure and QT prolongation on electrocardiogram. Cardiac enzyme levels were not elevated and coronary computed tomography angiography showed no significant stenosis. On admission, sudden-onset torsade de pointes required electrocardioversion. Thus, drug-induced cardiac failure was strongly suspected and we stopped osimertinib therapy. Cardiac function and the electrocardiogram abnormality improved. To our knowledge, this is the third case of coincidence of cardiac failure and QT prolongation and the second case of sudden-onset torsade de pointes associated with osimertinib treatment. In our case, osimertinib-induced cardiac failure with QT prolongation was recovered by stopping the drug treatment. The potential for cardiotoxicity should be considered with osimertinib treatment.
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Affiliation(s)
- Saori Ikebe
- Department of Respiratory Medicine, Osaka Police Hospital, 10-31 Kitayama-cho, Tennoji-ku, Osaka, 543-0035 Japan
| | - Ryohei Amiya
- Department of Cardiology, Osaka Police Hospital, 10-31 Kitayama-cho, Tennoji-ku, Osaka, 543-0035 Japan
| | - Seigo Minami
- Department of Respiratory Medicine, Osaka Police Hospital, 10-31 Kitayama-cho, Tennoji-ku, Osaka, 543-0035 Japan
| | - Shoichi Ihara
- Department of Respiratory Medicine, Osaka Police Hospital, 10-31 Kitayama-cho, Tennoji-ku, Osaka, 543-0035 Japan
- Department of Respiratory Medicine, Daini Osaka Police Hospital, 2-6-40 Karasuga-tuji, Tennoji-ku, Osaka, 543-0042 Japan
| | - Yoshiharu Higuchi
- Department of Cardiology, Osaka Police Hospital, 10-31 Kitayama-cho, Tennoji-ku, Osaka, 543-0035 Japan
| | - Kiyoshi Komuta
- Department of Respiratory Medicine, Osaka Police Hospital, 10-31 Kitayama-cho, Tennoji-ku, Osaka, 543-0035 Japan
- Department of Respiratory Medicine, Daini Osaka Police Hospital, 2-6-40 Karasuga-tuji, Tennoji-ku, Osaka, 543-0042 Japan
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7
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Shoop S, Maria Z, Campolo A, Rashdan N, Martin D, Lovern P, Lacombe VA. Glial Growth Factor 2 Regulates Glucose Transport in Healthy Cardiac Myocytes and During Myocardial Infarction via an Akt-Dependent Pathway. Front Physiol 2019; 10:189. [PMID: 30971932 PMCID: PMC6445869 DOI: 10.3389/fphys.2019.00189] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2018] [Accepted: 02/14/2019] [Indexed: 12/23/2022] Open
Abstract
Neuregulin (NRG), a paracrine factor in myocytes, promotes cardiac development via the ErbB receptors. NRG-1β also improves cardiac function and cell survival after myocardial infarction (MI), although the mechanisms underlying these cardioprotective effects are not well elucidated. Increased glucose uptake has been shown to be cardio-protective during MI. We hypothesized that treatment with a recombinant version of NRG-1β, glial growth factor 2 (GGF2), will enhance glucose transport in the healthy myocardium and during MI. Cardiac myocytes were isolated from MI and healthy adult rats, and subsequently incubated with or without insulin or GGF2. Glucose uptake was measured using a fluorescent D-glucose analog. The translocation of glucose transporter (GLUT) 4 to the cell surface, the rate-limiting step in glucose uptake, was measured using a photolabeled biotinylation assay in isolated myocytes. Similar to insulin, acute in vitro GGF2 treatment increased glucose uptake in healthy cardiac myocytes (by 40 and 49%, respectively, P = 0.002). GGF2 treatment also increased GLUT4 translocation in healthy myocytes by 184% (P < 0.01), while ErbB 2/4 receptor blockade (by afatinib) abolished these effects. In addition, GGF2 treatment enhanced Akt phosphorylation (at both threonine and serine sites, by 75 and 139%, respectively, P = 0.029 and P = 0.01), which was blunted by ErbB 2/4 receptor blockade. GGF2 treatment increased the phosphorylation of AS160 (an Akt effector) by 72% (P < 0.05), as well as the phosphorylation of PDK-1 and PKC (by 118 and 92%, respectively, P < 0.05). During MI, cardiac GLUT4 translocation was downregulated by 44% (P = 0.004) and was partially rescued by both in vitro insulin and GGF2 treatment. Our data demonstrate that acute GGF2 treatment increased glucose transport in cardiac myocytes by activating the ErbB 2/4 receptors and subsequent key downstream effectors (i.e., PDK-1, Akt, AS160, and PKC). These findings highlight novel mechanisms of action of GGF2, which warrant further investigation in patients with heart failure.
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Affiliation(s)
- Shanell Shoop
- Department of Physiological Sciences, Oklahoma State University, Stillwater, OK, United States.,Department of Biochemistry and Molecular Biology, Oklahoma State University, Stillwater, OK, United States
| | - Zahra Maria
- Department of Physiological Sciences, Oklahoma State University, Stillwater, OK, United States.,Harold Hamm Diabetes Center, University of Oklahoma, Oklahoma City, OK, United States
| | - Allison Campolo
- Department of Physiological Sciences, Oklahoma State University, Stillwater, OK, United States.,Harold Hamm Diabetes Center, University of Oklahoma, Oklahoma City, OK, United States
| | - Nabil Rashdan
- Department of Physiological Sciences, Oklahoma State University, Stillwater, OK, United States
| | - Dominic Martin
- Department of Biochemistry and Molecular Biology, Oklahoma State University, Stillwater, OK, United States
| | - Pamela Lovern
- Department of Physiological Sciences, Oklahoma State University, Stillwater, OK, United States
| | - Véronique A Lacombe
- Department of Physiological Sciences, Oklahoma State University, Stillwater, OK, United States.,Department of Biochemistry and Molecular Biology, Oklahoma State University, Stillwater, OK, United States.,Harold Hamm Diabetes Center, University of Oklahoma, Oklahoma City, OK, United States
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8
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Song J, Jang S, Lee JW, Jung D, Lee S, Min KH. Click chemistry for improvement in selectivity of quinazoline-based kinase inhibitors for mutant epidermal growth factor receptors. Bioorg Med Chem Lett 2018; 29:477-480. [PMID: 30554954 DOI: 10.1016/j.bmcl.2018.12.020] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 11/30/2018] [Accepted: 12/10/2018] [Indexed: 12/12/2022]
Abstract
Discovery of mutant-selective kinase inhibitors is one of the challenges in medicinal chemistry and is a main issue for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. We tried to improve the selectivity of pan-HER inhibitors for mutant EGFRs. Utilizing click chemistry, triazole-tethered quinazoline derivatives were synthesized, based on a quinazoline scaffold showing pan-HER inhibition. The representative compound 5j exhibited 17- and 52-fold improved selectivity for EGFR L858R/T790M over wild-type EGFR and HER2, respectively, and demonstrated 6.7-fold more potent antiproliferative activity against PC9 cells harboring EGFR-activating mutation than gefitinib. Although the described quinazolines did not surpass pyrimidines as 3rd generation EGFR inhibitors in terms of selectivity for mutant EGFRs, our approach might provide information that would help in the identification of mutant-selective compounds among pan-HER inhibitors using the quinazoline scaffold.
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Affiliation(s)
- Jiho Song
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Soyeon Jang
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Jung Wuk Lee
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Danbee Jung
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Seul Lee
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Kyung Hoon Min
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea.
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9
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Oberg HH, Kellner C, Gonnermann D, Sebens S, Bauerschlag D, Gramatzki M, Kabelitz D, Peipp M, Wesch D. Tribody [(HER2) 2xCD16] Is More Effective Than Trastuzumab in Enhancing γδ T Cell and Natural Killer Cell Cytotoxicity Against HER2-Expressing Cancer Cells. Front Immunol 2018; 9:814. [PMID: 29725336 PMCID: PMC5916959 DOI: 10.3389/fimmu.2018.00814] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Accepted: 04/04/2018] [Indexed: 12/31/2022] Open
Abstract
An enhanced expression of human epidermal growth factor receptor 2 (HER2, ErbB2) often occurs in an advanced stage of breast, ovarian, gastric or esophageal cancer, and pancreatic ductal adenocarcinoma (PDAC). Commonly, HER2 expression is associated with poor clinical outcome or chemoresistance in ovarian and breast cancer patients. Treatment with humanized anti-HER2 monoclonal antibodies, such as trastuzumab or pertuzumab, has improved the outcome of patients with HER2-positive metastatic gastric or breast cancer, but not all patients benefit. In this study, the bispecific antibody [(HER2)2xCD16] in the tribody format was employed to re-direct CD16-expressing γδ T lymphocytes as well as natural killer (NK) cells to the tumor-associated cell surface antigen HER2 to enhance their cytotoxic anti-tumor activity. Tribody [(HER2)2xCD16] comprises two HER2-specific single chain fragment variable fused to a fragment antigen binding directed to the CD16 (FcγRIII) antigen expressed on γδ T cells and NK cells. Our results revealed the superiority of tribody [(HER2)2xCD16] compared to trastuzumab in triggering γδ T cell and NK cell-mediated lysis of HER2-expressing tumor cells, such as PDAC, breast cancer, and autologous primary ovarian tumors. The increased efficacy of [(HER2)2xCD16] can be explained by an enhanced degranulation of immune cells. Although CD16 expression was decreased on γδ T cells in several PDAC patients and the number of tumor-infiltrating NK cells and γδ T cells was impaired in ovarian cancer patients, [(HER2)2xCD16] selectively enhanced cytotoxicity of cells from these patients. Here, unique anti-tumor properties of tribody [(HER2)2xCD16] are identified which beyond addressing HER2 overexpressing solid tumors may allow to treat with similar immunoconstructs combined with the adoptive transfer of γδ T cells and NK cells refractory hematological malignancies. A major advantage of γδ T cells and NK cells in the transplant situation of refractory hematological malignancies is given by their HLA-independent killing and a reduced graft-versus-host disease.
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Affiliation(s)
- Hans H Oberg
- Institute of Immunology, University Hospital Schleswig-Holstein (UKSH), Christian-Albrechts University (CAU) of Kiel, Kiel, Germany
| | - Christian Kellner
- Division of Stem Cell Transplantation and Immunotherapy, Department of Medicine II, University Hospital Schleswig-Holstein (UKSH), Christian-Albrechts University (CAU) of Kiel, Kiel, Germany
| | - Daniel Gonnermann
- Institute of Immunology, University Hospital Schleswig-Holstein (UKSH), Christian-Albrechts University (CAU) of Kiel, Kiel, Germany
| | - Susanne Sebens
- Institute for Experimental Cancer Research, University Hospital Schleswig-Holstein (UKSH), Christian-Albrechts University (CAU) of Kiel, Kiel, Germany
| | - Dirk Bauerschlag
- Clinic of Gynecology and Obstetrics, University Hospital Schleswig-Holstein (UKSH), Christian-Albrechts University (CAU) of Kiel, Kiel, Germany
| | - Martin Gramatzki
- Division of Stem Cell Transplantation and Immunotherapy, Department of Medicine II, University Hospital Schleswig-Holstein (UKSH), Christian-Albrechts University (CAU) of Kiel, Kiel, Germany
| | - Dieter Kabelitz
- Institute of Immunology, University Hospital Schleswig-Holstein (UKSH), Christian-Albrechts University (CAU) of Kiel, Kiel, Germany
| | - Matthias Peipp
- Division of Stem Cell Transplantation and Immunotherapy, Department of Medicine II, University Hospital Schleswig-Holstein (UKSH), Christian-Albrechts University (CAU) of Kiel, Kiel, Germany
| | - Daniela Wesch
- Institute of Immunology, University Hospital Schleswig-Holstein (UKSH), Christian-Albrechts University (CAU) of Kiel, Kiel, Germany
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10
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Lua WH, Ling WL, Yeo JY, Poh JJ, Lane DP, Gan SKE. The effects of Antibody Engineering CH and CL in Trastuzumab and Pertuzumab recombinant models: Impact on antibody production and antigen-binding. Sci Rep 2018; 8:718. [PMID: 29335579 PMCID: PMC5768722 DOI: 10.1038/s41598-017-18892-9] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Accepted: 12/19/2017] [Indexed: 12/17/2022] Open
Abstract
Current therapeutic antibodies such as Trastuzumab, are typically of the blood circulatory IgG1 class (Cκ/ CHγ1). Due to the binding to Her2 also present on normal cell surfaces, side effects such as cardiac failure can sometimes be associated with such targeted therapy. Using antibody isotype swapping, it may be possible to reduce systemic circulation through increased tissue localization, thereby minimising unwanted side effects. However, the effects of such modifications have yet to be fully characterized, particularly with regards to their biophysical properties in antigen binding. To do this, we produced all light and heavy chain human isotypes/subtypes recombinant versions of Trastuzumab and Pertuzumab, and studied them with respect to recombinant production and Her2 binding. Our findings show that while the light chain constant region changes have no major effects on production or Her2 binding, some heavy chain isotypes, in particularly, IgM and IgD isotypes, can modulate antigen binding. This study thus provides the groundwork for such isotype modifications to be performed in the future to yield therapeutics of higher efficacy and efficiency.
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Affiliation(s)
- Wai-Heng Lua
- Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Wei-Li Ling
- Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Joshua Yi Yeo
- Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Jun-Jie Poh
- Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - David Philip Lane
- p53 Laboratory, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Samuel Ken-En Gan
- Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore. .,p53 Laboratory, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
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11
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Regulation of ErbB2 localization and function in breast cancer cells by ERM proteins. Oncotarget 2018; 7:25443-60. [PMID: 27029001 PMCID: PMC5041916 DOI: 10.18632/oncotarget.8327] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2015] [Accepted: 03/10/2016] [Indexed: 12/20/2022] Open
Abstract
The ERM protein family is implicated in processes such as signal transduction, protein trafficking, cell proliferation and migration. Consequently, dysregulation of ERM proteins has been described to correlate with carcinogenesis of different cancer types. However, the underlying mechanisms are poorly understood. Here, we demonstrate a novel functional interaction between ERM proteins and the ErbB2 receptor tyrosine kinase in breast cancer cells. We show that the ERM proteins ezrin and radixin are associated with ErbB2 receptors at the plasma membrane, and depletion or functional inhibition of ERM proteins destabilizes the interaction of ErbB2 with ErbB3, Hsp90 and Ebp50. Accompanied by the dissociation of this protein complex, binding of ErbB2 to the ubiquitin-ligase c-Cbl is increased, and ErbB2 becomes dephosphorylated, ubiquitinated and internalized. Furthermore, signaling via Akt- and Erk-mediated pathways is impaired upon ERM inhibition. Finally, interference with ERM functionality leads to receptor degradation and reduced cellular levels of ErbB2 and ErbB3 receptors in breast cancer cells.
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Dokmanovic M, King KE, Mohan N, Endo Y, Wu WJ. Cardiotoxicity of ErbB2-targeted therapies and its impact on drug development, a spotlight on trastuzumab. Expert Opin Drug Metab Toxicol 2017; 13:755-766. [PMID: 28571477 DOI: 10.1080/17425255.2017.1337746] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
INTRODUCTION Trastuzumab, a therapeutic monoclonal antibody directed against ErbB2, is often noted as a successful example of targeted therapy. Trastuzumab improved outcomes for many patients with ErbB2-positive breast and gastric cancers, however, cardiac side effects [e.g., left ventricular dysfunction and congestive heart failure (CHF)] were reported in the early phase clinical studies. This finding, subsequently corroborated by multiple clinical studies, raised concerns that the observed cardiotoxicity induced by trastuzumab might adversely impact the clinical development of other therapeutics targeting ErbB family members. Areas covered: In this review we summarize both basic research and clinical findings regarding trastuzumab-induced cardiotoxicity and assess if there has been an impact of trastuzumab-induced cardiotoxicity on the development of other agents targeting ErbB family members. Expert opinion: There are a number of scientific gaps that are critically important to address for the continued success of HER2-targeted agents. These include: 1) elucidating the molecular mechanisms contributing to cardiotoxicity; 2) developing relevant preclinical testing systems for predicting cardiotoxicity; 3) developing clinical strategies to identify patients at risk of cardiotoxicity; and 4) enhancing management of clinical symptoms of cardiotoxicity.
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Affiliation(s)
- Milos Dokmanovic
- a Division of Biotechnology Review and Research I, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research , U.S. Food and Drug Administration , Silver Spring , MD 20993 , USA
| | - Kathryn E King
- a Division of Biotechnology Review and Research I, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research , U.S. Food and Drug Administration , Silver Spring , MD 20993 , USA
| | - Nishant Mohan
- a Division of Biotechnology Review and Research I, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research , U.S. Food and Drug Administration , Silver Spring , MD 20993 , USA
| | - Yukinori Endo
- a Division of Biotechnology Review and Research I, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research , U.S. Food and Drug Administration , Silver Spring , MD 20993 , USA
| | - Wen Jin Wu
- a Division of Biotechnology Review and Research I, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research , U.S. Food and Drug Administration , Silver Spring , MD 20993 , USA
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Dias A, Claudino W, Sinha R, Perez C, Jain D. Human epidermal growth factor antagonists and cardiotoxicity—A short review of the problem and preventative measures. Crit Rev Oncol Hematol 2016; 104:42-51. [DOI: 10.1016/j.critrevonc.2016.04.015] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2015] [Revised: 03/09/2016] [Accepted: 04/27/2016] [Indexed: 01/21/2023] Open
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Eryilmaz U, Demirci B, Aksun S, Boyacioglu M, Akgullu C, Ilgenli TF, Yalinkilinc HS, Bilgen M. S100A1 as a Potential Diagnostic Biomarker for Assessing Cardiotoxicity and Implications for the Chemotherapy of Certain Cancers. PLoS One 2015; 10:e0145418. [PMID: 26682543 PMCID: PMC4687715 DOI: 10.1371/journal.pone.0145418] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Accepted: 12/03/2015] [Indexed: 01/02/2023] Open
Abstract
This study examined the value of blood marker S100A1 in detecting cardiotoxicity induced by chemotherapy agents; trastuzumab and lapatinib, in normal rat heart. The rats were divided into three groups: control (n = 8, no treatment), T (n = 8, one time ip treatment with 10 mg/kg trastuzumab) and L (n = 8, oral treatment with 100 mg/kg/day lapatinib for 7 days). The activities of oxidative stress parameters Malondialdehyde (MDA), Superoxide dismutase (SOD), Catalase (CAT) and Glutathione (GSH) were measured from the extracted cardiac tissues. The levels of troponinI and S100A1 expressions were measured from blood samples. All biomarkers responded to the treatments as they exhibited alterations from their normative values, validating the chemically induced cardiotoxicity. S100A1 expression attenuated significantly (75%), which made the sensitive detection of cardiotoxicity feasible. Assessment of cardiotoxicity with S100A1 may be a valuable alternative in clinical oncology of cancers in some organs such as breast and prostate, as they do not overexpress it to compete against.
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Affiliation(s)
- Ufuk Eryilmaz
- Department of Cardiology, Medical Faculty, Adnan Menderes University, Aydin, Turkey
- * E-mail:
| | - Buket Demirci
- Department of Medical Pharmacology, Medical Faculty, Adnan Menderes University, Aydin, Turkey
| | - Saliha Aksun
- Department of Medical Biochemistry, Medical Faculty, Katip Celebi University, Izmir, Turkey
| | - Murat Boyacioglu
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Adnan Menderes University, Aydin, Turkey
| | - Cagdas Akgullu
- Department of Cardiology, Medical Faculty, Adnan Menderes University, Aydin, Turkey
| | | | - Hande Sultan Yalinkilinc
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Adnan Menderes University, Aydin, Turkey
| | - Mehmet Bilgen
- Department of Biophysics, Medical Faculty, Adnan Menderes University, Aydin, Turkey
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Design and Optimization of Peptide Ligands to Target Breast Cancer-Positive HER2 by Grafting and Truncation of MIG6 Peptide. Int J Pept Res Ther 2015. [DOI: 10.1007/s10989-015-9501-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
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Renal toxicity of anticancer agents targeting HER2 and EGFR. J Nephrol 2015; 28:647-57. [DOI: 10.1007/s40620-015-0226-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Accepted: 08/08/2015] [Indexed: 01/29/2023]
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Simmons C, Dent S, Brezden-Masley C. Duration of Trastuzumab. In matters of the heart, one size may not fit all? Eur J Cancer 2015; 51:1657-9. [PMID: 26185034 DOI: 10.1016/j.ejca.2015.06.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Accepted: 06/16/2015] [Indexed: 11/16/2022]
Abstract
The PHARE trial was initially reported in 2013 and demonstrated that 6 months of Trastuzumab therapy was inferior to 12 months of therapy in terms of reducing risk of Her2+ breast cancer recurrence. Updated results of this study have been presented and demonstrate that while there is a reduction in breast cancer risk with 12 months of therapy, there is an increase in risk of cardiac events. This may have implications for patient selection, and certainly has implications for future studies. As cardiac outcomes of cancer therapies become increasingly prevalent, an integrated approach to trial design and clinical management is needed.
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Affiliation(s)
| | - Susan Dent
- Medical Oncology, Ottawa Hospital Cancer Centre, Canada
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