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Molecular Cancer Research : MCR Apr 2020The antibody-drug conjugate trastuzumab-emtansine (T-DM1) offers an additional treatment option for patients with HER2-amplified tumors. However, primary and acquired...
The antibody-drug conjugate trastuzumab-emtansine (T-DM1) offers an additional treatment option for patients with HER2-amplified tumors. However, primary and acquired resistance is a limiting factor in a significant subset of patients. Hypoxia, a hallmark of cancer, regulates the trafficking of several receptor proteins with potential implications for tumor targeting. Here, we have investigated how hypoxic conditions may regulate T-DM1 treatment efficacy in breast cancer. The therapeutic effect of T-DM1 and its metabolites was evaluated in conjunction with biochemical, flow cytometry, and high-resolution imaging studies to elucidate the functional and mechanistic aspects of hypoxic regulation. HER2 and caveolin-1 expression was investigated in a well-annotated breast cancer cohort. We find that hypoxia fosters relative resistance to T-DM1 in HER2 cells (SKBR3 and BT474). This effect was not a result of deregulated HER2 expression or resistance to emtansine and its metabolites. Instead, we show that hypoxia-induced translocation of caveolin-1 from cytoplasmic vesicles to the plasma membrane contributes to deficient trastuzumab internalization and T-DM1 chemosensitivity. Caveolin-1 depletion mimicked the hypoxic situation, indicating that vesicular caveolin-1 is indispensable for trastuzumab uptake and T-DM1 cytotoxicity. studies suggested that HER2 and caveolin-1 are not coregulated, which was supported by IHC analysis in patient tumors. We find that phosphorylation-deficient caveolin-1 inhibits trastuzumab internalization and T-DM1 cytotoxicity, suggesting a specific role for caveolin-1 phosphorylation in HER2 trafficking. IMPLICATIONS: Together, our data for the first time identify hypoxic regulation of caveolin-1 as a resistance mechanism to T-DM1 with potential implications for individualized treatment of breast cancer.
Topics: Antineoplastic Agents, Immunological; Breast Neoplasms; Caveolin 1; Cell Hypoxia; Female; Humans; Maytansine; Transfection; Trastuzumab
PubMed: 31900313
DOI: 10.1158/1541-7786.MCR-19-0856 -
Current Oncology (Toronto, Ont.) Apr 2022Approximately 20% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2), providing an actionable target for many different therapies. In the... (Review)
Review
Approximately 20% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2), providing an actionable target for many different therapies. In the metastatic setting, prognosis has improved greatly with the use of anti-HER2 drugs such as trastuzumab, pertuzumab, and trastuzumab-emtansine. In the third line setting and beyond, several emerging treatments have shown benefits, including novel small molecule targeted agents and antibody-drug conjugates. Systemic treatment of brain metastases in HER2-positive patients and the role of endocrine-based treatment for patients with hormone receptor (HR) positive disease remain areas of research interest. This article will review the current approach to systemic management of metastatic HER2-positive breast cancer in Canada, and present novel treatments that may be available in the near future.
Topics: Ado-Trastuzumab Emtansine; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Humans; Immunoconjugates; Trastuzumab
PubMed: 35448182
DOI: 10.3390/curroncol29040208 -
Bioconjugate Chemistry Jul 2021Herein, we present the syntheses and characterization of a new undecadendate chelator, Hpy4pa, and its bifunctional analog Hpy4pa-phenyl-NCS, conjugated to the...
Herein, we present the syntheses and characterization of a new undecadendate chelator, Hpy4pa, and its bifunctional analog Hpy4pa-phenyl-NCS, conjugated to the monoclonal antibody, Trastuzumab, which targets the HER2+ cancer. Hpy4pa possesses excellent affinity for Ac (α, = 9.92 d) for targeted alpha therapy (TAT), where quantitative radiolabeling yield was achieved at ambient temperature, pH = 7, in 30 min at 10 M chelator concentration, leading to a complex highly stable in mouse serum for at least 9 d. To investigate the chelation of Hpy4pa with large metal ions, lanthanum (La), which is the largest nonradioactive metal of the lanthanide series, was adopted as a surrogate for Ac to enable a series of nonradioactive chemical studies. In line with the H NMR spectrum, the DFT (density functional theory)-calculated structure of the [La(py4pa)] anion possessed a high degree of symmetry, and the La ion was secured by two distinct pairs of picolinate arms. Furthermore, the [La(py4pa)] complex also demonstrated a superb thermodynamic stability (log ∼ 20.33, pLa = 21.0) compared to those of DOTA (log ∼ 24.25, pLa = 19.2) or Hmacropa (log = 14.99, pLa ∼ 8.5). Moreover, the functional versatility offered by the bifunctional py4pa precursor permits facile incorporation of various linkers for bioconjugation through direct nucleophilic substitution. In this work, a short phenyl-NCS linker was incorporated to tether Hpy4pa to Trastuzumab. Radiolabeling studies, serum stability, and animal studies were performed in parallel with the DOTA-benzyl-Trastuzumab. Both displayed excellent stability and tumor specificity.
Topics: Actinium; Alpha Particles; Animals; Antineoplastic Agents, Immunological; Chelating Agents; Coordination Complexes; Density Functional Theory; Humans; Mice; Radiopharmaceuticals; Thermodynamics; Tissue Distribution; Trastuzumab; Xenograft Model Antitumor Assays
PubMed: 32216377
DOI: 10.1021/acs.bioconjchem.0c00171 -
Anti-cancer Agents in Medicinal... 2022The discovery of trastuzumab as anti-HER2 therapy has markedly improved disease control and the survival rates of patients with HER2+ breast cancer. However, as...
BACKGROUND
The discovery of trastuzumab as anti-HER2 therapy has markedly improved disease control and the survival rates of patients with HER2+ breast cancer. However, as trastuzumab is considered a complex molecule, the cost of production is usually elevated, which significantly affects health budgets and limits the treatment access for patients who live in underdeveloped countries. Recently, trastuzumab production has become more accessible and sustainable due to the patents' expiration, allowing biosimilar versions of trastuzumab to be developed.
OBJECTIVE
Our main goal was to shed more light on the uses of biosimilars in breast cancer treatment, emphasizing trastuzumab.
METHOD
An integrative search was carried out on the PubMed, Scielo, Web of Science, and SCOPUS databases using the terms "biosimilar," "breast cancer," "monoclonal antibody," and "trastuzumab." The time range included scientific articles published from 2015 to 2021.
RESULTS AND DISCUSSION
The bibliographic survey showed the complexities in biological medicine manufacturing and how the monoclonal antibody's therapy with trastuzumab improved the patients' life expectancy, revolutionizing HER2+ breast cancer treatment. Nonetheless, despite its benefits, trastuzumab generates certain restrictions, especially from the economic perspective. Trastuzumab biosimilars have high selectivity and rarely cause adverse effects compared to conventional chemotherapy.
CONCLUSION
This study shows that trastuzumab biosimilars improve patients' accessibility to breast cancer treatment through a safe and effective therapy compared to the drug reference.
Topics: Antibodies, Monoclonal; Biosimilar Pharmaceuticals; Breast Neoplasms; Female; Humans; Receptor, ErbB-2; Trastuzumab
PubMed: 35236272
DOI: 10.2174/1871520622666220302114313 -
Redox Biology Nov 2023Trastuzumab notably improves the outcome of human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients, however, resistance to trastuzumab remains a...
Trastuzumab notably improves the outcome of human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients, however, resistance to trastuzumab remains a major hurdle to clinical treatment. In the present study, we identify a circular RNA intimately linked to trastuzumab resistance. circ-β-TrCP, derived from the back-splicing of β-TrCP exon 7 and 13, confers trastuzumab resistance by regulating NRF2-mediated antioxidant pathway in a KEAP1-independent manner. Concretely, circ-β-TrCP encodes a novel truncated 343-amino acid peptide located in the nucleus, referred as β-TrCP-343aa, which competitively binds to NRF2, blocks SCF-mediated NRF2 proteasomal degradation, and this protective effect of β-TrCP-343aa on NRF2 protein requires GSK3 activity. Subsequently, the elevated NRF2 transcriptionally upregulates a cohort of antioxidant genes, giving rise to trastuzumab resistance. Moreover, the translation ability of circ-β-TrCP is inhibited by eIF3j under both basal and oxidative stress conditions, and eIF3j is transcriptionally repressed by NRF2, thus forming a positive feedback circuit between β-TrCP-343aa and NRF2, expediting trastuzumab resistance. Collectively, our data demonstrate that circ-β-TrCP-encoded β-TrCP protein isoform drives HER2-targeted therapy resistance in a NRF2-dependent manner, which provides potential therapeutic targets for overcoming trastuzumab resistance.
Topics: Humans; Female; Kelch-Like ECH-Associated Protein 1; Antioxidants; beta-Transducin Repeat-Containing Proteins; RNA, Circular; Trastuzumab; Breast Neoplasms; NF-E2-Related Factor 2; Glycogen Synthase Kinase 3; Protein Isoforms; Drug Resistance, Neoplasm; Cell Line, Tumor
PubMed: 37783059
DOI: 10.1016/j.redox.2023.102896 -
Clinics (Sao Paulo, Brazil) 2023Trastuzumab is the preferred drug for the treatment of breast cancer. However, research on the cellular mechanisms of trastuzumab's potential cardiotoxicity is...
OBJECTIVE
Trastuzumab is the preferred drug for the treatment of breast cancer. However, research on the cellular mechanisms of trastuzumab's potential cardiotoxicity is insufficient. The purpose of this study was to explore the toxic effects and potential mechanism of action of trastuzumab on cardiomyocytes.
METHOD
Human Cardiomyocyte (HCM) viability was assessed using the MTT method. HCM apoptosis was detected using the Hoechst33342/PI Fluorescent staining. The LDH and CK activities of the cell were measured using commercially available LDH and CK assay kits. The expression levels of Notch2, JAK2, STAT3, cleaved caspase 3, bax, and bcl 2 in HCMs were detected using western blotting.
RESULTS
The results showed that 250 mg/L trastuzumab induced cardiomyocyte injury and apoptosis, inhibited viability, activated the Notch2 receptor, and inhibited JAK2/STAT3 expression in HCM. Inhibition of Notch2 expression in HCM by targeted siNotch2 transfection reversed the trastuzumab-induced injury and apoptosis, and the expression of JAK2/STAT3 returned to normal levels.
CONCLUSIONS
Trastuzumab induces Notch2 expression by inhibiting the JAK2/STAT3 pathway of HCMs, promotes cell apoptosis, and causes cardiomyocyteinjury. Notch2 may be a potential target of trastuzumab-inducedmyocardial injury. This experiment reveals the mechanism of trastuzumab-induced cardiotoxicity, providing a theoretical basis for the application of trastuzumab.
Topics: Humans; Myocytes, Cardiac; Trastuzumab; Cardiotoxicity; Receptor, Notch2; Apoptosis; Janus Kinase 2; STAT3 Transcription Factor
PubMed: 37567042
DOI: 10.1016/j.clinsp.2023.100268 -
Acta Oncologica (Stockholm, Sweden) Jun 2023The purpose was to investigate the treatment flow of patients with HER2-positive metastatic breast cancer (mBC), progression-free survival (PFS) and overall survival...
BACKGROUND
The purpose was to investigate the treatment flow of patients with HER2-positive metastatic breast cancer (mBC), progression-free survival (PFS) and overall survival (OS) across treatment lines and adherence to guidelines (defined as trastuzumab, pertuzumab and chemotherapy first line, where 85% received vinorelbine as backbone and T-DM1 second line). Furthermore, we identified clinical markers to predict the risk of developing brain metastases.
MATERIAL AND METHODS
Patients with HER2-positive mBC, diagnosed between 01.01.2014-31.12.2019, registered in the database of the Danish Breast Cancer Group were included in this real-word study. Clinical follow-up was assessed until 01.10.2020 and complete follow-up for overall survival until 01.10.2021. Survival data were analyzed using the Kaplan-Meier method with guidelines adherence analyzed as a time-varying covariate, and the risk of CNS metastasis was estimated by the cumulative incidence function.
RESULTS
631 patients were included. 329 (52%) patients followed the guidelines. The median OS for all patients was 42.3 months (95% Cl, 38.2-48.4), and significantly higher for the patients who followed guidelines; NA (95% CI, 78.2-NA). The median PFS for all patients was 13.4 months (95% Cl, 12.1-14.8), 6.6 (95% Cl, 5.8-7.6) and 5.8 (95% Cl, 4.9-6.9) for first, second and third line of treatment, respectively. Patients with ER-negative mBC had a higher risk of developing brain metastases and patients with high tumor burden had a higher risk of developing brain metastases with an adjusted HR of 0.69 (95% CI, 0.49-0.98), = 0.047 and 2.69 (95% CI, 1.45-5.00), = 0.002, respectively.
CONCLUSION
We found that only half of the patients with HER2-positive mBC, received first and second-line treatment according to national guidelines. Patients receiving treatment according to guidelines had a significantly higher median OS compared to patients who did not. We also found that patients with ER-negative disease or high tumor burden had a significantly higher risk of developing brain metastases.
Topics: Humans; Female; Breast Neoplasms; Receptor, ErbB-2; Trastuzumab; Ado-Trastuzumab Emtansine; Denmark; Antineoplastic Combined Chemotherapy Protocols; Retrospective Studies
PubMed: 37338513
DOI: 10.1080/0284186X.2023.2224926 -
Journal For Immunotherapy of Cancer Oct 2022Preclinical and clinical data support potential synergy between anti-HER2 therapy plus immune checkpoint blockade. The safety and tolerability of trastuzumab emtansine...
BACKGROUND
Preclinical and clinical data support potential synergy between anti-HER2 therapy plus immune checkpoint blockade. The safety and tolerability of trastuzumab emtansine (T-DM1) combined with pembrolizumab is unknown.
METHODS
This was a single-arm phase Ib trial (registration date January 26, 2017) of T-DM1 plus pembrolizumab in metastatic, human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Eligible patients had HER2-positive, metastatic breast cancer previously treated with taxane, trastuzumab, and pertuzumab, and were T-DM1-naïve. A dose de-escalation design was used, with a dose-finding cohort followed by an expansion cohort at the recommended phase 2 dose (RP2D), with mandatory baseline biopsies. The primary endpoint was safety and tolerability. Secondary endpoints included objective response rate (ORR) and progression-free survival (PFS). Immune biomarkers were assessed using histology, protein/RNA expression, and whole exome sequencing. Associations between immune biomarkers and treatment response, and biomarker changes before and during treatment, were explored.
RESULTS
20 patients received protocol therapy. There were no dose-limiting toxicities. The RP2D was 3.6 mg/kg T-DM1 every 21 days plus 200 mg pembrolizumab every 21 days. 85% of patients experienced treatment-related adverse events (AEs) ≥grade 2, 20% of patients experienced grade 3 AEs, and no patients experienced grade >4 AEs. Four patients (20%) experienced pneumonitis (three grade 2 events; one grade 3 event). ORR was 20% (95% CI 5.7% to 43.7%), and median PFS was 9.6 months (95% CI 2.8 to 16.0 months). Programmed cell death ligand-1 and tumor infiltrating lymphocytes did not correlate with response in this small cohort.
CONCLUSIONS
T-DM1 plus pembrolizumab was a safe and tolerable regimen. Ongoing trials will define if there is a role for checkpoint inhibition in the management of HER2-positive metastatic breast cancer.
TRIAL REGISTRATION NUMBER
NCT03032107.
Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Humans; Immune Checkpoint Inhibitors; Ligands; RNA; Taxoids; Trastuzumab
PubMed: 36252998
DOI: 10.1136/jitc-2022-005119 -
Frontiers in Immunology 2023Pancreatic cancer is associated with poor prognosis, and limited treatment options are available for the majority of patients. Natural killer (NK) cells in combination...
INTRODUCTION
Pancreatic cancer is associated with poor prognosis, and limited treatment options are available for the majority of patients. Natural killer (NK) cells in combination with antibodies inducing antibody-dependent cell-mediated cytotoxicity (ADCC) could be a highly effective new therapeutic option in pancreatic cancer. Accurate predictive preclinical models are needed to develop successful NK cell immunotherapy. Tumor organoids, in vitro 3D organ-like structures that retain important pathophysiological characteristics of the in vivo tumor, may provide such a model. In the current study, we assessed the cytotoxic potential of adoptive NK cells against human pancreatic cancer organoids. We hypothesized that NK cell anti-tumor responses could be enhanced by including ADCC-triggering antibodies.
METHODS
We performed cytotoxicity assays with healthy donor-derived IL-2-activated NK cells and pancreatic cancer organoids from four patients. A 3D cytotoxicity assay using live-cell-imaging was developed and enabled real-time assessment of the response.
RESULTS
We show that NK cells migrate to and target pancreatic cancer organoids, resulting in an increased organoid death, compared to the no NK cell controls (reaching an average fold change from baseline of 2.1±0.8 vs 1.4±0.6). After 24-hours of co-culture, organoid 2D growth increased. Organoids from 2 out of 4 patients were sensitive to NK cells, while organoids from the other two patients were relatively resistant, indicating patient-specific heterogeneity among organoid cultures. The ADCC-inducing antibodies avelumab (anti-PD-L1) and trastuzumab (anti-HER2) increased NK cell-induced organoid cell death (reaching an average fold change from baseline of 3.5±1.0 and 4.5±1.8, respectively). Moreover, combination therapy with avelumab or trastuzumab resulted in complete disintegration of organoids. Finally, inclusion of ADCC-inducing antibodies was able to overcome resistance in NK-organoid combinations with low or no kill.
DISCUSSION
These results support the use of organoids as a relevant and personalized model to study the anti-tumor response of NK cells and the potential of ADCC-inducing antibodies to enhance NK cell effector function.
Topics: Humans; Antibodies, Monoclonal; Antibody-Dependent Cell Cytotoxicity; Trastuzumab; Killer Cells, Natural; Pancreatic Neoplasms
PubMed: 37520563
DOI: 10.3389/fimmu.2023.1133796 -
Targeted Oncology Dec 2019ABP 980 was developed as a biosimilar to trastuzumab, a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2), that is indicated for the... (Review)
Review
ABP 980 was developed as a biosimilar to trastuzumab, a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2), that is indicated for the treatment of HER2-positive metastatic breast cancer, early breast cancer (EBC), and metastatic gastric cancer. ABP 980 is approved in the United States, European Union, and Japan for all the indications of trastuzumab, based on the totality of evidence (TOE) gathered by the systematic step-wise accumulation of comparative analytical, preclinical, and clinical (pharmacokinetics [PK], efficacy, safety and immunogenicity) data for ABP 980 and trastuzumab reference product (RP). As a key first step of the ABP 980 biosimilar program, comprehensive analytical characterization of critical quality attributes established that ABP 980 is structurally and functionally similar to trastuzumab RP. Complementing these data, results of non-clinical pharmacology, toxicology, and toxicokinetic studies supported similarity between ABP 980 and trastuzumab RP. A randomized study in healthy subjects demonstrated clinical PK equivalence of ABP 980 relative to trastuzumab RP in these subjects. In the final clinical evaluation step, a randomized comparative study (LILAC) confirmed the lack of clinically meaningful differences between ABP 980 and trastuzumab RP in efficacy, safety, and immunogenicity in women with HER2-positive EBC in the neoadjuvant-adjuvant setting. Neoadjuvant EBC represented a sensitive homogenous population for biosimilar demonstrations, and the primary endpoint of pathologic complete response served as a sensitive surrogate endpoint. An important aspect of the LILAC study design is that it is the only study that evaluated the effect of switching from the trastuzumab RP to a trastuzumab biosimilar during the adjuvant phase. No new or unexpected safety signals emerged in the clinical evaluations, with the safety profile of ABP 980 consistent with that previously described for trastuzumab. Overall, the TOE data generated for ABP 980 support the conclusion that it is highly similar to trastuzumab RP, thus providing the scientific justification for extrapolation to all the approved indications of trastuzumab.
Topics: Adult; Antineoplastic Agents, Immunological; Biosimilar Pharmaceuticals; Breast Neoplasms; Comparative Effectiveness Research; Female; Humans; Randomized Controlled Trials as Topic; Receptor, ErbB-2; Trastuzumab
PubMed: 31620980
DOI: 10.1007/s11523-019-00675-z