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Liu X, Cheng J, Tang M, Liao C, Yang Y, Luo M, Xu L, Zhong X, Ma Q, Guo X. Exploring the novel role and mechanistic insights of skeletal muscle relaxant cyclobenzaprine hydrochloride in esophageal squamous cell carcinoma treatment. Eur J Pharm Sci 2025; 210:107051. [PMID: 40021097 DOI: 10.1016/j.ejps.2025.107051] [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: 11/25/2024] [Revised: 02/18/2025] [Accepted: 02/21/2025] [Indexed: 03/03/2025]
Abstract
OBJECTIVE Cyclobenzaprine hydrochloride (Flexeril) is a muscle relaxant primarily used to relieve muscle pain and spasms. However, its potential anti-cancer role remains largely unexplored. This study aims to investigate the inhibitory effect of Flexeril on esophageal squamous cell carcinoma (ESCC) and to uncover the molecular mechanisms through which it affects the proliferation and metastasis of ESCC. METHODS A compound library approved by the FDA was employed to screen drugs with inhibitory effects on ESCC. Cell viability was assessed using the Cell Counting Kit-8 (CCK-8) assay, and Plate colony formation was analyzed to evaluate the proliferative ability of ESCC cell lines (KYSE150 and Eca109) after treatment with Flexeril. Migratory ability was examined through Transwell and Scratch assays. Proteomics was performed to identify proteins regulated by Flexeril in KYSE150 and Eca109 cells. RT-PCR and Western blot were used to detect changes in related genes at the mRNA and protein levels after treatment with Flexeril. Drug affinity responsive target stability (DARTS) assay and cellular thermal shift assay (CETSA) were employed to identify the binding of Flexeril and JAK1 protein. Additionally, the comet assay was conducted to assess the DNA damage response in ESCC cells following WDHD1 knockdown or Flexeril exposure. Finally, tumor‑bearing nude mice model were constructed to evaluate the in vivo anticancer effects of Flexeril on ESCC. RESULTS Flexeril significantly inhibited the proliferation and migration of ESCC cells in a time- and dose-dependent manner. Proteomics analysis identified WDHD1 as a downstream target of Flexeril exposure, and knockdown of WDHD1 mimicked the effects of Flexeril on proliferation and migration of ESCC. Conversely, overexpression of WDHD1 attenuated the inhibitory effects of Flexeril on ESCC. Mechanistically, the JAK1-STAT3 signaling pathway, but not the JAK2-STAT3 or PI3K-Akt-mTOR pathways, was involved in regulating WDHD1 expression in ESCC cells following Flexeril treatment. Overexpression of STAT3 or WDHD1 mitigated the inhibitory effects of Flexeril on ESCC proliferation and migration. Moreover, both Flexeril exposure and WDHD1 knockdown induced a DNA damage response (DDR) in ESCC cells. In addition, Flexeril significantly inhibited the growth of ESCC tumors in nude mice, downregulating the JAK1-STAT3-WDHD1 signaling pathway, with no significant damage observed in vital organs such as the heart, liver, spleen, lungs, or kidneys, as shown by histological examination. CONCLUSION Flexeril exhibits anti-cancer effects in ESCC by inhibiting the JAK1-STAT3-WDHD1 axis and inducing DDR. These findings suggest that Flexeril may serve as a potential novel therapeutic agent for the treatment of ESCC.
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Affiliation(s)
- Xiao Liu
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, PR China; School of Laboratory Medicine & Translational Medicine Research Center, North Sichuan Medical College, Nanchong 637000, PR China
| | - Jibing Cheng
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, PR China; School of Laboratory Medicine & Translational Medicine Research Center, North Sichuan Medical College, Nanchong 637000, PR China
| | - Maoju Tang
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, PR China; School of Laboratory Medicine & Translational Medicine Research Center, North Sichuan Medical College, Nanchong 637000, PR China
| | - Chongbo Liao
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, PR China; School of Laboratory Medicine & Translational Medicine Research Center, North Sichuan Medical College, Nanchong 637000, PR China
| | - Yong Yang
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, PR China; School of Laboratory Medicine & Translational Medicine Research Center, North Sichuan Medical College, Nanchong 637000, PR China
| | - Man Luo
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, PR China; School of Laboratory Medicine & Translational Medicine Research Center, North Sichuan Medical College, Nanchong 637000, PR China
| | - Lei Xu
- School of Laboratory Medicine & Translational Medicine Research Center, North Sichuan Medical College, Nanchong 637000, PR China
| | - Xiaowu Zhong
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, PR China; School of Laboratory Medicine & Translational Medicine Research Center, North Sichuan Medical College, Nanchong 637000, PR China
| | - Qiang Ma
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, PR China; School of Laboratory Medicine & Translational Medicine Research Center, North Sichuan Medical College, Nanchong 637000, PR China.
| | - Xiaolan Guo
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, PR China; School of Laboratory Medicine & Translational Medicine Research Center, North Sichuan Medical College, Nanchong 637000, PR China.
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Peng X, Lan B, Wang J, Li Q, Wang J, Fan Y, Luo Y, Chen S, Mo H, Li L, Sun X, Zhang J, Cai R, Zhang P, Xu B, Ma F. The ideal strategies of antibody‒drug conjugate sequential treatment in HER2-expressing metastatic breast cancer: A multi-center real-world study. Breast 2025; 81:104470. [PMID: 40203774 PMCID: PMC12008598 DOI: 10.1016/j.breast.2025.104470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 03/22/2025] [Accepted: 04/03/2025] [Indexed: 04/11/2025] Open
Abstract
BACKGROUND A growing number of antibody‒drug conjugates (ADCs) have been approved for breast cancer treatment. However, the proper sequential strategies of ADCs remain uncertain. Our study aimed to explore the ideal ADC sequential treatment strategies in human epidermal growth factor receptor 2 (HER2)-expressing metastatic breast cancer (MBC). METHODS Our multi-centre retrospective study enrolled MBC patients who received at least 2 lines of different types of ADCs between Jan 1, 2018, and Jul 1, 2024. The efficacy of both ADC1 and ADC2 was evaluated. RESULTS A total of 111 patients (83 HER2-positive and 28 HER2-low) were included. In HER2-positive populations, Patients who received ADC2 with a different payload from ADC1 exhibited significantly longer progression-free survival 2 (PFS2) (6.8 vs. 2.7 months, p < 0.001) and overall PFS (progression-free Interval 1 (PFI1) + PFS2) (15.0 vs. 8.5 months, p = 0.043) compared to those treated with ADC2 containing a similar payload with ADC1. Patients received ADC2 immediately after ADC1 progression showed longer PFS2 ADC2 delayed sequential patients (median PFS2: 6.0 vs. 3.0 months, p = 0.004). In HER2-low patients, the efficacy of ADC2 tended to be lower than ADC1 (median PFI1 vs. PFS2: 3.1 vs. 2.4 months, p = 0.078). No significant differences of efficacy were observed, no matter what ADC sequential treatment strategy used. CONCLUSIONS Sequential treatment with ADCs showed clinical benefit especially for HER2-positive patients treated with ADC2 which have different types of payloads from ADC1. In HER2-low patients, the benefit of ADC sequential therapy seemed to be limited.
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Affiliation(s)
- Xuenan Peng
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Bo Lan
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Jiayu Wang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Qiao Li
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Jiani Wang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Ying Fan
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yang Luo
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Shanshan Chen
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Hongnan Mo
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Lixi Li
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xiaoying Sun
- Department of Medical Oncology, Cancer Hospital of HuanXing ChaoYang District, Beijing, 100164, China
| | - Jintao Zhang
- Department of Medical Oncology, SanHuan Cancer Hospital, Beijing, 100021, China
| | - Ruigang Cai
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Pin Zhang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Binghe Xu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Fei Ma
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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Yang C, Zhang C, Huang Y, Zhu X, Jiang J, Zeng Y, Zhang H, Li L, Liu Y, Li Y. Efficacy of disitamab vedotin (RC48) for previously treated human epidermal growth factor receptor 2-positive breast cancer with symptomatic brain metastases: a case report and review of the literature. Anticancer Drugs 2025; 36:440-445. [PMID: 40063535 DOI: 10.1097/cad.0000000000001702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/05/2025]
Abstract
Local radiotherapy or surgery is the standard of care for treating brain metastases among patients with breast cancer. However, affected by tumor subtype, more than 50% of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer and brain metastases will still develop local recurrence or new brain lesions within 1 year after radiotherapy. As systemic therapies demonstrate higher and clinically relevant levels of intracranial activity and longer survival, there is limited evidence to guide how to weigh the options of radiotherapy versus systemic therapy (and deferral of radiation) in patients with progressive brain metastases, particularly those that are symptomatic. This study presents a case of progressive symptomatic HER2-positive brain metastases in a patient previously treated with whole brain radiotherapy and various targeted therapies. Due to limited access to novel HER2-targeted drugs, a new antibody-drug conjugate drug, disitamab vedotin (RC48) monotherapy, was chosen for postprogression treatment. The patient experienced rapid relief of neurological symptoms, partial regression of the brain tumor, and sustained disease remission for over 12 months without any treatment-related toxicity, also avoided reirradiation exposure and potential neurocognitive decline. The treatment of brain metastasis has been a topic of ongoing discussion. Our experience may offer valuable insights into managing HER2-positive progressive symptomatic brain metastases.
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Affiliation(s)
- Can Yang
- Second Clinical College, Guizhou University of Traditional Chinese Medicine, Guiyang
| | | | | | | | - Jia Jiang
- Second Clinical College, Guizhou University of Traditional Chinese Medicine, Guiyang
| | - Yuting Zeng
- Department of Oncology, Guizhou Provincial People's Hospital, Guiyang, China
| | - Hanqun Zhang
- Department of Oncology, Guizhou Provincial People's Hospital, Guiyang, China
| | - Libo Li
- Department of Oncology, Guizhou Provincial People's Hospital, Guiyang, China
| | - Yuncong Liu
- Department of Oncology, Guizhou Provincial People's Hospital, Guiyang, China
| | - Yong Li
- Department of Oncology, Guizhou Provincial People's Hospital, Guiyang, China
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Shen K, Yuan S, Su N, Tang F, Rehim S, Wang H, Guo H, Zhang Y, Wu Y, Wang H. Monotherapy and combination therapy using antibody‑drug conjugates for platinum‑resistant ovarian cancer. Oncol Rep 2025; 53:68. [PMID: 40242965 PMCID: PMC12046379 DOI: 10.3892/or.2025.8901] [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: 12/04/2024] [Accepted: 03/17/2025] [Indexed: 04/18/2025] Open
Abstract
Platinum‑resistant ovarian cancer (PROC) is a significant clinical challenge due to the limited number of treatment options and poor outcomes. Moreover, cytotoxic drugs have an unsatisfactory therapeutic efficacy, high toxicity and side effects. An antibody‑drug conjugate (ADC) is a novel cancer therapeutic strategy that combines an antibody, a linker and a payload. ADCs precisely target the tumor cells by binding to the antigen on the surface of tumor cells, thus accurately delivering the cytotoxic drugs and minimizing systemic toxicity. The approval of mirvetuximab soravtansine by the US Food and Drug Administration for treating folate receptor alpha‑positive, platinum‑resistant epithelial ovarian cancer has promoted studies on the use of ADCs in ovarian cancer. A phase III clinical trial showed that mirvetuximab soravtansine achieved an objective remission rate of 42.3% in platinum‑resistant, FRα‑positive ovarian cancer, compared with 15.9% using chemotherapy, demonstrating its immense potential for ADC development. The present review summarizes the research progress on the use of ADCs in PROC as a monotherapy and combination therapy and considers the future development direction of ADCs in PROC.
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Affiliation(s)
- Ke Shen
- Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan 610041, P.R. China
| | - Shuang Yuan
- Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan 610041, P.R. China
| | - Ning Su
- Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan 610041, P.R. China
- Department of Gynecologic Oncology, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, Henan 450008, P.R. China
| | - Furong Tang
- Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan 610041, P.R. China
| | - Shamsnur Rehim
- Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan 610041, P.R. China
| | - Han Wang
- Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan 610041, P.R. China
| | - Huihui Guo
- Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan 610041, P.R. China
| | - Yu Zhang
- Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan 610041, P.R. China
| | - Yufeng Wu
- Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan 610041, P.R. China
| | - Hongjing Wang
- Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan 610041, P.R. China
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Song S, Liu Y, Liu J, Tai W. In Silico-Driven THIOMAB Approach for Stable PROTAC Conjugates by Docking Payloads in Antibody Cavities. Bioconjug Chem 2025; 36:960-970. [PMID: 40196986 DOI: 10.1021/acs.bioconjchem.4c00588] [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: 04/09/2025]
Abstract
The heterobifunctional proteolysis targeting chimeras (PROTACs) are a class of emerging therapeutic modalities that enable selective degradation of target proteins in cells. As antibody payloads, they offer several advantages compared to conventional chemical toxins, such as catalytic nature, potent and long-lasting activity, and precise selectivity to avoid systemic toxicity. However, the relatively large size and high hydrophobicity of these chimeric payloads may result in challenging the stability of antibodies, which complicates the in vivo performance. In this work, we use the highly hydrophobic GNE-987 as model PROTAC to evaluate a THIOMAB approach for mitigating the conjugate's hydrophobicity while maintaining the therapeutic potency. We describe an in silico method to select the less hydrophobic site in an antibody and employ the stable tetrapeptide-aminomethoxy linker to conjugate the PROTAC payloads. The resulting degrader-antibody conjugate (J591 DAC) displays antigen-dependent BRD4 degradation and potent cytotoxic activity in PSMA-positive cancer cells. Finally, this DAC, bearing two highly hydrophobic PROTACs, also exhibits a long blood retention and strong antitumor efficacy in mouse models, likely owing to the homogeneous and stable conjugation from the THIOMAB approach. This work provides an example of the design and construction of antibody conjugates with highly hydrophobic payloads.
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Affiliation(s)
- Shiwei Song
- Department of Pharmaceutical Engineering, School of Pharmaceutical Sciences, Wuhan University, Wuhan, Hubei 430071, China
| | - Yahui Liu
- Department of Pharmaceutical Engineering, School of Pharmaceutical Sciences, Wuhan University, Wuhan, Hubei 430071, China
| | - Jiaqi Liu
- Department of Pharmaceutical Engineering, School of Pharmaceutical Sciences, Wuhan University, Wuhan, Hubei 430071, China
| | - Wanyi Tai
- Department of Pharmaceutical Engineering, School of Pharmaceutical Sciences, Wuhan University, Wuhan, Hubei 430071, China
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Rao B, Huo P, Lu J, Huang W. Advances in Targeted Therapy for Brain Metastases in Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancer: A Focus on ADCs and TKIs. BREAST CANCER (DOVE MEDICAL PRESS) 2025; 17:423-432. [PMID: 40416059 PMCID: PMC12102737 DOI: 10.2147/bctt.s503703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 04/28/2025] [Indexed: 05/27/2025]
Abstract
Aim Brain metastasis remains a significant therapeutic challenge in HER2-positive breast cancer, contributing to poor prognosis and limited treatment options. This review aims to summarize recent advancements in targeted therapies for brain metastasis in HER2-positive breast cancer, with a focus on the efficacy, mechanisms, and clinical implications of antibody-drug conjugates (ADCs) and tyrosine kinase inhibitors (TKIs). Methods We conducted a comprehensive review of clinical trials, real-world studies, and preclinical research. Main Content This review summarizes the latest clinical and preclinical evidence on targeted therapies for brain metastasis in HER2-positive breast cancer. Key therapies, including trastuzumab deruxtecan (T-DXd) and tucatinib, are discussed, with a focus on their mechanisms, efficacy, and ability to overcome the blood-brain barrier (BBB). Clinical trials such as HER2CLIMB and DESTINY-Breast03, as well as real-world studies, are highlighted to demonstrate the superior intracranial response rates and survival benefits of these therapies. Conclusion ADCs and TKIs represent a paradigm shift in the management of brain metastases, offering new hope for patients with HER2-positive breast cancer. Future research should focus on optimizing combination therapies, exploring novel biomarkers, and addressing resistance mechanisms to further improve outcomes. This review underscores the importance of continued innovation in targeted therapies for brain metastasis.
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Affiliation(s)
- Bin Rao
- Breast Surgery, Wuzhou Red Cross Hospital, Wuzhou City, Guangxi, 543002, People’s Republic of China
| | - Peicheng Huo
- Breast Surgery, Wuzhou Red Cross Hospital, Wuzhou City, Guangxi, 543002, People’s Republic of China
| | - Jieming Lu
- Breast Surgery, Wuzhou Red Cross Hospital, Wuzhou City, Guangxi, 543002, People’s Republic of China
| | - Wenwen Huang
- Breast Surgery, Wuzhou Red Cross Hospital, Wuzhou City, Guangxi, 543002, People’s Republic of China
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Yaghoubi N, Fatemi B, Ahmadi R, Metghalchi Y, Shahrami B, Vaezi M, Rezaei S. Trastuzumab deruxtecan versus trastuzumab emtansine for human epidermal growth factor receptor 2 positive metastatic breast cancer: cost-effectiveness analysis from Iranian experience. BMC Health Serv Res 2025; 25:711. [PMID: 40380283 PMCID: PMC12084944 DOI: 10.1186/s12913-025-12876-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Accepted: 05/12/2025] [Indexed: 05/19/2025] Open
Abstract
BACKGROUND This study aims to evaluate the cost-effectiveness of Trastuzumab deruxtecan (T-DXd), compared to trastuzumab emtansine (T-DM1) as second-line treatments for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) patients in Iran. METHODS A partitioned survival model was developed based on time-to-event data from the DESTINY-Breast 03 trial to evaluate the cost-effectiveness of T-DXd versus T-DM1 from a societal perspective and over a lifetime horizon. Costs and utility inputs were derived from published literature and official Iranian sources. Key outcomes included total costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICER). The willingness-to-pay (WTP) threshold of $2413/QALY was applied. One-way sensitivity analyses and probabilistic sensitivity analyses (PSA) were conducted to assess uncertainty. RESULTS In the base-case analysis, T-DXd yielded 3.59 QALYs for $261,315, while T-DM1 yielded 1.89 QALYs at $258,039, resulting in an ICER of $1,927 per QALY. This value is below Iran's WTP threshold of $2413/QALY. One-way sensitivity analysis identified the unit price of T-DXd as the most influential parameter. PSA results indicated that T-DXd has a 52% probability of being cost-effective. CONCLUSION T-DXd represents a cost-effective alternative to T-DM1 as a second-line treatment for HER2-positive MBC in Iran. Its clinical advantages, combined with an ICER below the local WTP threshold, support its adoption in this patient population.
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Affiliation(s)
- Neda Yaghoubi
- Department of Pharmacoeconomics and Pharma Management, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Behzad Fatemi
- Pharmaceutical Management and Economic Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran
| | - Razieh Ahmadi
- Department of Pharmacoeconomics and Pharma Management, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Yalda Metghalchi
- Department of Pharmacoeconomics and Pharma Management, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bita Shahrami
- Department of Clinical Pharmacy, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Hematology, Oncology, and Stem Cell Transplantation Research Center, Research Institute for Oncology, Hematology, and Cell Therapy, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Vaezi
- Hematology, Oncology, and Stem Cell Transplantation Research Center, Research Institute for Oncology, Hematology, and Cell Therapy, Tehran University of Medical Sciences, Tehran, Iran
| | - Soheila Rezaei
- Department of Pharmacoeconomics and Pharma Management, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Miski H, Krupa K, Budzik MP, Deptała A, Badowska-Kozakiewicz A. HER2-Positive Breast Cancer-Current Treatment Management and New Therapeutic Methods for Brain Metastasis. Biomedicines 2025; 13:1153. [PMID: 40426980 PMCID: PMC12109299 DOI: 10.3390/biomedicines13051153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2025] [Revised: 04/28/2025] [Accepted: 04/30/2025] [Indexed: 05/29/2025] Open
Abstract
Background: Breast cancer can be classified based on the immunohistochemistry (IHC) phenotypes, defined by the presence or absence of the main IHC markers. IHC phenotyping is important as it determines the prognosis and guides treatment. For example, human epidermal growth factor receptor 2 (HER2) overexpression, which triggers cell growth and division, is observed in HER2-positive breast cancer. Methods: The standard treatment is based on trastuzumab plus pertuzumab in combination with taxane chemotherapy. The possibility of developing metastases depends on those phenotypes. Approximately 25-50% of patients with HER2-positive breast cancer experience brain metastases. This aspect is especially important, as 20% of those patients die as a result. Results: Through the years, many advanced therapies have been introduced to treat brain metastases, including whole brain radiotherapy, stereotactic radiosurgery, and a tyrosine kinase inhibitor (TKI), neratinib. Nonetheless, this still remains a therapeutic challenge. Conclusions: In this review, we focus on the treatment and efficiency of therapies targeting HER2-positive breast cancer, mainly concentrating on the current and newly developed treatment options for brain metastases, such as trastuzumab deruxtecan and tucatinib.
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Affiliation(s)
- Hanna Miski
- Students’ Scientific Organization of Cancer Cell Biology, Department of Oncology Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland; (H.M.); (K.K.)
| | - Kamila Krupa
- Students’ Scientific Organization of Cancer Cell Biology, Department of Oncology Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland; (H.M.); (K.K.)
| | - Michał Piotr Budzik
- Department of Oncology Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland; (A.D.); (A.B.-K.)
| | - Andrzej Deptała
- Department of Oncology Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland; (A.D.); (A.B.-K.)
| | - Anna Badowska-Kozakiewicz
- Department of Oncology Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland; (A.D.); (A.B.-K.)
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Yeh R, Pareja F, Shobeiri P, Ross D, Jayaprakasam VS, Razmaria AA, Drago JZ, Mauguen A, Lyashchenko SK, Zeglis BM, Lewis JS, Ulaner GA. Detection of HER2-Low Lesions Using HER2-Targeted PET Imaging in Patients with Metastatic Breast Cancer: A Paired HER2 PET and Tumor Biopsy Analysis. J Nucl Med 2025:jnumed.124.269227. [PMID: 40341092 DOI: 10.2967/jnumed.124.269227] [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: 11/25/2024] [Accepted: 03/31/2025] [Indexed: 05/10/2025] Open
Abstract
Trastuzumab deruxtecan (T-DXd), a human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate, demonstrated remarkable efficacy in previously treated patients with HER2-low metastatic breast cancer (mBC), marking a new therapeutic option for this patient population. Prior studies with HER2 PET using 89Zr-radiolabeled antibodies were limited by high rates of imaging false positives for HER2-positive malignancy. In this retrospective study, we investigate whether these false positives (HER2-negative on pathology) could be explained by HER2-low lesions. Methods: A retrospective study was conducted of mBC patients who previously enrolled in 2 prospective HER2 PET imaging trials: NCT02286843 using 89Zr-trastuzumab and 89Zr-pertuzumab and NCT04692831 using 89Zr-ss-pertuzumab. Patients were included if paired HER2 PET scan and biopsy were performed within a 2-mo period. Of 56 total patients, 23 patients met the inclusion criteria. Pathology results for biopsied lesions were collected, without repeat interpretation, and lesions were classified as HER2-positive, HER2-low, or HER2-0. SUVmax of biopsied lesions were compared between pathologic classifications to determine whether lesion uptake intensity could differentiate between HER2-positive and HER2-low lesions. Results: All prior false-positive lesions on HER2 PET scans from NCT02286843 were reclassified as HER2-low (instead of HER2-negative). In the 89Zr-trastuzumab cohort, 3 lesions were HER2-positive (33%) and 6 were HER2-low (67%); in the 89Zr-pertuzumab cohort, 2 were HER2-positive (29%) and 5 were HER2-low (71%). In the 89Zr-ss-pertuzumab cohort (NCT04692831), 7 patients underwent recent biopsies of 8 total lesions demonstrating 1 HER2-positive (12%), 5 HER2-low (62%), and 2 HER2-0 lesions (25%). HER2 PET SUVmax of biopsied lesions were compared between HER2-positive and HER2-low lesions for the combination of all 3 radiotracer cohorts. HER2-low lesions had a significantly higher SUVmax (median, 12.7; interquartile range, 8.05) than did HER2-positive lesions (median, 6.4; interquartile range, 1.98; P = 0.01). Conclusion: HER2 PET imaging with 89Zr-radiolabeled antibodies detects HER2-low lesions in addition to HER2-positive lesions in patients with mBC, suggesting its ability to visualize the entire spectrum of HER2 expression. All prior false positives on 89Zr-trastuzumab and 89Zr-pertuzumab PET scans were reclassified as HER2-low. Lesion SUVmax is not reliable in differentiating HER2-positive from HER2-low lesions; however, it may be useful in distinguishing lesions expressing HER2 from HER2-0 lesions.
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Affiliation(s)
- Randy Yeh
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York;
- Department of Radiology, Weill Cornell Medical College, New York, New York
| | - Fresia Pareja
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Parnian Shobeiri
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Dara Ross
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Pathology, Weill Cornell Medical College, New York, New York
| | - Vetri S Jayaprakasam
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Radiology, Weill Cornell Medical College, New York, New York
| | - Ali Aria Razmaria
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Radiology, Weill Cornell Medical College, New York, New York
| | - Joshua Z Drago
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Medicine, Weill Cornell Medical College, New York, New York
| | - Audrey Mauguen
- Department of Biostatistics and Epidemiology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Serge K Lyashchenko
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Radiology, Weill Cornell Medical College, New York, New York
| | - Brian M Zeglis
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Radiology, Weill Cornell Medical College, New York, New York
- Department of Chemistry, Hunter College, New York, New York
| | - Jason S Lewis
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Radiology, Weill Cornell Medical College, New York, New York
- Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Gary A Ulaner
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
- Molecular Imaging and Therapy, Hoag Family Cancer Institute, Newport Beach, California; and
- Departments of Radiology and Translational Genomics, University of Southern California, Los Angeles, California
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10
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Bruzzone F, Barigazzi C, Di Muzio A, Tallarico I, Dipasquale A, Losurdo A, Persico P, Navarria P, Pessina F, Santoro A, Simonelli M. Exploring the Role of ADCs in Brain Metastases and Primary Brain Tumors: Insight and Future Directions. Cancers (Basel) 2025; 17:1591. [PMID: 40361515 PMCID: PMC12072133 DOI: 10.3390/cancers17091591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2025] [Revised: 04/28/2025] [Accepted: 05/02/2025] [Indexed: 05/15/2025] Open
Abstract
Primary and secondary brain tumors have always been a challenge due to their high morbidity and poor prognosis. The incidence of brain metastasis is also increasing with the advent of effective new treatments. Traditional systemic treatments have historically had limited success, partly due to poor central nervous system (CNS) penetration. However, the advent in recent decades of new therapies that have shown high encephalic response rates are challenging this paradigm. ADCs represent a new class of compounds revolutionizing cancer treatment with high systemic response rates and lower toxicities. The continuing evolution of ADCs has shown that certain structural features such as payload, linker, and drug-to-antibody ratio (DAR) are essential in determining their efficacy at the encephalic level, and some ADCs have started to exhibit promising efficacy in treating primary and secondary brain tumors. Unfortunately, most patients with untreated encephalic metastases are excluded from clinical trials, with data primarily from retrospective studies or post hoc analyses. This review describes the early signs of ADC efficacy in brain tumors, the role of complementary treatments like radiation therapy, and critical points to improve ADC efficacy in brain malignancies.
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Affiliation(s)
- Francesco Bruzzone
- Department of Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy; (F.B.); (C.B.); (A.D.M.); (I.T.); (A.D.); (A.L.); (P.P.); (A.S.)
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20072 Milan, Italy;
| | - Chiara Barigazzi
- Department of Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy; (F.B.); (C.B.); (A.D.M.); (I.T.); (A.D.); (A.L.); (P.P.); (A.S.)
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20072 Milan, Italy;
| | - Antonio Di Muzio
- Department of Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy; (F.B.); (C.B.); (A.D.M.); (I.T.); (A.D.); (A.L.); (P.P.); (A.S.)
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20072 Milan, Italy;
| | - Isabel Tallarico
- Department of Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy; (F.B.); (C.B.); (A.D.M.); (I.T.); (A.D.); (A.L.); (P.P.); (A.S.)
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20072 Milan, Italy;
| | - Angelo Dipasquale
- Department of Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy; (F.B.); (C.B.); (A.D.M.); (I.T.); (A.D.); (A.L.); (P.P.); (A.S.)
| | - Agnese Losurdo
- Department of Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy; (F.B.); (C.B.); (A.D.M.); (I.T.); (A.D.); (A.L.); (P.P.); (A.S.)
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20072 Milan, Italy;
| | - Pasquale Persico
- Department of Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy; (F.B.); (C.B.); (A.D.M.); (I.T.); (A.D.); (A.L.); (P.P.); (A.S.)
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20072 Milan, Italy;
| | - Pierina Navarria
- Department of Radiotherapy and Radiosurgery, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy;
| | - Federico Pessina
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20072 Milan, Italy;
- Department of Neurosurgery, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
| | - Armando Santoro
- Department of Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy; (F.B.); (C.B.); (A.D.M.); (I.T.); (A.D.); (A.L.); (P.P.); (A.S.)
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20072 Milan, Italy;
| | - Matteo Simonelli
- Department of Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy; (F.B.); (C.B.); (A.D.M.); (I.T.); (A.D.); (A.L.); (P.P.); (A.S.)
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20072 Milan, Italy;
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11
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Lv Y, Cui X, Li T, Liu C, Wang A, Wang T, Zhou X, Li R, Zhang F, Hu Y, Zhang T, Liu Z. Mechanism of action and future perspectives of ADCs in combination with immune checkpoint inhibitors for solid tumors. Clin Exp Med 2025; 25:139. [PMID: 40319436 PMCID: PMC12050234 DOI: 10.1007/s10238-025-01655-6] [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: 02/12/2025] [Accepted: 03/26/2025] [Indexed: 05/07/2025]
Abstract
Antibody-drug conjugates (ADCs) are a promising cancer therapy for targeted delivery of drugs to tumor cells. However, resistance to ADCs remains a challenge, necessitating the exploration of combination therapies. A strong biological theory suggests that ADCs interact with cancer cells and immune cells by triggering mechanisms such as immunogenic cell death, dendritic cell activation, and memory T-cell activation, resulting in long-term anti-tumor immunity and ultimately potential synergistic effects with immunotherapy. Based on extensive and reliable preclinical data, several clinical trials are currently combining ADCs with immune checkpoint inhibitors (ICIs) for the treatment of various cancers, including breast, gastric, and non-small-cell lung cancers, to evaluate the safety and anti-tumor activity of the combination therapy. Preliminary evidence from early clinical trials has reported more effective efficacy data. This paper reviews the combination of ADCs and immunotherapy, highlights the key mechanisms by which the two act synergistically, and summarizes the available clinical evidence against different ADCs targets. The paper also explores the re-challenges used for combination therapies and optimized design options for ADCs drugs.
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Affiliation(s)
- Yahui Lv
- Senior Department of Oncology, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
- Chinese PLA Key Laboratory of Oncology, Key Laboratory for Tumor Targeting Therapy and Antibody Drugs (Ministry of Education, China), Beijing, China
- Medical School of Chinese PLA, Beijing, 100853, China
| | - Xiaoran Cui
- Medical School of Chinese PLA, Beijing, 100853, China
- Senior Department of Oncology, The Fifth Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
| | - Tao Li
- Senior Department of Oncology, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
- Medical School of Chinese PLA, Beijing, 100853, China
- Department of Stomatology, The First Medical Center of PLA General Hospital, Beijing, 100853, China
- Changchun Veterinary Research Institute, Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Chinese Academy of Agricultural Sciences, Yujinxiang Street 573, ChangchunJilin, 130122, China
| | - Chang Liu
- Senior Department of Oncology, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
- Medical School of Chinese PLA, Beijing, 100853, China
- School of Medicine, Nankai University, TianJin, 30071, China
| | - An Wang
- Senior Department of Oncology, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
- Medical School of Chinese PLA, Beijing, 100853, China
| | - Ting Wang
- Senior Department of Oncology, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
- Medical School of Chinese PLA, Beijing, 100853, China
- School of Medicine, Nankai University, TianJin, 30071, China
| | - Xin Zhou
- Senior Department of Oncology, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
- Medical School of Chinese PLA, Beijing, 100853, China
| | - Ruixin Li
- Senior Department of Oncology, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
- Medical School of Chinese PLA, Beijing, 100853, China
| | - Fan Zhang
- Senior Department of Oncology, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
- Medical School of Chinese PLA, Beijing, 100853, China
| | - Yi Hu
- Senior Department of Oncology, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China.
- Medical School of Chinese PLA, Beijing, 100853, China.
| | - Tong Zhang
- Medical School of Chinese PLA, Beijing, 100853, China.
- Department of Stomatology, The First Medical Center of PLA General Hospital, Beijing, 100853, China.
| | - Zhefeng Liu
- Senior Department of Oncology, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China.
- Medical School of Chinese PLA, Beijing, 100853, China.
- Senior Department of Oncology, The Third Medical Center, Chinese PLA General Hospital, Beijing, 100853, China.
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12
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Russo G, Scimone C, Palumbo L, Roscigno G, Sarracino C, Tomaiuolo I, Pisapia P, Pepe F, Rocco D, Gridelli C, Troncone G, Malapelle U. Biologics for novel driver altered non-small cell lung cancer: potential and pitfalls. Crit Rev Oncol Hematol 2025; 212:104748. [PMID: 40324663 DOI: 10.1016/j.critrevonc.2025.104748] [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: 03/06/2025] [Revised: 04/22/2025] [Accepted: 04/25/2025] [Indexed: 05/07/2025] Open
Abstract
Precision medicine has revolutionized clinical paradigm of lung cancer (LC) patients optimizing therapeutical options on the basis of molecular fingerprinting of tumor cells. The advent of the genomic era contributed to the widespread diffusion of sequencing technologies laying the basis for the approval of an increasing number of clinically relevant predictive biomarkers in clinical settings. In the rapidly evolving scenario of predictive biomarkers, mandatory testing genes demonstrated a statistically significant clinical benefit in LC patients elected to molecular tests, but emerging biomarkers are under investigation to raise the bar in the clinical management of LC patients. To date, promising IHC-based predictive biomarkers emerged as potentially integrative tools in the panel of clinically approved biomarkers. On this basis, genomic, transcriptomic and proteomic data are gaining ground toward "3D" biology" supporting the need of a multidimensional analysis of tumor cells to clinically stratify LC patients. Here we sought to overview the most promising biomarkers investigated in clinical trials to be integrated into diagnostic panel of predictive biomarkers tools for NSCLC patients.
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Affiliation(s)
- Gianluca Russo
- Department of Public Health, University Federico II of Naples, Naples, Italy
| | - Claudia Scimone
- Department of Public Health, University Federico II of Naples, Naples, Italy
| | - Lucia Palumbo
- Department of Public Health, University Federico II of Naples, Naples, Italy
| | - Giuseppina Roscigno
- Department of Biology, Complesso Universitario Monte Sant'Angelo, University of Naples Federico II, Via Cintia 4, 80126 Naples, Italy
| | - Claudia Sarracino
- Department of Public Health, University Federico II of Naples, Naples, Italy
| | - Ilaria Tomaiuolo
- Department of Public Health, University Federico II of Naples, Naples, Italy
| | - Pasquale Pisapia
- Department of Public Health, University Federico II of Naples, Naples, Italy
| | - Francesco Pepe
- Department of Public Health, University Federico II of Naples, Naples, Italy
| | - Danilo Rocco
- Department of Pulmonary Oncology, AORN dei Colli Monaldi, Napoli, Italy
| | - Cesare Gridelli
- Division of Medical Oncology, 'S. G. Moscati' Hospital, Avellino, Italy
| | - Giancarlo Troncone
- Department of Public Health, University Federico II of Naples, Naples, Italy
| | - Umberto Malapelle
- Department of Public Health, University Federico II of Naples, Naples, Italy.
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13
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Pretzsch E, Peschel CA, Rokavec M, Torlot L, Li P, Hermeking H, Werner J, Klauschen F, Neumann J, Jung A, Kumbrink J. Five-Gene Expression Signature Associated With Acquired FOLFIRI Resistance and Survival in Metastatic Colorectal Cancer. J Transl Med 2025; 105:104107. [PMID: 39954853 DOI: 10.1016/j.labinv.2025.104107] [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: 08/15/2024] [Revised: 01/25/2025] [Accepted: 02/06/2025] [Indexed: 02/17/2025] Open
Abstract
FOLFIRI, a combination of folinic acid, 5-fluorouracil, and irinotecan, is one of the recommended first-line chemotherapeutic treatments for metastatic colorectal cancer. Unfortunately, acquired FOLFIRI resistance represents a common obstacle in the treatment of metastatic colorectal cancer patients. Thus, we aimed to identify mechanisms, gene alterations, and gene expression signatures contributing to acquired FOLFIRI resistance by mimicking this problem in a cell culture model and subsequent translation in clinical data sets. Three FOLFIRI-resistant colorectal cancer (CRC) cell lines were established by continuous FOLFIRI treatment. Comparative mutation screening (161 genes) and transcriptomics (pathway and differential expression analyses) were performed in parental and resistant cells. Data reconciliation was performed in GSE62322, a clinical FOLFIRI responder data set (intrinsic resistance). Relapse-free survival (RFS) associations of identified differentially expressed genes and potential gene signatures were investigated in 8 clinical CRC data sets. No mutual genetic alterations were found in FOLFIRI-resistant derivatives. Resistant cell lines displayed activation of mitogen-activated protein kinase, immune response, and epithelial-mesenchymal transition pathways. Twelve differentially expressed genes, significantly differentially expressed in at least 2 of the 3 resistant cell lines, were identified. Comparison with GSE62322 and subsequent survival analyses revealed a 5-gene FOLFIRI signature comprised of CAV2, TNC, TACSTD2, SERPINE2, and PERP that was associated with RFS in multiple data sets including the cancer genome atlas CRC (hazard ratio [HR] =2.634, P = 4.53 × 10-6), in pooled samples of all data sets (all stages [N = 1981]: HR = 1.852, P = 6.44 × 10-13; stage IV [N = 260]: HR = 2.462, P = 5.22 × 10-9). A multivariate Cox regression analysis identified the 5-gene signature as an independent prognostic factor in the cancer genome atlas data set (HR = 1.89, P = .0202). Our analyses revealed a 5-gene FOLFIRI resistance signature associated with RFS that may help predict FOLFIRI resistance and thus avoid unnecessary ineffective treatment. Signature members might also represent targets to fight FOLFIRI resistance.
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Affiliation(s)
- Elise Pretzsch
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich and German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Christiane A Peschel
- Institute of Pathology, Medical Faculty, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Matjaz Rokavec
- Experimental and Molecular Pathology, Institute of Pathology, Medical Faculty, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Lucien Torlot
- Department of Anaesthesiology, LMU University Hospital, LMU Munich, Germany
| | - Pan Li
- Institute of Pathology, Medical Faculty, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Heiko Hermeking
- German Cancer Consortium (DKTK), Partner Site Munich and German Cancer Research Centre (DKFZ), Heidelberg, Germany; Experimental and Molecular Pathology, Institute of Pathology, Medical Faculty, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Jens Werner
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich and German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Frederick Klauschen
- German Cancer Consortium (DKTK), Partner Site Munich and German Cancer Research Centre (DKFZ), Heidelberg, Germany; Institute of Pathology, Medical Faculty, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Jens Neumann
- German Cancer Consortium (DKTK), Partner Site Munich and German Cancer Research Centre (DKFZ), Heidelberg, Germany; Institute of Pathology, Medical Faculty, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Andreas Jung
- German Cancer Consortium (DKTK), Partner Site Munich and German Cancer Research Centre (DKFZ), Heidelberg, Germany; Institute of Pathology, Medical Faculty, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Jörg Kumbrink
- German Cancer Consortium (DKTK), Partner Site Munich and German Cancer Research Centre (DKFZ), Heidelberg, Germany; Institute of Pathology, Medical Faculty, Ludwig-Maximilians-University Munich, Munich, Germany.
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14
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Xie H, Sun L, Yao S, Tian X, Jin L, Dai Y, Li Y, Li Y, Fang J, Guo P, Zhang Y. Therapeutically targeting endometrial cancer in preclinical models by ICAM1 antibody-drug conjugates. Gynecol Oncol 2025; 196:16-27. [PMID: 40147093 DOI: 10.1016/j.ygyno.2025.03.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 03/16/2025] [Accepted: 03/18/2025] [Indexed: 03/29/2025]
Abstract
OBJECTIVE The incidence of mortality and morbidity from endometrial cancer (EC) is increasing annually, and there is a paucity of effective targeted therapies for the condition. Antibody-drug conjugates (ADCs) represent a promising approach to tumor-targeted therapy. In this study, we aim to identify a novel molecular target for the preclinical development of EC-targeted ADCs. METHODS Through quantitative and unbiased bioinformatics analyses intercellular adhesion molecule-1 (ICAM1) was identified as a potential cell membrane target. Two ADCs, ICAM1-MMAE and ICAM1-DXd, were subsequently developed by conjugating ICAM1 monoclonal antibodies with microtubule inhibitors and DNA topoisomerase inhibitors, respectively. The preclinical efficacy and biosafety of these ICAM1 ADCs were validated in both in vitro and in vivo models. Furthermore, transcriptomic analysis was conducted to elucidate the therapeutic effects of the ICAM1 ADCs. RESULTS Quantitative flow screening and bioinformatics analyses revealed significant overexpression of ICAM1 in EC. ICAM1-MMAE and ICAM1-DXd were developed using clinically effective linkers and payloads. In preclinical models, ICAM1 ADCs showed superior antitumor efficacy compared to standard chemotherapy, achieving sustained tumor regression with an excellent safety profile in both subcutaneous and orthotopic xenograft models. Transcriptomic analysis further revealed that ICAM1-DXd potently activated tumor immunity. CONCLUSIONS ICAM1 was identified as a promising cell membrane protein target for ADC development in EC. As-synthesized ICAM1 ADCs demonstrated potent antitumor activity, favorable biosafety profiles in vitro and in vivo, and the ability to activate tumor immunity. These findings support the potential of ICAM1 ADCs as a therapeutic strategy and warrant further investigation in clinical studies.
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Affiliation(s)
- Hanfei Xie
- Department of Gynecologic Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China; Clinical and Translational Research Center, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China; Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou 310022, China
| | - Lu Sun
- Department of Gynecologic Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China; Clinical and Translational Research Center, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China
| | - Shili Yao
- Clinical and Translational Research Center, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China; School of Materials Science and Engineering, Tianjin University, Tianjin 300072, China
| | - Xuefei Tian
- Clinical and Translational Research Center, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China; Department of Biological Medicines and Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai 201203, China
| | - Liming Jin
- Clinical and Translational Research Center, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China; Department of Urology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Structural Birth Defect and Reconstruction, Chongqing 400014, China
| | - Yujie Dai
- Clinical and Translational Research Center, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China; MOE Frontier Science Centre for Precision Oncology, Faculty of Health Sciences, University of Macau, Macau SAR 999078, China
| | - Yuanzheng Li
- Clinical and Translational Research Center, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China; School of Chemistry and Materials Science, University of Science and Technology of China, Hefei 230026, China
| | - Yuxuan Li
- Clinical and Translational Research Center, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China
| | - Jianmin Fang
- School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Peng Guo
- Department of Gynecologic Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China; Clinical and Translational Research Center, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China; School of Materials Science and Engineering, Tianjin University, Tianjin 300072, China; Department of Urology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Structural Birth Defect and Reconstruction, Chongqing 400014, China; School of Chemistry and Materials Science, University of Science and Technology of China, Hefei 230026, China; MOE Frontier Science Centre for Precision Oncology, Faculty of Health Sciences, University of Macau, Macau SAR 999078, China; Eye Research Center, Hangzhou Institute of Medicine, Chinese Academy of Sciences, Eye Hospital, Wenzhou Medical University, Hangzhou, Zhejiang 310018, China.
| | - Yingli Zhang
- Department of Gynecologic Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China; Clinical and Translational Research Center, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China; Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou 310022, China.
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15
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Wang M, Ma Q, Suthe SR, Hudson RE, Pan JY, Mikelis C, Zhu MJ, Wu ZG, Shi DR, Yao HP. Humanized dual-targeting antibody-drug conjugates specific to MET and RON receptors as a pharmaceutical strategy for the treatment of cancers exhibiting phenotypic heterogeneity. Acta Pharmacol Sin 2025; 46:1375-1389. [PMID: 39837982 PMCID: PMC12032285 DOI: 10.1038/s41401-024-01458-7] [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: 08/13/2024] [Accepted: 12/12/2024] [Indexed: 01/23/2025]
Abstract
Cancer heterogeneity, characterized by diverse populations of tumorigenic cells, involves the occurrence of differential phenotypes with variable expressions of receptor tyrosine kinases. Aberrant expressions of mesenchymal-epithelial transition (MET) and recepteur d'origine nantais (RON) receptors contribute to the phenotypic heterogeneity of cancer cells, which poses a major therapeutic challenge. This study aims to develop a dual-targeting antibody-drug conjugate (ADC) that can act against both MET and RON for treating cancers with high phenotypic heterogeneity. Through immunohistochemical staining, we show that MET and RON expressions are highly heterogeneous with differential combinations in more than 40% of pancreatic and triple-negative breast cancer cases. This expressional heterogeneity provides the rationale to target both receptors for cancer therapy. A humanized bispecific monoclonal antibody specific to both MET and RON (PCMbs-MR) is generated through IgG recombination using monoclonal antibody sequences specific to MET and RON, respectively. Monomethyl auristatin E is conjugated to PCMbs-MR to generate a dual-targeting ADC (PCMdt-MMAE), with a drug-to-antibody ratio of 4:1. Various cancer cell lines were used to determine PCMdt-MMAE-mediated biological activities. The efficacy of PCMdt-MMAE in vivo is evaluated using multiple xenograft tumor models. PCMdt-MMAE shows a favorable pharmacokinetic profile, with a maximum tolerated dose of ~30 mg/kg in mice. Toxicological studies using Sprague-Dawley rats reveal that PCMdt-MMAE is relatively safe with slight-to-moderate, temporary, and reversible adverse events. Functionally, PCMdt-MMAE induces a robust internalization of both MET and RON and causes a large-scale cell death in cancer cell lines exhibiting MET and RON heterogeneous co-expressions. Both in vitro and in vivo studies demonstrate that the dual-targeting approach in the form of an ADC is highly effective with a long-lasting effect against tumors exhibiting MET/RON heterogeneous phenotypes. Hence, we can suggest that a dual-targeting ADC specific to both MET and RON can be employed as a novel therapeutic strategy for tumors with expressional phenotypic heterogeneity.
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Affiliation(s)
- Minghai Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
- Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, 79106, TX, USA
- Cancer Biology Research Center, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, 79106, TX, USA
| | - Qi Ma
- Comprehensive Genitourinary Cancer Center, First Affiliated Hospital of Ningbo University, Ningbo, 315000, China
- Translational Research Laboratory for Urology, The Key Laboratory of Ningbo City, Ningbo, 315000, China
| | - Sreedhar Reddy Suthe
- Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, 79106, TX, USA
| | - Rachel E Hudson
- Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, 79106, TX, USA
| | - Jing-Ying Pan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Constantinos Mikelis
- Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, 79106, TX, USA
- Cancer Biology Research Center, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, 79106, TX, USA
| | - Miao-Jin Zhu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Zhi-Gang Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Dan-Rong Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Hang-Ping Yao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
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Wang Z, Hong H. Anti‑HER2‑targeted therapies for the treatment of advanced HER2‑positive breast cancer with brain metastases (Review). Mol Clin Oncol 2025; 22:45. [PMID: 40170686 PMCID: PMC11959222 DOI: 10.3892/mco.2025.2840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 02/17/2025] [Indexed: 04/03/2025] Open
Abstract
Compared with other metastatic sites, breast cancer brain metastases (BCBMs) are associated with the shortest survival time. In addition, human epidermal growth factor receptor 2 (HER2) is observed to be amplified in 20-25% of breast cancer cases where it is a poor prognostic factor for brain metastases. Various anti-HER2 targeted therapies have brought both new opportunities and challenges to patients with HER2-positive BCBM over the past decade. However, prolonging survival time and improving quality of life of patients have become controversial issues in the field of clinical research on BCBMs. On the basis of the latest literature, the present review documents the anti-HER2 targeted drugs applied in patients with HER2-positive BCBM. Further studies on the efficacy and safety of novel HER2-targeted drugs and combined or sequential therapy in clinical treatment are expected to provide more effective strategies for the treatment of patients with HER2-positive BCBM.
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Affiliation(s)
- Zhangyan Wang
- Department of Medical Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610041, P.R. China
| | - Huangming Hong
- Department of Medical Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610041, P.R. China
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17
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Greenman M, Demirkiran C, Bellone S, Hartwich TM, McNamara B, Ettorre VM, Santin NG, Sethi N, Yang-Hartwich Y, Papatla K, Ratner E, Santin AD. Preclinical Activity of Datopotamab Deruxtecan, an Antibody-Drug Conjugate Targeting Trophoblast Cell-Surface Antigen 2, in Uterine Serous Carcinoma. CANCER RESEARCH COMMUNICATIONS 2025; 5:774-782. [PMID: 40299780 PMCID: PMC12062949 DOI: 10.1158/2767-9764.crc-25-0057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Revised: 03/27/2025] [Accepted: 04/23/2025] [Indexed: 05/01/2025]
Abstract
Uterine serous carcinoma (USC) is a rare subset of endometrial cancer with a poor prognosis and high recurrence rate. Datopotamab deruxtecan (Dato-DXd) is a novel antibody-drug conjugate (ADC). The objective of this study was to evaluate the preclinical activity of Dato-DXd in USC in vitro against primary USC cell lines with various trophoblast cell-surface antigen 2 (TROP2) expression and in vivo in TROP2-overexpressing cell line-derived mice xenografts. USC primary tumor cell lines were treated with Dato-DXd and a control ADC (CTL ADC) to evaluate cell viability following exposure. Antibody-dependent cell-mediated cytotoxicity against TROP2-overexpressing and -nonexpressing cell lines was evaluated using a 4-hour chromium release assay. USC xenografts in mice were treated with Dato-DXd, CTL ADC, datopotamab, and vehicle to assess the in vivo effects via retro-orbital Dato-DXd administration. We found USC cell lines with TROP2 overexpression to be significantly more sensitive to killing induced by Dato-DXd compared with CTL ADC in vitro (e.g., IC50: 0.11 µmol/L vs. 30.07 µmol/L, P = 0.0074 and 0.11 µmol/L vs. 48.95 µmol/L, P = 0.0127, respectively). Dato-DXd induced antibody-dependent cell-mediated cytotoxicity in the presence of peripheral blood lymphocytes from healthy donors. TROP2-nonexpressing cell lines demonstrated minimal killing by Dato-DXd; however, when admixed with TROP2-overexpressing cells, a significant bystander effect was appreciated. In vivo, mice xenografts overexpressing TROP2 treated with Dato-DXd demonstrated tumor growth suppression and longer overall survival compared with CTL ADC-treated xenografts. These data demonstrate Dato-DXd to be highly active against TROP2-overexpressing USC in vitro and in vivo. Our preclinical activity results warrant future clinical trials for patients with advanced or recurrent USC. SIGNIFICANCE Targeted treatment of USC using the biomarker TROP2 represents a significant opportunity for further treatment options for patients already resistant to other lines of treatment. In this study, we present data showing preclinical evidence of effectiveness of this biomarker-targeted therapy in USC.
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Affiliation(s)
- Michelle Greenman
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut
| | - Cem Demirkiran
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut
| | - Stefania Bellone
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut
| | - Tobias M.P. Hartwich
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut
| | - Blair McNamara
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut
| | - Victoria M. Ettorre
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut
| | - Niccolo G. Santin
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut
| | - Namrata Sethi
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut
| | - Yang Yang-Hartwich
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut
| | - Katyayani Papatla
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut
| | - Elena Ratner
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut
| | - Alessandro D. Santin
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut
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Bukhalid RA, Duvall JR, Lancaster K, Catcott KC, Malli Cetinbas N, Monnell T, Routhier C, Thomas JD, Bentley KW, Collins SD, Ditty E, Eitas TK, Kelleher EW, Shaw P, Soomer-James J, Ter-Ovanesyan E, Xu L, Zurita J, Toader D, Damelin M, Lowinger TB. XMT-2056, a HER2-Directed STING Agonist Antibody-Drug Conjugate, Induces Innate Antitumor Immune Responses by Acting on Cancer Cells and Tumor-Resident Immune Cells. Clin Cancer Res 2025; 31:1766-1782. [PMID: 40029253 PMCID: PMC12010966 DOI: 10.1158/1078-0432.ccr-24-2449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 09/24/2024] [Accepted: 02/19/2025] [Indexed: 03/05/2025]
Abstract
PURPOSE Targeted tumor delivery may be required to potentiate the clinical benefit of innate immune modulators. The objective of the study was to apply an antibody-drug conjugate (ADC) approach to STING agonism and develop a clinical candidate. EXPERIMENTAL DESIGN XMT-2056, a HER2-directed STING agonist ADC, was designed, synthesized, and tested in pharmacology and toxicology studies. The ADC was compared with a clinical benchmark intravenously administered a STING agonist. RESULTS XMT-2056 achieved tumor-targeted delivery of the STING agonist upon systemic administration in mice and induced innate antitumor immune responses; single dose administration of XMT-2056 induced tumor regression in a variety of tumor models with high and low HER2 expressions. Notably, XMT-2056 demonstrated superior efficacy and reduced systemic inflammation compared with a free STING agonist. XMT-2056 exhibited concomitant immune-mediated killing of HER2-negative cells specifically in the presence of HER2-positive cancer cells, supporting the potential for activity against tumors with heterogeneous HER2 expression. The antibody does not compete for binding with trastuzumab or pertuzumab, and a benefit was observed when combining XMT-2056 with each of these therapies as well as with trastuzumab deruxtecan ADC. The combination of XMT-2056 with anti-PD-1 conferred benefit on antitumor activity and induced immunologic memory. XMT-2056 was well tolerated in nonclinical toxicology studies. CONCLUSIONS These data provide a robust preclinical characterization of XMT-2056 and provide rationale and strategy for its clinical evaluation.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | - Pamela Shaw
- Mersana Therapeutics, Inc., Cambridge, Massachusetts
| | | | | | - Ling Xu
- Mersana Therapeutics, Inc., Cambridge, Massachusetts
| | | | - Dorin Toader
- Mersana Therapeutics, Inc., Cambridge, Massachusetts
| | - Marc Damelin
- Mersana Therapeutics, Inc., Cambridge, Massachusetts
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Yaacobi Peretz S, Kessner R, Bar Y, Sonnenblick A, Lerner S, Deutsch-Lukatsky A, Popuri K, Beg MF, Shachar SS. Body composition metrics as a determinant of trastuzumab deruxtecan related toxicity and response. NPJ Breast Cancer 2025; 11:38. [PMID: 40281028 PMCID: PMC12032009 DOI: 10.1038/s41523-025-00754-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Accepted: 04/09/2025] [Indexed: 04/29/2025] Open
Abstract
Body composition is an important predictor in cancer patients, with skeletal muscle loss and high adiposity associated with poorer prognosis. This study evaluated how body composition affects treatment efficacy in 48 women with metastatic breast cancer receiving trastuzumab deruxtecan. Using computed tomography, skeletal muscle, visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were assessed within 60 days before initiating treatment. High SAT and VAT areas were significantly associated with a higher likelihood of dose reductions (Odds Ratio [OR] = 5.34, p = .032 and OR = 5.52, p = 0.032, respectively). Higher SAT areas correlated with a lower objective response rate (OR = 0.22, p = 0.047). Medium SAT and low/medium VAT densities increased the risk of dose reductions. A body mass index over 25 kg/m2 was linked to higher dose reductions (OR = 4.97, p = 0.016). These findings emphasize the need for personalized treatment strategies based on body composition.
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Affiliation(s)
| | - Rivka Kessner
- Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel
- Radiology Department, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Yael Bar
- Oncology Department, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Amir Sonnenblick
- Oncology Department, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Shir Lerner
- Oncology Department, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | | | - Karteek Popuri
- Computer Science Department, Memorial University of Newfoundland, St. John's, NL, Canada
| | - Mirza Faisal Beg
- School of Engineering Science, Simon Fraser University, Burnaby, BC, Canada
| | - Shlomit Strulov Shachar
- Oncology Department, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
- Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel.
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20
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Fukuda K, Osumi H, Shimozaki K, Chin K, Ogura M, Fukuoka S, Udagawa S, Yoshino K, Tamba M, Wakatsuki T, Shinozaki E, Yamaguchi K, Ooki A. Impact of early tumor shrinkage on survival outcomes in patients with HER2-positive advanced gastric cancer treated with trastuzumab deruxtecan in third- or later-line settings. Therap Adv Gastroenterol 2025; 18:17562848251333538. [PMID: 40297207 PMCID: PMC12035244 DOI: 10.1177/17562848251333538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Accepted: 03/24/2025] [Indexed: 04/30/2025] Open
Abstract
Background Trastuzumab deruxtecan (T-DXd) has been approved for a third- or later-line treatment of HER2-positive advanced gastric cancer (AGC) in Japan. However, clinical data on the use of T-DXd in real-world practice remain insufficient. Although early tumor shrinkage (ETS) serves as an early on-treatment indicator of high treatment sensitivity, the use of ETS in predicting T-DXd efficacy remains unclear. Objectives This study aimed to evaluate the clinical efficacy and safety of T-DXd and investigate the clinical utility of ETS as a predictor of long-term efficacy and survival. Design Single-center retrospective cohort study. Methods This study consecutively enrolled patients with HER2-positive AGC who received T-DXd as a third- or later-line treatment between March 2018 and December 2023. Data on patient characteristics, adverse events (AEs), and clinical outcomes were obtained from electronic medical records. Clinical efficacy was assessed using progression-free survival (PFS) and overall survival (OS). In patients with measurable lesions, the overall response rate (ORR), ETS, and depth of response (DpR) were evaluated. Prognostic outcomes were assessed using the log-rank test and the Cox proportional hazards model. Results A total of 65 patients received T-DXd, with a median age of 66 years (range, 31-82 years); 77% had HER2 immunohistochemistry score of 3+, 71% received T-DXd as a third-line treatment, and 32% required initial dose reduction. At a median follow-up of 33.6 months, the median PFS and OS were 4.5 months and 7.7 months, respectively. Among the 47 patients with measurable lesions, the ORR was 36%. A median DpR of 15.8% was observed, with higher DpR correlating with longer OS. ETS was achieved in 38% of the patients and was an independent predictor of favorable PFS (hazard ratio (HR), 0.21; 95% confidence interval (CI), 0.09-0.49; p < 0.01) and OS (HR, 0.23; 95% CI, 0.10-0.52; p < 0.01). Longer second-line treatment duration was independently associated with improved OS. Overall, grade ⩾ 3 AEs occurred in 37% of the patients. Initial dose reduction reduced AE-induced discontinuation of treatment without compromising efficacy. Conclusion T-DXd demonstrated notable efficacy and a manageable safety profile in patients with HER2-positive AGC. Rapid and deep tumor shrinkage may have a significant impact on survival.
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Affiliation(s)
- Koshiro Fukuda
- Department of Gastroenterological Chemotherapy, Japanese Foundation for Cancer Research, Ganken Ariake Byoin Cancer Institute Hospital, Koto-ku, Tokyo, Japan
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hiroki Osumi
- Department of Gastroenterological Chemotherapy, Japanese Foundation for Cancer Research, Ganken Ariake Byoin Cancer Institute Hospital, Koto-ku, Tokyo, Japan
| | - Keitaro Shimozaki
- Department of Gastroenterological Chemotherapy, Japanese Foundation for Cancer Research, Ganken Ariake Byoin Cancer Institute Hospital, Koto-ku, Tokyo, Japan
| | - Keisho Chin
- Department of Gastroenterological Chemotherapy, Japanese Foundation for Cancer Research, Ganken Ariake Byoin Cancer Institute Hospital, Koto-ku, Tokyo, Japan
| | - Mariko Ogura
- Department of Gastroenterological Chemotherapy, Japanese Foundation for Cancer Research, Ganken Ariake Byoin Cancer Institute Hospital, Koto-ku, Tokyo, Japan
| | - Shota Fukuoka
- Department of Gastroenterological Chemotherapy, Japanese Foundation for Cancer Research, Ganken Ariake Byoin Cancer Institute Hospital, Koto-ku, Tokyo, Japan
| | - Shohei Udagawa
- Department of Gastroenterological Chemotherapy, Japanese Foundation for Cancer Research, Ganken Ariake Byoin Cancer Institute Hospital, Koto-ku, Tokyo, Japan
| | - Koichiro Yoshino
- Department of Gastroenterological Chemotherapy, Japanese Foundation for Cancer Research, Ganken Ariake Byoin Cancer Institute Hospital, Koto-ku, Tokyo, Japan
| | - Mikako Tamba
- Department of Gastroenterological Chemotherapy, Japanese Foundation for Cancer Research, Ganken Ariake Byoin Cancer Institute Hospital, Koto-ku, Tokyo, Japan
| | - Takeru Wakatsuki
- Department of Gastroenterological Chemotherapy, Japanese Foundation for Cancer Research, Ganken Ariake Byoin Cancer Institute Hospital, Koto-ku, Tokyo, Japan
| | - Eiji Shinozaki
- Department of Gastroenterological Chemotherapy, Japanese Foundation for Cancer Research, Ganken Ariake Byoin Cancer Institute Hospital, Koto-ku, Tokyo, Japan
| | - Kensei Yamaguchi
- Department of Gastroenterological Chemotherapy, Japanese Foundation for Cancer Research, Ganken Ariake Byoin Cancer Institute Hospital, Koto-ku, Tokyo, Japan
| | - Akira Ooki
- Department of Gastroenterological Chemotherapy, Japanese Foundation for Cancer Research, Ganken Ariake Byoin Cancer Institute Hospital, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan
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21
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Vincken R, Armendáriz-Martínez U, Ruiz-Sáenz A. ADCC: the rock band led by therapeutic antibodies, tumor and immune cells. Front Immunol 2025; 16:1548292. [PMID: 40308580 PMCID: PMC12040827 DOI: 10.3389/fimmu.2025.1548292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Accepted: 03/27/2025] [Indexed: 05/02/2025] Open
Abstract
Antibody-dependent cellular cytotoxicity (ADCC) is a critical mechanism by which therapeutic antibodies leverage the immune system to target and eliminate cancer cells. The key agents of ADCC are natural killer (NK) cells, specifically targeting antibody-covered cancer cells through the CD16 receptor. While other immune cells and Fc receptors can contribute and enhance ADCC, NK cells and the CD16 receptor are crucial for the efficacy of cancer therapies such as trastuzumab, cetuximab and rituximab. Co-culture assays are essential for understanding the mechanisms of these therapies, overcoming resistance and optimizing novel therapeutic antibodies. This review highlights the importance of measuring ADCC to assess the efficacy of therapeutic antibodies. Here we also present the various in vitro models and assay methodologies available for studying ADCC, comparing the strengths and limitations of approaches like using PBMCs to better reflect real-life conditions or NK cell lines for standardization. It also covers different readouts for ADCC, either focusing on effector cells activation, including reporter and degranulation assays or in the target cell killing, including different molecule release assays, flow cytometry and immunofluorescence techniques. Selecting the best model for studying ADCC is crucial for the translational significance of therapeutic antibody research.
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Affiliation(s)
- Roos Vincken
- Department of Cell Biology, Erasmus University Medical Center Rotterdam, CN, Rotterdam, Netherlands
- Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Derio, Spain
| | - Uxue Armendáriz-Martínez
- Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Derio, Spain
| | - Ana Ruiz-Sáenz
- Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Derio, Spain
- IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
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22
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Lee H, Ryu JM, Lee SK, Chae BJ, Yu J, Lee JE, Kim SW, Nam SJ, Cho YA, Cho EY. HER2 mRNA Score From Quantitative ERBB2 mRNA Expression of Oncotype Dx : Can It Replace the HER2 Immunohistochemistry? Am J Surg Pathol 2025:00000478-990000000-00499. [PMID: 40170597 DOI: 10.1097/pas.0000000000002396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/03/2025]
Abstract
As novel human epidermal growth factor receptor-2 (HER2) and drug conjugates have proven to be effective treatments for both HER2-positive breast cancer (BC) and HER2-low BC, the need to develop more accurate methods to quantify HER2 status has increased. We compared the correlation between the HER2 mRNA score (HS), obtained using the Oncotype DX (ODX) test, and HER2 immunohistochemistry (IHC) to verify the accuracy of HER2 quantification and its correlation with clinicopathologic characteristics. We retrospectively collected ODX test data from 1524 estrogen-receptor positive, HER2-negative patients with BC. No significant differences in clinicopathologic characteristics, including ODX Recurrence Score (RS), were observed between HER2-0 and HER2-low BC. The median HS value of the HER2-low subgroup was significantly higher than that of the HER2-0 subgroup ( P <0.001) and increased significantly between the 4 subgroups classified by HER2 IHC ( P <0.001). The receiver operating characteristic curve showed acceptable utility in distinguishing HER2-0 from HER2-low (area under the curve=0.76) and HER2-null and HER2-ultralow subgroups (area under the curve=0.81), but the overlap between subgroups was also prominent. After defining 8.9 as a suboptimal cutoff mRNA score, multivariate analysis revealed that low Ki-67 (<20%) and RS (≤25) were statistically associated with higher HS (>8.9), whereas progesterone receptor negativity, high Ki-67, high nuclear grade, lower HS, and older age (>50 y) were statistically associated with high RS. Our study revealed that HS is significantly associated with HER2 IHC results and clinicopathologic parameters other than HER2 IHC.
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Affiliation(s)
- Hyunwoo Lee
- Department of Pathology and Translational Genomics
| | - Jai Min Ryu
- Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Se Kyung Lee
- Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Byung Joo Chae
- Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jonghan Yu
- Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jeong Eon Lee
- Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Seok Won Kim
- Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Seok Jin Nam
- Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Yoon Ah Cho
- Department of Pathology and Translational Genomics
| | - Eun Yoon Cho
- Department of Pathology and Translational Genomics
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23
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Han J, Zhai X, Tao X, Li Y, Zhao Z, Yu Z, Dong D, Yang S, Lv L. Pharmacovigilance study of adverse reactions of anti-HER-2 drugs for the treatment of HER-2-positive breast cancer based on the FAERS database. Breast Cancer Res 2025; 27:54. [PMID: 40205546 PMCID: PMC11983758 DOI: 10.1186/s13058-025-02013-w] [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: 11/27/2024] [Accepted: 03/29/2025] [Indexed: 04/11/2025] Open
Abstract
OBJECTIVE There are three categories of drugs that treat human epidermal growth factor receptor type 2 (HER-2) positive breast cancer: monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs), and tyrosine kinase inhibitors (TKIs). The purpose of this study is to analyze and compare the adverse reactions of three classes of anti-HER-2 drugs to various body systems in patients based on the FDA Adverse Event Reporting System (FAERS). METHODS All data reports were extracted from the FAERS between 2004 and 2024. Data mining of adverse events associated with anti-HER-2 drugs was carried out using disproportionality analysis. A multivariate logistic regression analysis was conducted to explore the risk factors associated with AEs leading to hospitalization. RESULTS A total of 47,799 patients were screened for the three classes of drugs, among which ADC drugs caused the largest proportion of deaths. MAb has the strongest ADR signals associated with "cardiac disorders". Moreover, trastuzumab was associated with a greater risk of cardiotoxicity. Logistic regression analysis revealed that the treatment with mAbs should be wary of serious adverse reactions in "infections and infestations" and "metabolism and nutrition disorders". Moreover, "endocrine disorders" were the factor associated with the highest risk of prolonged hospitalization due to trastuzumab deruxtecan (T-DXd). The safety of tucatinib among TKI drugs is greater than that of other drugs. CONCLUSION In general, from the perspective of the effects of the three classes of drugs on the various body systems of patients, we should focus on mAb-associated "cardiac disorders", ADC-associated "hepatobiliary disorders", "respiratory, thoracic and mediastinal disorders", and TKI-associated "gastrointestinal disorders.
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Affiliation(s)
- Jinming Han
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, 116024, China
| | - Xiaohan Zhai
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, 116024, China
| | - Xufeng Tao
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, 116024, China
| | - Yunming Li
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, 116024, China
| | - Ziqi Zhao
- Department of Breast Surgery, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Zhan Yu
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, 116024, China
| | - Deshi Dong
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, 116024, China
| | - Shilei Yang
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, 116024, China
| | - Linlin Lv
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, 116024, China.
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Yin Q, Zhang Y, Xie X, Hou M, Chen X, Ding J. Navigating the future of gastric cancer treatment: a review on the impact of antibody-drug conjugates. Cell Death Discov 2025; 11:144. [PMID: 40188055 PMCID: PMC11972320 DOI: 10.1038/s41420-025-02429-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 03/07/2025] [Accepted: 03/21/2025] [Indexed: 04/07/2025] Open
Abstract
Gastric cancer, marked by its high incidence and poor prognosis, demands the urgent development of novel and effective treatment strategies, especially for patients ineligible for surgery or those who have had limited success with chemotherapy, radiotherapy and targeted therapies. Recently, antibody-drug conjugates (ADCs) have become a key area of investigation due to their high specificity and potent antitumor effects. These therapies combine monoclonal antibodies, designed to bind to tumor-specific antigens, with cytotoxic agents that selectively target and destroy malignant cells. ADCs have generated significant interest in clinical trials as a promising approach to improve both treatment efficacy and patient outcomes in gastric cancer. However, their clinical application is not without challenges and limitations that must be addressed. This review discusses the recent progress in the use of ADCs for gastric cancer treatment.
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Affiliation(s)
- Qingling Yin
- GuiZhou University Medical College, Guiyang, 550025, Guizhou, China
- NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People's Hospital, Guiyang, 550002, Guizhou, China
| | - Yanlong Zhang
- GuiZhou University Medical College, Guiyang, 550025, Guizhou, China
| | - Xueqing Xie
- GuiZhou University Medical College, Guiyang, 550025, Guizhou, China
| | - Meijun Hou
- Graduate School, Zunyi Medical University, Zunyi, Guizhou, 563006, China
| | - Xunsheng Chen
- Department of Gastrointestinal Surgery, Guizhou Provincial People's Hospital, Guiyang, 550002, Guiyang, China
| | - Jie Ding
- Department of Gastrointestinal Surgery, Guizhou Provincial People's Hospital, Guiyang, 550002, Guiyang, China.
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25
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Wróbel A, Vandenberghe M, Scott M, Jones F, Matsuo T, Boothman AM, Whiteley J, Barker C. Accuracy of human epidermal growth factor receptor 2 (HER2) immunohistochemistry scoring by pathologists in breast cancer, including the HER2-low cutoff : HER2 IHC scoring concordance in breast cancer. Diagn Pathol 2025; 20:35. [PMID: 40186179 PMCID: PMC11969812 DOI: 10.1186/s13000-025-01624-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Accepted: 02/26/2025] [Indexed: 04/07/2025] Open
Abstract
BACKGROUND Breast cancer was previously categorized as human epidermal growth factor receptor 2 (HER2)-positive (immunohistochemistry [IHC] 3+, IHC 2+ / in situ hybridization [ISH]-positive) or HER2-negative (IHC 0, IHC 1+, IHC 2+/ISH-). Recent studies of trastuzumab deruxtecan, a HER2-directed antibody-drug conjugate, have explored the spectrum of HER2 expression in tumors categorized as HER2-negative, including HER2-low (IHC 1+, IHC 2+/ISH-) and HER2-ultralow (IHC 0 with membrane staining). Clinical relevance of HER2-low and HER2-ultralow is reinforced by encouraging efficacy findings in these populations. OBJECTIVE To assess HER2-low and HER2-ultralow scoring performance by pathologists, and compare real-world HER2-low scoring with centralized scoring by trained pathologists. METHODS Formalin-fixed, paraffin-embedded breast cancer samples stained by the VENTANA anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody (Roche) assay were selected to ensure adequate representation across all HER2 IHC scores (N = 500). Samples were rescored in a central laboratory by three pathologists trained in HER2-low scoring, and a majority consensus generated. Agreement between consensus and historical real-world HER2 scores was assessed by Fleiss' kappa across HER2 scores (IHC 0, 1+, 2+, 3+). RESULTS Substantial agreement was observed among central pathologists across HER2 scores (κ = 0.69), for the HER2-low cutoff (IHC 0 vs. IHC 1+, 2+, 3+; κ = 0.79), and the HER2-ultralow cutoff (IHC 0 absent membrane staining vs. IHC 0 with membrane staining, 1+, 2+, 3+; κ = 0.68). Substantial agreement was observed between real-world pathologists and central consensus for the HER2-low cutoff (κ = 0.72). CONCLUSIONS Pathologists can reproducibly score HER2-low and HER2-ultralow when supported by training. Findings may aid decision-making for patients with breast cancer who are potentially eligible for HER2-directed therapy.
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Affiliation(s)
- Agata Wróbel
- Oncology R&D, AstraZeneca, Postępu 14, Warsaw, 02-676, Poland.
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Wen L, Zhang Y, Sun C, Wang SS, Gong Y, Jia C, Luo J. Fundamental properties and principal areas of focus in antibody-drug conjugates formulation development. Antib Ther 2025; 8:99-110. [PMID: 40177644 PMCID: PMC11959695 DOI: 10.1093/abt/tbaf005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 02/18/2025] [Accepted: 02/26/2025] [Indexed: 04/05/2025] Open
Abstract
Antibody-drug conjugates (ADCs) have emerged as a rapidly expanding class of therapeutics driven by their superior specificity and clinical efficacy. 14 out of 16 commercially approved ADCs are formulated as lyophilized forms because ADC is generally considered to be less stable than unmodified antibody. The formulation development for ADCs, particularly liquid formulation, presents unique challenges due to their intricate structural complexity, physicochemical properties, and degradation pathways. This review provides the first comprehensive analysis of formulation strategies employed in commercial ADCs. Furthermore, this review discusses the key areas of focus for ADCs throughout the formulation development workflow, spanning from the initial formulation development to the final stage of drug product manufacturing. In addition, we identify and analyze the distinctive technical challenges in ADC formulation development compared to unconjugated antibody, while proposing potential solutions to these challenges. Finally, we offer strategic perspectives on future directions in ADC formulation development to advance this promising therapeutic modality.
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Affiliation(s)
- Lili Wen
- Department of Bioconjugate Product Development and Manufacturing, WuXi XDC Co., Ltd., Wuxi, Jiangsu, P.R. China
| | - Yuanyuan Zhang
- Department of Bioconjugate Product Development and Manufacturing, WuXi XDC Co., Ltd., Wuxi, Jiangsu, P.R. China
| | - Chenxi Sun
- Department of Bioconjugate Product Development and Manufacturing, WuXi XDC Co., Ltd., Wuxi, Jiangsu, P.R. China
| | - Shawn Shouye Wang
- Business Enablement North America, XDC ConjuTech USA LLC, Middletown, DE, United States
| | - Yuhui Gong
- Department of Bioconjugate Product Development and Manufacturing, WuXi XDC Co., Ltd., Wuxi, Jiangsu, P.R. China
| | - Chunyuan Jia
- Department of Bioconjugate Product Development and Manufacturing, WuXi XDC Co., Ltd., Wuxi, Jiangsu, P.R. China
| | - Jianjun Luo
- Department of Bioconjugate Product Development and Manufacturing, WuXi XDC Co., Ltd., Wuxi, Jiangsu, P.R. China
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Park YH, Bianchini G, Cortés J, Licata L, Vidal M, Iihara H, Roeland EJ, Jordan K, Scotté F, Schwartzberg L, Navari RM, Aapro M, Rugo HS. Nausea and vomiting in an evolving anticancer treatment landscape: long-delayed and emetogenic antibody-drug conjugates. Future Oncol 2025; 21:1261-1272. [PMID: 40105595 PMCID: PMC11988240 DOI: 10.1080/14796694.2025.2479417] [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: 10/08/2024] [Accepted: 03/11/2025] [Indexed: 03/20/2025] Open
Abstract
Nausea and vomiting are common, distressing side effects associated with chemotherapeutic regimens, resulting in reduced quality of life and treatment adherence. Appropriate antiemetic prophylaxis strategies may reduce/prevent chemotherapy-induced nausea and vomiting (CINV). Historically, investigators assessed antiemetics up to 120 hours after chemotherapy. However, CINV can extend beyond this time. Thus, the effect of antiemetics during the long-delayed period (>120 hours) requires investigation. Emerging treatment options, including certain antibody-drug conjugates (ADCs), are associated with high rates of acute and late-onset nausea and vomiting that can last for extended duration. With the increasing number of ADCs approved and in development, there is urgency to control nausea and vomiting in patients receiving these new therapies. In this narrative review, we present the emetogenic potential of ADCs and CINV in the long-delayed period along with antiemetic prophylaxis strategies used to date. We also discuss the promising role of the fixed-combination antiemetic NEPA ([fos]netupitant plus palonosetron) in controlling long-delayed nausea and vomiting, addressing characteristics that may contribute to its longer efficacy duration compared to other antiemetics. Finally, we highlight encouraging results with NEPA in patients receiving the ADCs trastuzumab deruxtecan or sacituzumab govitecan, which suggest NEPA may be an effective antiemetic prophylaxis in these settings.
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Affiliation(s)
- Yeon Hee Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Giampaolo Bianchini
- Department of Medical Oncology, IRCCS San Raffaele Hospital, Milan, Italy
- School of Medicine and Surgery, Vita-Salute San Raffaele University, Milan, Italy
| | - Javier Cortés
- International Breast Cancer Center (IBCC), Pangaea Oncology, Quironsalud Group, Barcelona, Spain
- IOB Madrid, Hospital Beata María Ana, Madrid, Spain
- Faculty of Biomedical and Health Sciences, Department of Medicine, Universidad Europea de Madrid, Madrid, Spain
| | - Luca Licata
- Department of Medical Oncology, IRCCS San Raffaele Hospital, Milan, Italy
| | - María Vidal
- Department of Medical Oncology, Hospital Clinic, Translational Genomics and Targeted Therapies in Solid Tumors, IDIBAPS, Barcelona, Spain
- Department of Medicine, University of Barcelona, Barcelona, Spain
| | | | - Eric J. Roeland
- Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA
| | - Karin Jordan
- Department of Hematology, Oncology and Palliative Medicine, Ernst von Bergmann Hospital, Potsdam, Germany
- Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany
| | - Florian Scotté
- Interdisciplinary Cancer Course Department, Gustave Roussy Cancer Institute, Villejuif, France
| | - Lee Schwartzberg
- Renown Health-Pennington Cancer Institute, University of Nevada, Reno, NV, USA
| | | | - Matti Aapro
- Genolier Cancer Centre, Clinique de Genolier, Genolier, Switzerland
| | - Hope S. Rugo
- University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA
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Theocharopoulos C, Ziogas IA, Mungo B, Gogas H, Ziogas DC, Kontis E. HER2-targeted therapies: Unraveling their role in biliary tract cancers. Crit Rev Oncol Hematol 2025; 208:104655. [PMID: 39923923 DOI: 10.1016/j.critrevonc.2025.104655] [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: 11/21/2024] [Revised: 01/31/2025] [Accepted: 02/05/2025] [Indexed: 02/11/2025] Open
Abstract
Biliary tract cancers (BTCs) constitute a heterogeneous group of malignancies with rising incidence and limited therapeutic options in advanced stages, leading to increased overall mortality. Extensive genomic profiling has identified key oncogenic drivers in BTCs that represent promising therapeutic targets and could change the treatment paradigm. Evidence suggests improved survival outcomes for patients with actionable molecular alterations who received matched targeted therapies. Human epidermal growth factor receptor 2 (HER2) is a receptor tyrosine kinase and proto-oncogene that has been extensively studied as a prognostic biomarker and a therapeutic target in multiple solid organ malignancies. Recent clinical trials on the combination of trastuzumab with tucatinib, FOLFOX, or pertuzumab for previously treated, HER2-positive, advanced BTCs have shown improved outcomes compared to current second-line therapies. Early evidence from observational studies on trastuzumab-containing regimens as first-line suggests promising efficacy. Furthermore, the recent tumor-agnostic approval of trastuzumab deruxtecan for HER2-positive solid tumors has formally introduced HER2-directed agents in the BTC therapeutic arsenal. This review aims to summarize the rapidly evolving landscape of HER2-directed agents for BTCs, highlighting current evidence of survival benefit. Beginning with a concise presentation of the structural and functional aspects of HER2, we detail the frequency and prognostic significance of HER2 alterations in BTCs and discuss all available preclinical and clinical data on anti-HER2 agents tested for BTCs.
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Affiliation(s)
| | - Ioannis A Ziogas
- Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
| | - Benedetto Mungo
- Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
| | - Helen Gogas
- First Department of Internal Medicine, Laikon General Hospital, School of Medicine, National Kapodistrian University of Athens, Athens 11527, Greece.
| | - Dimitrios C Ziogas
- First Department of Internal Medicine, Laikon General Hospital, School of Medicine, National Kapodistrian University of Athens, Athens 11527, Greece.
| | - Elissaios Kontis
- Department of Surgery, Metaxa Cancer Hospital, Piraeus 18537, Greece.
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29
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Debbi K, Benderra MA, Medioni J, Durdux C, To NH, Boukhobza C, Grellier N, Benmaziane A, Monnier L, Gligorov J, Assaf E, Belkacemi Y. Safety and efficacy of combined trastuzumab-deruxtecan and concurrent radiation therapy in breast cancer. The TENDANCE multicentric French study. Breast 2025; 80:104421. [PMID: 39983437 PMCID: PMC11893322 DOI: 10.1016/j.breast.2025.104421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 02/02/2025] [Accepted: 02/13/2025] [Indexed: 02/23/2025] Open
Abstract
PURPOSE Trastuzumab Deruxtecan (T DXD), a new antibody drug conjugate is a new treatment option for 2nd line metastatic breast cancer (MBC) for HER2 + or HER2 low tumors. Palliative or ablative radiotherapy (RT) may be required in patients who are being treated with T-DXd. However there is a lack of evidence regarding the safety profile of combining T-DXd with RT. TENDANCE study aimed to evaluate safety and efficacy of combined T-DXd and RT. MATERIALS AND METHODS This retrospective multicenter study included 54 patients treated concurrently with T-DXd and RT for HER2+ and HER2 low MBC between February 2021 and December 2023. All data were collected from a web-questionnaire, centralized after medical records and validation of the protocol by the local ethical committee. Primary endpoint was the safety of combined therapy. RESULTS Median age was 60 years. Patients who received T-DXD were further categorized into HER2+ (40.7 %), HER2 low/hormonal receptors HR+ (40.8 %) or HER2 low/HR- (18.5 %). In the HER2+ patients, T-DXd was administered as 2nd (18.2 %) or 3rd (31.8 %) or 4th (50 %) line therapy. RT was delivered using palliative (72.2 %) or ablative doses (27.8 %). Indications consisted mostly of palliative bone irradiation (46.3 %) and stereotactic radiosurgery (SRS) (25.9 %). With the median follow-up of 9 months, 22.2 % of patients had a complete response and 77.8 % had either a partial response or stable disease. Grade 1 or 2 asthenia was observed in 51.8 % of patients, while only 16.6 % experienced other grade 1 or 2 adverse effects. There was no T-DXd therapy discontinuation related to RT. CONCLUSION To our knowledge, TENDANCE is the largest study evaluating concurrent T-DXd and RT. This preliminary report suggests the feasibility of the combination of RT and T-DXd with manageable toxicity rate. Longer follow-up and further prospective studies are required to confirm these results.
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Affiliation(s)
- K Debbi
- Department of Radiation Oncology and Henri Mondor Breast Center. Henri Mondor University Hospital, APHP, UPEC, Créteil, France; Institut Mondor de Recherche Biomédicale (IMRB), INSERM U955, i-Biot, UPEC, Créteil, France.
| | - M A Benderra
- Medical Oncology Department, Institut Universitaire de Cancérologie Assistance Publique-Hôpitaux de Paris-Sorbonne Université, Paris, France
| | - J Medioni
- Centre of Early Clinical Trials in Cancer, Hôpital Européen Georges-Pompidou, Université Paris Cité, Paris, France
| | - C Durdux
- Department of Radiation Oncology, European Hospital Georges Pompidou, University of Paris Descartes, Paris, France
| | - N H To
- Department of Radiation Oncology and Henri Mondor Breast Center. Henri Mondor University Hospital, APHP, UPEC, Créteil, France; Institut Mondor de Recherche Biomédicale (IMRB), INSERM U955, i-Biot, UPEC, Créteil, France
| | - C Boukhobza
- Department of Radiation Oncology and Henri Mondor Breast Center. Henri Mondor University Hospital, APHP, UPEC, Créteil, France
| | - N Grellier
- Department of Radiation Oncology and Henri Mondor Breast Center. Henri Mondor University Hospital, APHP, UPEC, Créteil, France
| | - A Benmaziane
- Medical Oncology Department, Hôpital Foch, Paris, France
| | - L Monnier
- Radiation Oncology Department, DMU Orphé, Hôpital Tenon, AP-HP.Sorbonne Université, France
| | - J Gligorov
- Medical Oncology Department, Institut Universitaire de Cancérologie Assistance Publique-Hôpitaux de Paris-Sorbonne Université, Paris, France
| | - E Assaf
- Department of Medical Oncology, The Henri Mondor University Hospital, Creteil, France
| | - Y Belkacemi
- Department of Radiation Oncology and Henri Mondor Breast Center. Henri Mondor University Hospital, APHP, UPEC, Créteil, France; Institut Mondor de Recherche Biomédicale (IMRB), INSERM U955, i-Biot, UPEC, Créteil, France
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Ahvati H, Roudi R, Sobhani N, Safari F. CD47 as a potent target in cancer immunotherapy: A review. Biochim Biophys Acta Rev Cancer 2025; 1880:189294. [PMID: 40057140 DOI: 10.1016/j.bbcan.2025.189294] [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: 09/24/2024] [Revised: 02/22/2025] [Accepted: 03/02/2025] [Indexed: 03/22/2025]
Abstract
Cancer is the second-highest cause of death worldwide. Accordingly, finding new cancer treatments is of great interest to researchers. The current platforms to fight cancer such as chemotherapy, radiotherapy, and surgery are limited in efficacy, especially in the metastatic setting. In this war against cancer, the immune system is a powerful ally, but tumor cells often outsmart it through alternative pathways. Cluster of differentiation 47 (CD47), a protein that normally prevents healthy cells from being attacked by immune cells, is often overexpressed on cancer cells. This makes CD47 a prime target for immunotherapy. Blocking of CD47 has the potential to unleash the immune system's cell populations-such as myeloid cells, macrophages, and T cells-to allow the immune system to discover and destroy cancer cells more successfully. In this review, we aimed to provide the latest information and findings about the roles of CD47 in the regulation of various cellular pathways and, thus, the importance of CD47 as a potential target in cancer therapy.
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Affiliation(s)
- Hiva Ahvati
- School of Biology, College of Science, University of Tehran, Tehran, Iran
| | - Raheleh Roudi
- Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, Stanford, CA 94305, USA.
| | - Navid Sobhani
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Fatemeh Safari
- Department of Biology, Faculty of Science, University of Guilan, Rasht, Iran
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Lee EK, Kolin DL, Matulonis UA, Erickson BK. Diagnostic and therapeutic advances for HER2-expressing or amplified gynecologic cancers. Gynecol Oncol 2025; 195:152-164. [PMID: 40117942 DOI: 10.1016/j.ygyno.2025.03.011] [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: 04/17/2024] [Revised: 02/21/2025] [Accepted: 03/06/2025] [Indexed: 03/23/2025]
Abstract
HER2-targeting therapies are well-described in breast, gastric, and lung cancers, however accumulating data supports a role for HER2-targeted therapies in gynecologic cancers. Despite varied methodologies for HER2 testing, evidence supports that a substantial proportion of endometrial, ovarian, cervical, and vulvar cancers overexpress HER2. This underscores the rationale for HER2-targeted therapies in these malignancies, including the use of HER2-directed tyrosine kinase inhibitors, antibody-drug conjugates, and immune-stimulating antibody conjugates. Understanding mechanisms of resistance to HER2-targeted therapies will inform possible combinatorial strategies.
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Affiliation(s)
- Elizabeth K Lee
- Division of Gynecologic Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States of America.
| | - David L Kolin
- Department of Pathology, Brigham & Women's Hospital, Boston, MA, United States of America
| | - Ursula A Matulonis
- Division of Gynecologic Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States of America
| | - Britt K Erickson
- Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, University of Minnesota, Minneapolis, MN, United States of America
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32
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Li Z, Wang Y, Sun Y, Wang L, Li X, Sun L, He Z, Yang H, Wang Y, Wang Q, Song Z, Hong W, Wang Y, Xia G, Yu Y, Peng M, Song Y, Wang D, Meng R, Fang J, Luo Y, Liang W, Hu S, Wang Z, Song K, Li Y, Yang L, Shi W, Lu S. Trastuzumab rezetecan, a HER2-directed antibody-drug conjugate, in patients with advanced HER2-mutant non-small-cell lung cancer (HORIZON-Lung): phase 2 results from a multicentre, single-arm study. Lancet Oncol 2025; 26:437-446. [PMID: 40020696 DOI: 10.1016/s1470-2045(25)00012-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 12/19/2024] [Accepted: 01/14/2025] [Indexed: 03/03/2025]
Abstract
BACKGROUND Trastuzumab rezetecan (also known as SHR-A1811) is a novel antibody-drug conjugate consisting of a humanised HER2-directed monoclonal antibody, cleavable tetrapeptide-based linker, and DNA topoisomerase I inhibitor. In the phase 1 portion of this phase 1/2 study, trastuzumab rezetecan showed preliminary anti-tumour activity and a favourable safety profile in patients with HER2-mutant non-small-cell lung cancer (NSCLC). We present phase 2 results from the study, which aimed to further evaluate the activity and safety of trastuzumab rezetecan at the recommended dose. METHODS In this multicentre, single-arm, phase 2 trial, conducted in 35 hospitals in China, we recruited patients aged 18-75 years, with locally advanced or metastatic NSCLC with an activating HER2 mutation and an Eastern Cooperative Oncology Group performance status score of 0-1, who had disease progression after or were intolerant to platinum-based chemotherapy and anti-PD-1 treatment or anti-PD-L1 treatment. Trastuzumab rezetecan was administered at 4·8 mg/kg intravenously once every 3 weeks. The primary endpoint was objective response rate assessed by an independent review committee in patients who received at least one cycle of study treatment. All patients who received at least one cycle of study treatment were included in safety analyses. This study is registered with ClinicalTrials.gov, NCT04818333, and is ongoing but not recruiting. FINDINGS Between April 14, 2023, and Dec 14, 2023, 94 patients were enrolled and treated. 42 (45%) patients were male, 52 (55%) female, 92 (98%) were Han Chinese, and two (2%) were other ethnicity Chinese. At data cutoff (June 14, 2024), the median duration of follow-up was 8·7 months (IQR 7·0-10·4). 69 (73%; 95% CI 63·3-82·0) of 94 patients had a confirmed objective response, as assessed by independent review committee. The most common grade 3-4 treatment-related adverse events were decreased neutrophil count (38 [40%] patients), decreased white blood cell count (25 [27%]), anaemia (22 [23%]), decreased platelet count (10 [11%]), and decreased lymphocyte count (seven [7%]). Treatment-related serious adverse events occurred in 22 (23%) patients, which were decreased platelet count (six [6%]), decreased neutrophil count (six [6%]), interstitial lung disease (five [5%]), decreased white blood cell count (four [4%]), anaemia (four [4%]), vomiting (three [3%]), pneumonia (three [3%]), hyponatraemia (two [2%]), and pyrexia (one [1%]), small intestinal obstruction (one [1%]), nausea (one [1%]), and chronic obstructive pulmonary disease (one [1%]). There were no treatment-related deaths. INTERPRETATION Trastuzumab rezetecan showed clinically meaningful activity and manageable safety in patients with previously treated HER2-mutant NSCLC. Further trials are justified. FUNDING Jiangsu Hengrui Pharmaceuticals, National Multi-disciplinary Treatment Project for Major Diseases, Collaborative Innovation Center for Clinical and Translational Science by the Ministry of Education & Shanghai. TRANSLATION For the Chinese translation of the abstract see Supplementary Materials section.
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MESH Headings
- Adolescent
- Adult
- Aged
- Female
- Humans
- Male
- Middle Aged
- Young Adult
- Antibodies, Monoclonal, Humanized/administration & dosage
- Antibodies, Monoclonal, Humanized/adverse effects
- Camptothecin/administration & dosage
- Camptothecin/adverse effects
- Camptothecin/analogs & derivatives
- Carcinoma, Non-Small-Cell Lung/drug therapy
- Carcinoma, Non-Small-Cell Lung/genetics
- Carcinoma, Non-Small-Cell Lung/pathology
- Carcinoma, Non-Small-Cell Lung/mortality
- China
- Immunoconjugates/administration & dosage
- Immunoconjugates/adverse effects
- Lung Neoplasms/drug therapy
- Lung Neoplasms/genetics
- Lung Neoplasms/pathology
- Lung Neoplasms/mortality
- Mutation
- Receptor, ErbB-2/genetics
- Receptor, ErbB-2/antagonists & inhibitors
- Trastuzumab/administration & dosage
- Trastuzumab/adverse effects
- Topoisomerase I Inhibitors/administration & dosage
- Topoisomerase I Inhibitors/adverse effects
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Affiliation(s)
- Ziming Li
- Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yan Wang
- Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Yuping Sun
- Phase I Clinical Research Center, The Affiliated Cancer Hospital of Shandong First Medical University, Jinan, China
| | - Linlin Wang
- Chest Radiotherapy Third Ward, The Affiliated Cancer Hospital of Shandong First Medical University, Jinan, China
| | - Xingya Li
- Department of Medical Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Longhua Sun
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Zhiyi He
- Pulmonary and Critical Care Medicine Ward, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Haiyan Yang
- Department of Lung & Gastrointestinal Oncology, Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Yongsheng Wang
- Division of Thoracic Tumor Multimodality Treatment Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Qiming Wang
- Department of Internal Medicine, The Affiliated Cancer Hospital of Zhengzhou University-Henan Cancer Hospital & Institute of Cancer Research, Henan Academy of Innovations in Medical Science, Zhengzhou, China
| | - Zhengbo Song
- Phase I Clinical Trial Ward, Zhejiang Cancer Hospital, Hangzhou, China
| | - Wei Hong
- Department of Thoracic Oncology, Zhejiang Cancer Hospital, Hangzhou, China
| | - Yong Wang
- Department of Medical Oncology, Anhui Provincial Hospital-The First Affiliated Hospital of the University of Science and Technology of China, Hefei, China
| | - Guohao Xia
- Department of Medical Oncology, Jiangsu Cancer Hospital-Jiangsu Institute of Cancer Research-The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Yan Yu
- Department of Thoracic Medicine, Harbin Medical University Cancer Hospital, Harbin, China
| | - Min Peng
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yong Song
- Department of Respiratory Medicine, Jinling Hospital, Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Donglin Wang
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Rui Meng
- Oncology Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jian Fang
- Department of Thoracic Oncology, Peking University Cancer Hospital, Beijing, China
| | - Yongzhong Luo
- Department of Thoracic Medicine, Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Wenhua Liang
- Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Sheng Hu
- Department of Thoracic Oncology, Hubei Cancer Hospital, Wuhan, China
| | - Zhihui Wang
- Department of Thoracic Oncology, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China
| | - Ke Song
- Jiangsu Hengrui Pharmaceuticals, Shanghai, China
| | - You Li
- Jiangsu Hengrui Pharmaceuticals, Shanghai, China
| | - Lulu Yang
- Jiangsu Hengrui Pharmaceuticals, Shanghai, China
| | - Wei Shi
- Jiangsu Hengrui Pharmaceuticals, Shanghai, China
| | - Shun Lu
- Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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33
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Ding M, Chen M, Cheng Z, Jin J, Lu W, Zhu S. Comparison of quaternary ammonium-based linkers for antibody-drug conjugates based on camptothecin derivatives. Bioorg Med Chem 2025; 120:118084. [PMID: 39893760 DOI: 10.1016/j.bmc.2025.118084] [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: 12/09/2024] [Revised: 01/17/2025] [Accepted: 01/22/2025] [Indexed: 02/04/2025]
Abstract
Antibody-drug conjugates (ADCs) with camptothecin derivatives as payloads have been a hot topic of interest and research since the launch of DS-8201a. As an important component of ADCs, the adequate stability of the linker during circulation and its rapid release at the target site are crucial for the efficient efficacy of ADCs. Although traditional quaternary ammonium ADCs based on dipeptide linkers were highly stable and could be released by specific enzymes, their poor in vitro anti-tumor activity had limited their further exploration. We applied a methylsulfonylethylamine-modified MAC self-elimination system to a valine-alanine linker and constructed a quaternary ammonium ADC (HER2-11) that combines both stability and cleavability. The optimization of the linker effectively improved the in vitro cellular activity of conventional quaternary ammonium ADCs, but the complex intracellular cleavage mechanism of HER2-11 resulted in a weaker anti-tumor activity compared to HER2-GGFG-DXd, which provides great reference value for the continued research of this type of linker in the future.
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Affiliation(s)
- Mengyuan Ding
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062 PR China
| | - Ming Chen
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062 PR China
| | - Zhiyang Cheng
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062 PR China
| | - Jiyu Jin
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062 PR China
| | - Wei Lu
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062 PR China.
| | - Shulei Zhu
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062 PR China; Innovation Center for AI and Drug Discovery, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062 PR China; ATLATL Innovation Center, 1077 Zhangheng Road, Shanghai 201203 PR China.
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34
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Riudavets M, Planchard D. The Era of Antibody Drug Conjugates in Lung Cancer: Trick or Threat? Cancer Res Treat 2025; 57:293-311. [PMID: 39608345 PMCID: PMC12016829 DOI: 10.4143/crt.2024.714] [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: 07/26/2024] [Accepted: 11/27/2024] [Indexed: 11/30/2024] Open
Abstract
Antibody drug conjugates (ADCs) are a novel class of therapeutics that structurally are composed by an antibody directed to a tumor epitope connected via a linker to a cytotoxic payload, and that have shown significant antitumor activity across a range of malignancies including lung cancer. In this article we review the pharmacology and design of ADCs, as well as we describe the results of different studies evaluating ADCs in lung cancer directed to several targets including HER2, HER3, TROP2, MET, CEACAM5 and DLL3.
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Affiliation(s)
| | - David Planchard
- Department of Cancer Medicine, Gustave Roussy Cancer Campus, Villejuif, France
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35
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Li N, Yang L, Zhao Z, Du T, Liang G, Li N, Tang J. Antibody-drug conjugates in breast cancer: current evidence and future directions. Exp Hematol Oncol 2025; 14:41. [PMID: 40114224 PMCID: PMC11924693 DOI: 10.1186/s40164-025-00632-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 03/04/2025] [Indexed: 03/22/2025] Open
Abstract
Antibody-drug conjugates (ADCs) are a rapidly evolving class of antitumor drugs and have already revolutionized the treatment strategy of many hematologic and solid cancers. So far, trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), sacituzumab govitecan (SG) and datopotamab deruxtecan (Dato-DXd) are the four ADCs that have been approved by US food and drug administration (FDA) in treatment of breast cancer, and SKB264 has been approved by Chinese national medical products administration (NMPA). Many ADCs for treatment of breast cancer are currently being tested in late-phase clinical trials, with several encouraging results achieved recently. However, major issues arise during the use of ADCs, including emergence of acquired resistance, occurrence of treated-related toxicities, and identification of biomarkers of response and resistance. ADCs are being increasingly tested in combination with other agents, and novel next-generation ADC development is progressing rapidly. A better understanding of the design and development of ADCs will promote ADC development for cancer treatment. In this review, we aim to provide a broad overview of the design and the recent advances of ADCs in breast cancer. We also propose several notable future directions of ADCs in treatment of breast cancer.
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Affiliation(s)
- Ning Li
- Department of Breast Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Lu Yang
- Department of Radiotherapy, Cancer Center, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, 510080, China
- Shantou University Medical College, Shantou University, Shantou, 515000, China
| | - Zixuan Zhao
- Department of Breast Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Tian Du
- Department of Breast Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Gehao Liang
- Department of Breast Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Na Li
- Department of Breast Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
| | - Jun Tang
- Department of Breast Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
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36
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Wang T, Quijada D, Ahmedna T, Castillo JR, Naji NS, Peske JD, Karakousis PC, Paul S, Karantanos T, Karanika S. Targeting CCRL2 enhances therapeutic outcomes in a tuberculosis mouse model. Front Immunol 2025; 16:1501329. [PMID: 40181978 PMCID: PMC11965133 DOI: 10.3389/fimmu.2025.1501329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 02/28/2025] [Indexed: 04/05/2025] Open
Abstract
Tuberculosis (TB) remains among the leading infectious causes of death. Due to the limited number of antimicrobials in the TB drug discovery pipeline, interest has developed in host-directed approaches to improve TB treatment outcomes. C-C motif chemokine-like receptor 2 (CCRL2) is a unique seven-transmembrane domain receptor that is upregulated by inflammatory signals and mediates leucocyte migration. However, little is known about its role in TB infection. Here, we show that Mycobacterium tuberculosis (Mtb) infection increases CCRL2 protein expression in macrophages in vitro and alveolar macrophages (AMs), dendritic cells (DCs) and neutrophils in mouse lungs. To target selectively CCRL2-expressing cells in vivo, we developed a novel mouse anti-CCRL2 antibody-drug conjugate (ADC) linked with the cytotoxic drug SG3249. We tested its adjunctive therapeutic efficacy against TB when combined with the first-line regimen for drug-susceptible TB (isoniazid, rifampin, pyrazinamide, ethambutol; RHZE). The anti-CCRL2 ADC treatment potentiated RHZE efficacy in Mtb-infected mice and decreased gross lung inflammation. CCRL2 expression in lung DCs and AMs was lower in mice receiving anti-CCRL2 ADC treatment+RHZE compared to those receiving RHZE alone or the control group, although the total innate cell populations did not differ across treatment groups. Interestingly, neutrophils were completely absent in the anti-CCRL2 ADC treatment + RHZE group, unlike in the other treatment groups. IFN-γ+-and IL17-α+-T-cell responses, which are associated with optimal TB control, were also elevated in the anti-CCRL2 ADC treatment + RHZE group. Our findings suggest that CCRL2-targeting approaches may improve TB treatment outcomes, possibly through selective killing of Mtb-infected innate immune cells.
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Affiliation(s)
- Tianyin Wang
- Division of Infectious Diseases, Department of Medicine, The Johns Hopkins Hospital, Baltimore, MD, United States
- Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Darla Quijada
- Division of Infectious Diseases, Department of Medicine, The Johns Hopkins Hospital, Baltimore, MD, United States
- Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Taha Ahmedna
- Ludwig Center and Lustgarten Laboratory, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Jennie Ruelas Castillo
- Division of Infectious Diseases, Department of Medicine, The Johns Hopkins Hospital, Baltimore, MD, United States
- Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Nour Sabiha Naji
- Division of Hematologic Malignancies, Department of Medical Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - J David Peske
- Division of Hematopathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Petros C. Karakousis
- Division of Infectious Diseases, Department of Medicine, The Johns Hopkins Hospital, Baltimore, MD, United States
- Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Suman Paul
- Ludwig Center and Lustgarten Laboratory, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
- Division of Hematopathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Theodoros Karantanos
- Division of Hematologic Malignancies, Department of Medical Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Styliani Karanika
- Division of Infectious Diseases, Department of Medicine, The Johns Hopkins Hospital, Baltimore, MD, United States
- Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
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37
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Qin Q. Advances in research and current challenges in the treatment of advanced HER2-low breast cancer. Front Cell Dev Biol 2025; 13:1451471. [PMID: 40177129 PMCID: PMC11962219 DOI: 10.3389/fcell.2025.1451471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Accepted: 02/20/2025] [Indexed: 04/05/2025] Open
Abstract
Human epidermal growth factor receptor 2 (HER2)-low breast cancer is defined as breast cancer with an immunohistochemistry (IHC) score of 1+ or 2+ and in situ hybridisation (ISH)-negative. The traditional HER2 classification (negative or positive) has limitations, with only 15%-20% of the breast cancer population being positive and suitable for HER2-targeted therapy. The new clinical study, DESTINY-Breast04, shows that trastuzumab deruxtecan (T-DXd) has a significant effect on advanced HER2-low breast cancers, a classification that accounts for approximately half of the advanced breast cancer population. However, the detection methods and evaluation criteria for HER2-low breast cancer have not yet been standardised, and the toxicity and resistance mechanisms associated with T-DXd therapy are still unclear. This article focuses on these issues and describes the progress and challenges of T-DXd-related therapy in the treatment of advanced breast cancer patients with low HER2 expression.
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Affiliation(s)
- Qiang Qin
- Breast and Thyroid Surgery Department, Nanning Maternal and Child Health Hospital, Nanning, China
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38
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Wharton T, Spring DR. Advances in the Release of Amide-Containing Molecules. Chemistry 2025; 31:e202404413. [PMID: 39836098 PMCID: PMC11914939 DOI: 10.1002/chem.202404413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 01/21/2025] [Accepted: 01/21/2025] [Indexed: 01/22/2025]
Abstract
The ability to release a molecule from a larger construct in a controlled manner is of great importance to produce effective prodrugs, antibody-drug conjugates, and chemical probes. Amides are ubiquitous functional groups and yet methods to utilise them as molecular release handles are seldom reported. This concept article highlights the advances made in amide release strategies and how these approaches have been utilised.
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Affiliation(s)
- Thomas Wharton
- Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
| | - David R Spring
- Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
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39
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Andriollo P, di Mascio D, Jackson PJM, Hasan MM, Pysz-Hosey I, Procopiou G, Fox KR, Rahman KM, Thurston DE. A novel DNA sequence-selective, guanine mono-alkylating ADC payload suitable for solid tumour treatment. RSC Med Chem 2025:d4md01040j. [PMID: 40352674 PMCID: PMC12059774 DOI: 10.1039/d4md01040j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Accepted: 03/01/2025] [Indexed: 05/14/2025] Open
Abstract
Pyridinobenzodiazepines (PDDs) are a new class of DNA mono-alkylating antibody-drug conjugate (ADC) payloads that can be linked through their C9 position to a sequence recognition component, guiding them to specific DNA sequences. Compound 18 is a PDD monomer with a unique sequence-selectivity profile and high cytotoxicity in vitro (e.g., IC50 = 0.30 nM in SW60; 1.6 nM in LIM1215 and 0.142 nM in SW48 cell line, after 96 hours incubation). To evaluate its potential as an ADC payload, an amine functionality was introduced into the terminal phenyl ring, and the modified compound was conjugated to trastuzumab (drug-antibody ratio [DAR] = 1.6). The resulting ADC exhibits significant in vivo efficacy in a pancreatic cancer xenograft model using BALB-c mice transplanted with the CAPAN-1 cell line. Complete tumour regression is observed out to 60 days after a single dose of 2 mg kg-1 comparing favourably to a 10 mg kg-1 dose of trastuzumab deruxtecan (Enhertu®). The novel ADC has a good tolerability profile, with a maximum tolerated dose (MTD) above 15 mg kg-1. The tolerability and efficacy profile of compound 18 in an ADC format suggests that PDDs represent a potentially valuable new class of payloads for the treatment of solid tumours.
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Affiliation(s)
- Paolo Andriollo
- School of Cancer & Pharmaceutical Sciences, King's College London WC2R 2LS UK +44 (0)20 7848 1891
| | | | - Paul J M Jackson
- School of Cancer & Pharmaceutical Sciences, King's College London WC2R 2LS UK +44 (0)20 7848 1891
| | - Md Mahbub Hasan
- School of Cancer & Pharmaceutical Sciences, King's College London WC2R 2LS UK +44 (0)20 7848 1891
- Department of Genetic Engineering and Biotechnology, Faculty of Biological Sciences, University of Chittagong Chattogram Bangladesh
| | - Ilona Pysz-Hosey
- School of Cancer & Pharmaceutical Sciences, King's College London WC2R 2LS UK +44 (0)20 7848 1891
| | - George Procopiou
- School of Cancer & Pharmaceutical Sciences, King's College London WC2R 2LS UK +44 (0)20 7848 1891
| | - Keith R Fox
- School of Biological Sciences, University of Southampton SO17 1BJ UK
| | - Khondaker Miraz Rahman
- School of Cancer & Pharmaceutical Sciences, King's College London WC2R 2LS UK +44 (0)20 7848 1891
| | - David E Thurston
- School of Cancer & Pharmaceutical Sciences, King's College London WC2R 2LS UK +44 (0)20 7848 1891
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40
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Larose ÉA, Hua X, Yu S, Pillai AT, Yi Z, Yu H. Antibody-drug conjugates in breast cancer treatment: resistance mechanisms and the role of therapeutic sequencing. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2025; 8:11. [PMID: 40201309 PMCID: PMC11977375 DOI: 10.20517/cdr.2024.180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 02/17/2025] [Accepted: 02/28/2025] [Indexed: 04/10/2025]
Abstract
Antibody-drug conjugates (ADCs) are a transformative approach in breast cancer therapy, offering targeted treatment with reduced toxicity by selectively delivering cytotoxic agents to cancer cells. While ADCs like trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), and sacituzumab govitecan have shown significant efficacy, resistance mechanisms such as antigen loss, impaired internalization, and efflux of cytotoxic payloads challenge their effectiveness. This review discusses these resistance mechanisms and explores advanced strategies to overcome them, including innovations in linker chemistry, multi-antigen targeting, and biomarker-driven personalization. Additionally, therapeutic sequencing - determining the optimal order of ADCs with other treatments such as chemotherapy, endocrine therapy, and immunotherapy - is examined as a crucial approach to maximize ADC efficacy and manage resistance. Evidence-based sequencing strategies, particularly for human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancer (TNBC), are supported by clinical trials demonstrating the benefits of ADCs in both early-stage and metastatic settings. The potential of combination therapies, such as ADCs with immune checkpoint inhibitors (ICIs), further highlights the evolving landscape of breast cancer treatment. As ADC technology advances, personalized approaches integrating biomarkers and optimized sequencing protocols offer promising avenues to enhance treatment outcomes and combat resistance in breast cancer.
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Affiliation(s)
- Émilie Audrey Larose
- Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei, China
- Authors contributed equally
| | - Xinying Hua
- Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei, China
- Authors contributed equally
| | - Silin Yu
- Wuhan Britain-China School, Wuhan 430071, Hubei, China
| | | | - Zongbi Yi
- Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei, China
| | - Haijun Yu
- Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei, China
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41
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Xie J, Yang Z, Li Z, Zhang T, Chen H, Chen X, Dai Z, Chen T, Hou J. Triple-positive breast cancer: navigating heterogeneity and advancing multimodal therapies for improving patient outcomes. Cancer Cell Int 2025; 25:77. [PMID: 40045297 PMCID: PMC11881339 DOI: 10.1186/s12935-025-03680-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 02/07/2025] [Indexed: 03/09/2025] Open
Abstract
Triple-positive breast cancer (TPBC), a unique subtype of luminal breast cancer, is characterized by concurrent positivity for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Owing to the crosstalk between the ER and HER2 signaling pathways, the standard of care and drug resistance of this particular subtype are difficult challenges. Recent research and clinical trials have indicated a shift in the treatment paradigm for TPBC from single-target therapies to multi-pathway, multitarget strategies aiming to comprehensively modulate intricate signaling networks, thereby overcoming resistance and enhancing therapeutic outcomes. Among multiple strategies, triple-drug therapy has emerged as a promising treatment modality, demonstrating potential efficacy in patients with TPBC. Moving forward, there is a critical need to perform in-depth analyses of specific mechanisms of cancer pathogenesis and metastasis, decipher the complex interactions between different genes or proteins, and identify concrete molecular targets, thus paving the way for the development of tailored therapeutic strategies to combat TPBC effectively.
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Affiliation(s)
- Jie Xie
- GuiZhou University Medical College, Guiyang, 550025, Guizhou Province, China
| | - Zhihui Yang
- Zunyi Medical University, No.6 Xuefu West Road, Zunyi, 563006, Guizhou Province, China
- Department of Breast Surgery, Guizhou Provincial People's Hospital, NO.83 Zhongshan East Road, Guiyang, 550002, Guizhou Province, China
| | - Zhuolin Li
- GuiZhou University Medical College, Guiyang, 550025, Guizhou Province, China
| | - Tianyu Zhang
- Urology Department, Guizhou Provincial People's Hospital, Guiyang city, 550002, Guizhou Province, China
| | - Huan Chen
- Department of Breast Surgery, Guizhou Provincial People's Hospital, NO.83 Zhongshan East Road, Guiyang, 550002, Guizhou Province, China
| | - Xueru Chen
- Department of Breast Surgery, Guizhou Provincial People's Hospital, NO.83 Zhongshan East Road, Guiyang, 550002, Guizhou Province, China
| | - Zehua Dai
- Department of Breast Surgery, Guizhou Provincial People's Hospital, NO.83 Zhongshan East Road, Guiyang, 550002, Guizhou Province, China
| | - Tao Chen
- Department of Breast Surgery, Guizhou Provincial People's Hospital, NO.83 Zhongshan East Road, Guiyang, 550002, Guizhou Province, China
| | - Jing Hou
- Department of Breast Surgery, Guizhou Provincial People's Hospital, NO.83 Zhongshan East Road, Guiyang, 550002, Guizhou Province, China.
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42
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Masmudi-Martín M, Oller-Salvia B, Perea M, Teixidó M, Valiente M, Giralt E, Sánchez-Navarro M. A Site-Specific MiniAp4-Trastuzumab Conjugate Prevents Brain Metastasis. Mol Pharm 2025; 22:1384-1395. [PMID: 39924896 PMCID: PMC11881140 DOI: 10.1021/acs.molpharmaceut.4c01091] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 01/22/2025] [Accepted: 01/23/2025] [Indexed: 02/11/2025]
Abstract
Monoclonal antibodies (mAbs) are changing cancer treatments. However, the presence of the blood-brain barrier (BBB) and the blood-tumor barrier (BTB) limits the use of mAbs to treat brain cancer or brain metastasis. Molecules that hijack endogenous transport mechanisms on the brain endothelium (brain shuttles) have been shown to increase the transport of large molecules and nanoparticles across the BBB. Among these shuttles, protease-resistant peptides such as MiniAp-4 are particularly efficient. Here, we report the synthesis, characterization, and evaluation of site-specific mAb-brainshuttle antibody conjugates (ASC) based on the anti-HER2 mAb trastuzumab (Tz) and four molecules of MiniAp-4. The ASCs preserve the binding and cell cycle arrest capacity of Tz. MiniAp-4 ASC displays enhanced transport across an in vitro BBB cellular model with respect to Tz and Tz conjugated to Angiopep-2, the brain shuttle that has advanced the most in clinical trials. More importantly, evaluation of Tz-MiniAp4 in a murine brain metastasis model demonstrated that the protease-resistant peptide showed preferential transport across the BBB/BTB, displaying a marked therapeutic effect and protecting against metastasis development. The technology described herein could be applied to any antibody of interest to treat central nervous system-related diseases. MiniAp-4 enhances the brain transport of the monoclonal antibody trastuzumab, preventing brain metastasis.
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Affiliation(s)
| | - Benjamí Oller-Salvia
- Institute
for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona 08028, Spain
- Grup d’Enginyeria
de Materials, Institut Químic de Sarrià (IQS), Universitat Ramon Llull, Barcelona 08017, Spain
| | - María Perea
- Brain Metastasis
Group, CNIO, Madrid 28029, Spain
| | - Meritxell Teixidó
- Institute
for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona 08028, Spain
| | | | - Ernest Giralt
- Institute
for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona 08028, Spain
- Department
of Inorganic and Organic Chemistry, University
of Barcelona, Barcelona 08028, Spain
| | - Macarena Sánchez-Navarro
- Institute
for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona 08028, Spain
- Department
of Biochemistry and Molecular Pharmacology, Instituto de Parasitologia y Biomedicina “López-Neyra”
(CSIC), Granada 18100, Spain
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Sloot WN, Bertotti E, Onidi M, Paoletti A, Salve ID, Tavano P, Vigna E, Mueller G. The Nonclinical Safety Assessment of a Novel Anti-CEACAM5 Antibody Exatecan Conjugate Predicts a Low Risk for Interstitial Lung Disease (ILD) in Patients-The Putative Mechanism Behind ILD. Int J Toxicol 2025; 44:153-169. [PMID: 39754485 DOI: 10.1177/10915818241306039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Abstract
The therapeutic window of antibody drug-conjugates (ADC) remains challenging due to safety issues such as interstitial lung disease (ILD) observed with specific deruxtecan-based ADCs. To avoid ILD, we designed M9140 by conjugating the maleimide-containing hydrophilic β-glucuronide linker to exatecan and our anti-CEACAM5 (CarcinoEmbryonic Antigen-related Cell Adhesion Molecule 5) specific antibody. Following repeated iv-infusion at 3 to 30 mg/kg of M9140 every 3 weeks, the pathological findings obtained in cynomolgus monkeys were confined to gastrointestinal and hematolymphoid tissues and resembled the toxicity of exatecan. At 24 mg/kg or higher, transient reductions in neutrophil and reticulocyte counts were observed with each dosing event along with reversible anemia throughout the study. The no observed adverse effect level was 24 mg/kg and the maximum tolerated dose was 30 mg/kg. The difference in toxicity by this small dose increment was correlated with a 2.5-fold difference in plasma exatecan exposure indicating antigen-independent toxicity. As anticipated, no lung toxicity was found with M9140 in these studies that were similar in study design to those used to confirm ILD with trastuzumab-deruxtecan in monkeys. Since the non-human primate model is regarded as predictive for the ILD risk in humans, this result indicates a low risk for ILD when applying M9140 to patients. The current M9140 safety data are discussed with special focus on the absence or presence of ILD with other antibody camptothecin-conjugates, for which a hypothetical pathogenic mechanism is postulated here. The favorable nonclinical profile of M9140 warrants further investigation in patients with CEACAM5-overexpressing tumors.
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Affiliation(s)
- Willem N Sloot
- Chemical and Preclinical Safety Department, Global Chemical and Preclinical Safety, Merck KGaA, Darmstadt, Germany
| | - Elisa Bertotti
- Chemical and Preclinical Safety Department, Global Chemical and Preclinical Safety, Merck KGaA, Darmstadt, Germany
- CPS (Clinical and Pre-Clinical Safety) and NBE-DMPK (New Biological Entity - Drug Metabolism and Pharmacokinetics), Istituto di Ricerche Biomediche "Antoine Marxer" - RBM, Colleretto Giacosa (TO), Italy
| | - Manuela Onidi
- Chemical and Preclinical Safety Department, Global Chemical and Preclinical Safety, Merck KGaA, Darmstadt, Germany
- CPS (Clinical and Pre-Clinical Safety) and NBE-DMPK (New Biological Entity - Drug Metabolism and Pharmacokinetics), Istituto di Ricerche Biomediche "Antoine Marxer" - RBM, Colleretto Giacosa (TO), Italy
| | - Andrea Paoletti
- Chemical and Preclinical Safety Department, Global Chemical and Preclinical Safety, Merck KGaA, Darmstadt, Germany
- CPS (Clinical and Pre-Clinical Safety) and NBE-DMPK (New Biological Entity - Drug Metabolism and Pharmacokinetics), Istituto di Ricerche Biomediche "Antoine Marxer" - RBM, Colleretto Giacosa (TO), Italy
| | - Ilse De Salve
- Chemical and Preclinical Safety Department, Global Chemical and Preclinical Safety, Merck KGaA, Darmstadt, Germany
- CPS (Clinical and Pre-Clinical Safety) and NBE-DMPK (New Biological Entity - Drug Metabolism and Pharmacokinetics), Istituto di Ricerche Biomediche "Antoine Marxer" - RBM, Colleretto Giacosa (TO), Italy
| | - Patrizia Tavano
- Chemical and Preclinical Safety Department, Global Chemical and Preclinical Safety, Merck KGaA, Darmstadt, Germany
- CPS (Clinical and Pre-Clinical Safety) and NBE-DMPK (New Biological Entity - Drug Metabolism and Pharmacokinetics), Istituto di Ricerche Biomediche "Antoine Marxer" - RBM, Colleretto Giacosa (TO), Italy
| | - Enrico Vigna
- Chemical and Preclinical Safety Department, Global Chemical and Preclinical Safety, Merck KGaA, Darmstadt, Germany
- CPS (Clinical and Pre-Clinical Safety) and NBE-DMPK (New Biological Entity - Drug Metabolism and Pharmacokinetics), Istituto di Ricerche Biomediche "Antoine Marxer" - RBM, Colleretto Giacosa (TO), Italy
| | - Gundi Mueller
- Chemical and Preclinical Safety Department, Global Chemical and Preclinical Safety, Merck KGaA, Darmstadt, Germany
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Pourjamal N, Le Joncour V, Vereb G, Honkamaki C, Isola J, Leyton JV, Laakkonen P, Joensuu H, Barok M. Disitamab vedotin in preclinical models of HER2-positive breast and gastric cancers resistant to trastuzumab emtansine and trastuzumab deruxtecan. Transl Oncol 2025; 53:102284. [PMID: 39837059 PMCID: PMC11788861 DOI: 10.1016/j.tranon.2025.102284] [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: 09/20/2024] [Revised: 12/27/2024] [Accepted: 01/13/2025] [Indexed: 01/23/2025] Open
Abstract
BACKGROUND Most HER2-positive breast or gastric cancers eventually become resistant to the approved anti-HER2 antibody-drug conjugates (ADC) trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd). Disitamab vedotin (DV) is a novel anti-HER2 ADC that binds to a different epitope on HER2 compared to trastuzumab. We assessed the efficacy of DV in breast and gastric cancer cell lines and xenografts, including tumor models resistant to T-DM1 and T-DXd. Additionally, we investigated whether combining two anti-HER2 ADCs could enhance the efficacy of the individual ADCs. METHODS The efficacy of DV, T-DM1, and T-DXd, both as single agents and in combinations, was assessed using an AlamarBlue cell proliferation assay in HER2-positive breast and gastric cancer cell lines, including those resistant to T-DM1 and T-DXd. The efficacy of DV was evaluated also in breast and gastric cancer SCID mouse xenografts that had progressed on T-DM1 and/or T-DXd. ADC combinations were tested in breast and gastric cancer xenografts. RESULTS DV was effective in cell lines resistant to T-DM1 and/or T-DXd, and it inhibited the growth of breast and gastric cancer xenografts that had progressed on T-DM1 and/or T-DXd. The combinations of DV plus T-DM1 and DV plus T-DXd showed greater efficacy than the corresponding single agents in both breast and gastric cancer cell lines and xenografts. CONCLUSIONS DV was effective in treating breast and gastric cancer xenograft tumors resistant to T-DM1 and/or T-DXd. The combination of DV with T-DM1 or T-DXd demonstrated promising activity.
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Affiliation(s)
- Negar Pourjamal
- Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Laboratory of Molecular Oncology, Biomedicum, University of Helsinki, Helsinki, Finland
| | - Vadim Le Joncour
- Neuroscience Center, Helsinki Institute of Life Sciences (HiLIFE), University of Helsinki, Helsinki, Finland
| | - György Vereb
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary; HUN-REN-UD Cell Biology and Signaling Research Group, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Cilla Honkamaki
- Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Laboratory of Molecular Oncology, Biomedicum, University of Helsinki, Helsinki, Finland
| | - Jorma Isola
- Laboratory of Cancer Biology, Medical Faculty, University of Tampere, Tampere, Finland
| | - Jeffrey V Leyton
- School of Pharmaceutical Sciences, Faculty of Medicine, University of Ottawa, Ottawa, Canada
| | - Pirjo Laakkonen
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Laboratory Animal Center, Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland; ICAN Digital Precision Medicine Flagship Program, University of Helsinki, Helsinki, Finland
| | - Heikki Joensuu
- Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Laboratory of Molecular Oncology, Biomedicum, University of Helsinki, Helsinki, Finland; Department of Oncology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Mark Barok
- Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Laboratory of Molecular Oncology, Biomedicum, University of Helsinki, Helsinki, Finland.
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Yamazaki S, Matsuda Y. Antibody Modification via Lipoic Acid Ligase A-Mediated Site-Specific Labeling. Chem Biodivers 2025; 22:e202402113. [PMID: 39435640 DOI: 10.1002/cbdv.202402113] [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: 08/26/2024] [Revised: 10/19/2024] [Accepted: 10/21/2024] [Indexed: 10/23/2024]
Abstract
Enzymatic modification, particularly utilizing lipoic acid ligase (LplA), has emerged as a transformative approach in biopharmaceuticals, enabling precise and site-specific protein modifications. This review delves into the innovative applications of LplA in antibody modifications, including the creation of antibody-drug conjugates (ADCs) and the advancement of tag-free conjugation techniques. LplA's ability to facilitate the incorporation of bioorthogonal groups and its adaptability to various substrates underscores its versatility. Key developments include the successful generation of dual-labeled antibodies and the application of LplA in modifying antibody fragments. Additionally, the review explores the potential for LplA to enhance the therapeutic efficacy of ADCs through improved drug-to-antibody ratios and site-specific payload attachment. The implications of these advancements are significant, suggesting that LplA-mediated modifications could lead to more effective and targeted antibody-based therapies. This review aims to provide a comprehensive overview of LplA's role in expanding the possibilities of enzymatic conjugation, setting the stage for future research and clinical applications.
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Affiliation(s)
- Shunsuke Yamazaki
- Ajinomoto, Co., Inc., 1-1 Suzuki-cho, Kawasaki, Kanagawa, 210-8681, Japan
| | - Yutaka Matsuda
- Ajinomoto, Co., Inc., 1-1 Suzuki-cho, Kawasaki, Kanagawa, 210-8681, Japan
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46
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Ellis H, Braconi C, Valle JW, Bardeesy N. Cholangiocarcinoma Targeted Therapies: Mechanisms of Action and Resistance. THE AMERICAN JOURNAL OF PATHOLOGY 2025; 195:437-452. [PMID: 39730074 PMCID: PMC11841491 DOI: 10.1016/j.ajpath.2024.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 11/18/2024] [Accepted: 11/25/2024] [Indexed: 12/29/2024]
Abstract
Cholangiocarcinoma is an aggressive bile duct malignancy with heterogeneous genomic features. Although most patients receive standard-of-care chemotherapy/immunotherapy, genomic changes that can be targeted with established or emerging therapeutics are common. Accordingly, precision medicine strategies are transforming the next-line treatment for patient subsets. Hotspot IDH1 mutations and activating fibroblast growth factor receptor 2 fusions occur frequently, and small-molecule inhibitors against these alterations are US Food and Drug Administration approved. Translational and basic science studies have elucidated the mechanisms of response and resistance in cholangiocarcinoma, providing insights into these targets that extend to other cancers. Additional US Food and Drug Administration-approved and National Comprehensive Cancer Network guideline-recommended treatments for recurrent genomic changes include BRAF inhibition (BRAF-V600E) and trastumazab deruxtecan (human epidermal growth factor receptor 2 amplification). Furthermore, ongoing clinical trials show promising results with KRAS inhibition (KRAS-codon 12 mutations), PRTM5 inhibition, alone or with methylthioadenosine inhibition (5-methylthioadenosine phosphorylase deletion), and murine double minute 2 inhibition (murine double minute 2 amplification). Despite these advances, the rate, depth, and duration of response to each treatment need improvement. Moreover, many patients do not have currently targetable genotypes. This review examines the clinical efficacy and mechanisms of resistance associated with these treatments, as well as insights into the molecular and biological effects of pathway activation and inhibition, based on study of patient samples and preclinical models. It also explores strategies to overcome resistance and possible precision medicine approaches for additional patient subsets.
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Affiliation(s)
- Haley Ellis
- Massachusetts General Hospital Cancer Center, Krantz Family Center for Cancer Research, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts
| | - Chiara Braconi
- School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom; Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom
| | - Juan W Valle
- Cholangiocarcinoma Foundation, Herriman, Utah; Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom
| | - Nabeel Bardeesy
- Massachusetts General Hospital Cancer Center, Krantz Family Center for Cancer Research, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.
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47
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Farhat J, Sakai H, Tsurutani J. Management of nausea and vomiting induced by antibody-drug conjugates. Breast Cancer 2025; 32:278-285. [PMID: 39878905 PMCID: PMC11842424 DOI: 10.1007/s12282-025-01670-1] [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: 11/11/2024] [Accepted: 01/18/2025] [Indexed: 01/31/2025]
Abstract
Antibody-drug conjugates (ADCs) are an emerging class of anticancer therapy that combines the specificity and long circulation half-life of monoclonal antibodies with the cytotoxic potency of the payload connected through a chemical linker. The optimal management of toxicities is crucial for improving quality of life in patients undergoing ADCs and for avoiding improper dose reductions or discontinuations. This article focuses on the characteristics and management of nausea and vomiting (NV) induced by three ADCs: trastuzumab deruxtecan (T-DXd), sacituzumab govitecan (SG), and datopotamab deruxtecan (Dato-DXd). We summarize the proposed mechanism of NV, clinical study data on NV, and recommendations from clinical guidelines. We also discuss three prospective studies evaluating prophylactic antiemetic therapy in patients receiving T-DXd, along with future perspectives.
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Affiliation(s)
| | - Hitomi Sakai
- Advanced Cancer Translational Research Institute, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan.
| | - Junji Tsurutani
- Advanced Cancer Translational Research Institute, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan
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Zhou L, Zhang Y, Zhang J, Wang H, Zhao B, Cai Y, Qu Y, Li X, Zhang D. Clinical characteristics and therapeutic direction of HER2 low-expression breast cancer. Front Oncol 2025; 15:1484103. [PMID: 40083869 PMCID: PMC11903420 DOI: 10.3389/fonc.2025.1484103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 01/31/2025] [Indexed: 03/16/2025] Open
Abstract
Human epidermal growth factor receptor 2 (HER2) is one of the oncogenic drivers of breast cancer and is often used as a definitive therapeutic marker for breast cancer. This has led to significant improvements in both targeted therapy and prognosis for HER2-targeted breast cancer. Due to the differences in HER2 gene and protein expression levels, they are clinically classified into HER2 zero-expression breast cancer, low-expression breast cancer and high-expression breast cancer. Among them, HER2 low-expression is considered a special expression state, which is insensitive to conventional anti-HER2 therapy and has a poorer prognosis and thus has received attention from researchers. Some studies demonstrate that patients with HER2 low-expression can benefit from antibody-drug conjugates (ADC). Several studies are currently exploring the efficacy of various ADC drugs in breast cancer with HER2 low-expression, opening up new treatment avenues for patients with HER2 low-expression breast cancer. This review aims to summarize the clinical features of HER2 low-expression breast cancer and the recent advances in its therapeutic agents.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Dongwei Zhang
- Department of Breast Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
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Dennis N, Dunton K, Livings C, Bogoeva N, Bourke S, Oluboyede Y, Hamilton E, Iwata H, Cortés J. Quality-adjusted time without symptoms or toxicity analysis of trastuzumab deruxtecan versus trastuzumab emtansine in HER2- positive metastatic breast cancer patients based on secondary use of the DESTINY-Breast03 trial. Eur J Cancer 2025; 217:115192. [PMID: 39798264 DOI: 10.1016/j.ejca.2024.115192] [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: 08/12/2024] [Revised: 11/25/2024] [Accepted: 12/10/2024] [Indexed: 01/15/2025]
Abstract
OBJECTIVE DESTINY-Breast03, a randomised, phase 3 trial, evaluated trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients with human epidermal growth factor receptor (HER2)-positive unresectable and/or metastatic breast cancer who progressed on or after treatment with trastuzumab and a taxane. At the current data cut off overall survival analysis, T-DXd demonstrated a substantial improvement in overall survival over T-DM1. This secondary analysis use of DESTINY-Breast03 aimed to further evaluate the treatment differences using quality-adjusted survival time without symptoms or toxicity (Q-TWiST) methods. METHODS Patients' survival data was divided into three health states: time spent with grade 3-4 adverse events (TOX), time without adverse events before disease progression (TWiST), and time from disease progression to death (PROG). Mean health state duration was weighted by patients' mean utility score in each health state based on the EQ-5D-5L questionnaire and summed to obtain the Q-TWiST value. A threshold utility analysis was also conducted using a range of hypothetical utility scores to assess the impact on Q-TWiST values obtained. RESULTS T-DXd was associated with a substantial and clinically important improvement in Q-TWiST compared to T-DM1 (mean difference = 3.80 months, 95 % CI: [1.91, 5.62], nominal P-value <0.001; relative gain = 11.64 %). The robustness of the results was supported by threshold utility analysis. CONCLUSION T-DXd produced a substantial improvement in quality-adjusted time without symptoms or toxicity when accounting for time on treatment exposure compared to T-DM1. Consequently, T-DXd is shown to improve both length and quality of life.
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Affiliation(s)
| | | | | | - Nataliya Bogoeva
- Putnam, Ceva House, Excelsior Road, Ashby-De-La-Zouch LE65 1NG, United Kingdom.
| | - Siobhan Bourke
- Putnam, Ceva House, Excelsior Road, Ashby-De-La-Zouch LE65 1NG, United Kingdom
| | - Yemi Oluboyede
- Putnam, Ceva House, Excelsior Road, Ashby-De-La-Zouch LE65 1NG, United Kingdom
| | - Erika Hamilton
- Sarah Cannon Research Institute, Nashville, United States
| | - Hiroji Iwata
- Nagoya City University, Graduate School of Medical Sciences, Nagoya, Japan
| | - Javier Cortés
- International Breast Cancer Center, Quirónsalud Group, Barcelona, Spain; IOB Madrid, Hospital Beata Maria Ana, Madrid, Spain; Medica Scientia Innovation Research (MEDSIR) - Oncoclínicas & Co, Jersey City (New Jersey, USA), Sao Paulo, Brazil; Department of Medicine, Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid, Madrid, Spain
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50
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Yamanaka T, Nishikawa T, Yoshida H. Development of Antibody-Drug Conjugates for Malignancies of the Uterine Corpus: A Review. Cells 2025; 14:333. [PMID: 40072062 PMCID: PMC11898814 DOI: 10.3390/cells14050333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 02/17/2025] [Accepted: 02/21/2025] [Indexed: 03/15/2025] Open
Abstract
Despite recent advances in cancer treatment, the prognosis for uterine malignancies (carcinoma and sarcoma) requires further improvement. Antibody-drug conjugates (ADCs) have emerged as a novel class of anti-cancer therapeutic agents, and multiple ADCs have been approved for other types of cancer. In 2024, trastuzumab deruxtecan received approval from the US Food and Drug Administration for cancer types and became the first ADC approved for the treatment of uterine malignancies. Many ADCs are currently being investigated in uterine malignancies, and therefore, there is a need to gain a deeper understanding of ADCs. In this article, we aim to provide a comprehensive overview of the advancements in ADCs. The contents of this article include the structure and mechanism of action, an analysis of recent clinical trials, and expected future clinical questions. This article also focuses on uterine sarcoma, which is not often highlighted as a target for ADC treatment.
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Affiliation(s)
- Taro Yamanaka
- Department of Medical Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan;
| | - Tadaaki Nishikawa
- Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo 105-8461, Japan;
| | - Hiroshi Yoshida
- Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo 104-0045, Japan
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