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International Journal of Molecular... Jul 2023To achieve the scheme of "magic bullets" in antitumor therapy, antibody-drug conjugates (ADCs) were developed. ADCs consist of antibodies targeting tumor-specific... (Review)
Review
To achieve the scheme of "magic bullets" in antitumor therapy, antibody-drug conjugates (ADCs) were developed. ADCs consist of antibodies targeting tumor-specific antigens, chemical linkers, and cytotoxic payloads that powerfully kill cancer cells. With the approval of ado-trastuzumab emtansine (T-DM1) and fam-trastuzumab deruxtecan (T-DXd), the therapeutic potentials of ADCs in breast cancer have come into the spotlight. Nearly 30 ADCs for breast cancer are under exploration to move targeted therapy forward. In this review, we summarize the presenting and emerging agents and targets of ADCs. The ADC structure and development history are also concluded. Moreover, the challenges faced and prospected future directions in this field are reviewed, which give insights into novel treatments with ADCs for breast cancer.
Topics: Humans; Female; Breast Neoplasms; Trastuzumab; Antineoplastic Agents; Ado-Trastuzumab Emtansine; Immunoconjugates
PubMed: 37569276
DOI: 10.3390/ijms241511903 -
Current Treatment Options in Oncology Nov 2023Approximately 15-20% of breast cancers (BC) demonstrate HER2 overexpression/gene amplification. Historically, before the era of HER2-directed therapies, this subtype was... (Review)
Review
Approximately 15-20% of breast cancers (BC) demonstrate HER2 overexpression/gene amplification. Historically, before the era of HER2-directed therapies, this subtype was associated with poor prognosis. Anti-HER2 agents dramatically changed the natural course of disease and significantly prolonged patients' survival. In recent years, a number of new anti-HER2 therapies have been developed, and their approvals offer new therapeutic options for patients with advanced HER2-positive breast cancer. At present, HER2 pathway blocking drugs used in the treatment of metastatic breast cancer worldwide include trastuzumab and pertuzumab in the first-line treatment; trastuzumab deruxtecan and trastuzumab emtansine in the second line; and tucatinib, neratinib, lapatinib, and margetuximab in further lines of treatment of advanced HER2 positive breast cancer. Additionally, there are many clinical trials underway evaluating drugs blocking the HER2 pathway in advanced disease setting. This article presents new treatment options, discussing the most important findings from clinical trials and real-world reports, clinical benefits and risks of treatment, as well as efficacy of re-treatment with trastuzumab in metastatic breast cancer. New data challenge the current standards, and a number of questions arise regarding the optimal sequence of anti-HER2 targeted therapies, the optimal combination, including endocrine agents in luminal HER2 positive tumors and treatment of special patient population such as patients with brain metastases (BM).
Topics: Humans; Female; Breast Neoplasms; Receptor, ErbB-2; Trastuzumab; Ado-Trastuzumab Emtansine; Lapatinib
PubMed: 37878202
DOI: 10.1007/s11864-023-01137-5 -
Plants (Basel, Switzerland) Jan 2022Even though maytansine was first discovered from Celastraceae plants, it was later proven to be an endophytic bacterial metabolite. However, a pure bacterial culture...
Genome Mining and Gene Expression Reveal Maytansine Biosynthetic Genes from Endophytic Communities Living inside (Eckl. and Zeyh.) Loes. and the Relationship with the Plant Biosynthetic Gene, Friedelin Synthase.
Even though maytansine was first discovered from Celastraceae plants, it was later proven to be an endophytic bacterial metabolite. However, a pure bacterial culture cannot synthesize maytansine. Therefore, an exclusive interaction between plant and endophytes is required for maytansine production. Unfortunately, our understanding of plant-endophyte interaction is minimal, and critical questions remain. For example: how do endophytes synthesize maytansine inside their plant host, and what is the impact of maytansine production in plant secondary metabolites? Our study aimed to address these questions. We selected as our model and used amino-hydroxybenzoic acid (AHBA) synthase and halogenase genes as biomarkers, as these two genes respond to biosynthesize maytansine. As a result, we found a consortium of seven endophytes involved in maytansine production in , based on genome mining and gene expression experiments. Subsequently, we evaluated the friedelin synthase (FRS) gene's expression level in response to biosynthesized 20-hydroxymaytenin in the plant. We found that the FRS expression level was elevated and linked with the expression of the maytansine biosynthetic genes. Thus, we achieved our goals and provided new evidence on endophyte-endophyte and plant-endophyte interactions, focusing on maytansine production and its impact on plant metabolite biosynthesis in .
PubMed: 35161302
DOI: 10.3390/plants11030321 -
Journal of Controlled Release :... Mar 2023Treatment with antibody drug conjugates targeting receptors over-expressed on cancer cells is well established for clinical use in several types of cancer, however,...
Treatment with antibody drug conjugates targeting receptors over-expressed on cancer cells is well established for clinical use in several types of cancer, however, resistance often occurs motivating the development of novel drugs. We have recently investigated a drug conjugate consisting of an affibody molecule targeting the human epidermal growth factor receptor 2 (HER2), fused to an albumin-binding domain (ABD) for half-life extension, loaded with the cytotoxic maytansine derivative DM1. In this study, we investigated the impact of the cytotoxic payload on binding properties, cytotoxicity and biodistribution by comparing DM1 with the auristatins MMAE and MMAF, as part of the drug conjugate. All constructs had specific and high affinity binding to HER2, human and mouse albumins with values in the low- to sub-nM range. Z-ABD-mcMMAF demonstrated the most potent cytotoxic effect on several HER2-over-expressing cell lines. In an experimental therapy study, the MMAF-based conjugate provided complete tumor regression in 50% of BALB/c nu/nu mice bearing HER2-over-expressing SKOV3 tumors at a 2.9 mg/kg dose, while the same dose of Z-ABD-mcDM1 provided only a moderate anti-tumor effect. A comparison with the non-targeting Z-ABD-mcMMAF control demonstrated HER2-targeting specificity. In conclusion, a combination of potent cytotoxicity in vitro, with minimal uptake in normal organs in vivo, and efficient delivery to tumors provided a superior anti-tumor effect of Z-ABD-mcMMAF, while maintaining a favorable toxicity profile with no observed adverse effects.
Topics: Animals; Mice; Humans; Maytansine; Pharmaceutical Preparations; Tissue Distribution; Cell Line, Tumor; Receptor, ErbB-2; Antineoplastic Agents
PubMed: 36773960
DOI: 10.1016/j.jconrel.2023.02.005 -
Clinical Cancer Research : An Official... Apr 2023Preclinical data showed that prophylactic, low-dose temozolomide (TMZ) significantly prevented breast cancer brain metastasis. We present results of a phase I trial...
PURPOSE
Preclinical data showed that prophylactic, low-dose temozolomide (TMZ) significantly prevented breast cancer brain metastasis. We present results of a phase I trial combining T-DM1 with TMZ for the prevention of additional brain metastases after previous occurrence and local treatment in patients with HER2+ breast cancer.
PATIENTS AND METHODS
Eligible patients had HER2+ breast cancer with brain metastases and were within 12 weeks of whole brain radiation therapy (WBRT), stereotactic radiosurgery, and/or surgery. Standard doses of T-DM1 were administered intravenously every 21 days (3.6 mg/kg) and TMZ was given orally daily in a 3+3 phase I dose escalation design at 30, 40, or 50 mg/m2, continuously. DLT period was one 21-day cycle. Primary endpoint was safety and recommended phase II dose. Symptom questionnaires, brain MRI, and systemic CT scans were performed every 6 weeks. Cell-free DNA sequencing was performed on patients' plasma and CSF.
RESULTS
Twelve women enrolled, nine (75%) with prior SRS therapy and three (25%) with prior WBRT. Grade 3 or 4 AEs included thrombocytopenia (1/12), neutropenia (1/12), lymphopenia (6/12), and decreased CD4 (6/12), requiring pentamidine for Pneumocystis jirovecii pneumonia prophylaxis. No DLT was observed. Four patients on the highest TMZ dose underwent dose reductions. At trial entry, 6 of 12 patients had tumor mutations in CSF, indicating ongoing metastatic colonization despite a clear MRI. Median follow-up on study was 9.6 m (2.8-33.9); only 2 patients developed new parenchymal brain metastases. Tumor mutations varied with patient outcome.
CONCLUSIONS
Metronomic TMZ in combination with standard dose T-DM1 shows low-grade toxicity and potential activity in secondary prevention of HER2+ brain metastases.
Topics: Humans; Female; Breast Neoplasms; Temozolomide; Cell-Free Nucleic Acids; Secondary Prevention; Receptor, ErbB-2; Ado-Trastuzumab Emtansine; Brain Neoplasms
PubMed: 36705597
DOI: 10.1158/1078-0432.CCR-22-0855 -
Archives of Biochemistry and Biophysics Sep 2022A tritiated derivative of the sponge-derived natural product spongistatin 1 was prepared, and its interactions with tubulin were examined. [H]Spongistatin 1 was found to...
A tritiated derivative of the sponge-derived natural product spongistatin 1 was prepared, and its interactions with tubulin were examined. [H]Spongistatin 1 was found to bind rapidly to tubulin at a single site (the low specific activity of the [H]spongistatin 1, 0.75 Ci/mmol, prevented our defining an association rate), and the inability of spongistatin 1 to cause an aberrant assembly reaction was confirmed. Spongistatin 1 bound to tubulin very tightly, and we could detect no significant dissociation reaction from tubulin. The tubulin-[H]spongistatin 1 complex did dissociate in 8 M urea, so there was no evidence for covalent bond formation. Apparent K values were obtained by Scatchard analysis of binding data and by Hummel-Dreyer chromatography (3.5 and 1.1 μM, respectively). The effects of a large cohort of vinca domain drugs on the binding of [H]spongistatin 1 to tubulin were evaluated. Compounds that did not cause aberrant assembly reactions (halichondrin B, eribulin, maytansine, and rhizoxin) caused little inhibition of [H]spongistatin 1 binding. Little inhibition also occurred with the peptides dolastatin 15, its active pentapeptide derivative, vitilevuamide, or diazonamide A, nor with the vinca alkaloid vinblastine. Strong inhibition was observed with dolastatin 10, hemiasterlin, and cryptophycin 1, all of which cause aberrant assembly reactions that might actually mask the spongistatin 1 binding site. Spongistatin 5 was found to be a competitive inhibitor of [H]spongistatin 1 binding, with an apparent K of 2.2 μM. We propose that the strong picomolar cytotoxicity of spongistatin 1 probably derives from its extremely tight binding to tubulin.
Topics: Antineoplastic Agents; Binding Sites; Macrolides; Microtubules; Tubulin; Vinblastine
PubMed: 35594923
DOI: 10.1016/j.abb.2022.109296 -
JAMA Network Open Oct 2023Targeted therapies directed against ERBB2 are the cornerstone of medical treatment for ERBB2-positive breast cancers but are contraindicated during pregnancy.
IMPORTANCE
Targeted therapies directed against ERBB2 are the cornerstone of medical treatment for ERBB2-positive breast cancers but are contraindicated during pregnancy.
OBJECTIVES
To describe the association of exposure to anti-ERBB2 agents during pregnancy with pregnancy and fetal or newborn outcomes, and to compare the risk and types of adverse outcomes reported more frequently in this context than after exposure to other anticancer agents.
DESIGN, SETTING, AND PARTICIPANTS
For this case-control study, All reports with a pregnancy-related condition and an antineoplastic agent (Anatomical Therapeutic Chemical classification group L01) registered in the World Health Organization international pharmacovigilance database VigiBase up to June 26, 2022, were extracted. All reports with a pregnancy, an antineoplastic treatment during pregnancy, and a cancer were retained. Reports with anticancer agents prescribed for nononcologic purposes were not included.
EXPOSURE
The exposure group was defined as reports that mention anti-ERBB2 agents compared with exposure to other anticancer agents.
MAIN OUTCOME AND MEASURES
The main outcome was the reporting odds ratio (ROR) for maternofetal complications in the group exposed to anti-ERBB2 agents compared with other anticancer agents, as determined using a disproportionality analysis.
RESULTS
A total of 3558 reports (anti-ERBB2 agents, 328; other anticancer agents, 3230) were included in the analysis. In the group exposed to anti-ERBB2 agents, most reports were from the US (159 [48.5%]), the mean (SD) age of participants was 30.8 (10.4) years, and 209 patients (97.7%) were treated for breast cancers. The molecules most frequently involved in cases with anti-ERBB2 agents were trastuzumab (n = 302), pertuzumab (n = 55), trastuzumab-emtansine (n = 20), and lapatinib (n = 18). The outcomes overreported in these cases included oligohydramnios (ROR, 17.68 [95% CI, 12.26-25.52]; P < .001), congenital respiratory tract disorders (ROR, 9.98 [95% CI, 2.88-34.67]; P < .001), and neonatal kidney failure (ROR, 9.15 [95% CI, 4.62-18.12]; P < .001). Sensitivity and multivariable analyses found similar results. Toxic effects were also significantly overreported for trastuzumab-emtansine (cardiovascular malformation: ROR, 4.46 [95% CI, 1.02-19.52]) and lapatinib (intrauterine growth restriction: ROR, 7.68 [95% CI, 3.01-19.59]).
CONCLUSIONS AND RELEVANCE
In this case-control study of 328 individuals exposed to anti-ERBB2 agents during pregnancy, exposure was associated with a severe specific adverse pregnancy and fetal or newborn outcomes compared with exposure to other anticancer treatments.
Topics: Infant, Newborn; Female; Pregnancy; Humans; Adult; Lapatinib; Case-Control Studies; Trastuzumab; Ado-Trastuzumab Emtansine; Breast Neoplasms; Antineoplastic Agents; Receptor, ErbB-2
PubMed: 37883083
DOI: 10.1001/jamanetworkopen.2023.39934 -
Clinical Breast Cancer Oct 2023Human epidermal growth factor receptor 2-positive breast cancer (HER2+ BC) is an aggressive tumor type, accounting for 15% to 20% of the approximately 300,000 new BC... (Review)
Review
Human epidermal growth factor receptor 2-positive breast cancer (HER2+ BC) is an aggressive tumor type, accounting for 15% to 20% of the approximately 300,000 new BC cases in the United States each year. The goal of this review is to discuss the evolving landscape of therapies for HER2+ metastatic BC (mBC). Targeted therapies that have been the standard of care (SOC) for HER2+ mBC for almost a decade have greatly improved patient outcomes. The SOC for the first-line treatment of HER2+ mBC continues to be HER2-targeted monoclonal antibodies (mAbs) + a taxane, but recent updates in the second-line setting favor use of a newer HER2-targeted antibody-drug conjugate (ADC), trastuzumab deruxtecan, versus the prior SOC ADC, trastuzumab emtansine. Numerous options are now available in the third line and beyond, including tyrosine kinase inhibitor (TKI) regimens, newer mAbs, and other ADCs. The optimal course of treatment for individual patients can be guided by location of metastases, prior therapies, concomitant biomarkers, and monitoring and management of adverse events. Ongoing trials will further the evolution of the HER2+ mBC treatment landscape. Furthermore, next-generation ADCs, TKIs, and classes of drugs that have not been approved for the treatment of HER2+ mBC, including immune checkpoint inhibitors and cyclin-dependent kinase 4 and 6 inhibitors, are also being evaluated for their efficacy in the first and second line. Although the influx of new drugs may complicate treatment decisions for physicians, having a multitude of options will undoubtedly further improve patient outcomes and patient-centered care.
Topics: Humans; Female; Breast Neoplasms; Antineoplastic Agents; Receptor, ErbB-2; Antibodies, Monoclonal, Humanized; Trastuzumab; Ado-Trastuzumab Emtansine
PubMed: 37407378
DOI: 10.1016/j.clbc.2023.05.003 -
Radiotherapy and Oncology : Journal of... Sep 2023In recent years, the treatment landscape for breast cancer has undergone significant advancements, with the introduction of several new anticancer agents. One such agent... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND PURPOSE
In recent years, the treatment landscape for breast cancer has undergone significant advancements, with the introduction of several new anticancer agents. One such agent is trastuzumab emtansine (T-DM1), an antibody drug conjugate that has shown improved outcomes in both early and advanced breast cancer. However, there is currently a lack of comprehensive evidence regarding the safety profile of combining T-DM1 with radiation therapy (RT). In this study, we aim to provide a summary of the available data on the safety of combining RT with T-DM1 in both early and metastatic breast cancer settings.
MATERIALS AND METHODS
This systematic review and meta-analysis project is part of the consensus recommendations by the European Society for Radiotherapy and Oncology (ESTRO) Guidelines Committee on integrating RT with targeted treatments for breast cancer. A thorough literature search was conducted using the PUBMED/MedLine, Embase, and Cochrane databases to identify original studies focusing on the safety profile of combining T-DM1 with RT.
RESULTS
After applying eligibility criteria, nine articles were included in the meta-analysis. Pooled data from these studies revealed a high incidence of grade 3 + radionecrosis (17%), while the rates of grade 3 + radiation-related pneumonitis (<1%) and skin toxicity (1%) were found to be very low.
CONCLUSION
Although there is some concern regarding a slight increase in pneumonitis when combining T-DM1 with postoperative RT, the safety profile of this combination was deemed acceptable for locoregional treatment in non-metastatic breast cancer. However, caution is advised when irradiating intracranial sites concurrently with T-DM1. There is a pressing need for international consensus guidelines regarding the safety considerations of combining T-DM1 and RT for breast cancer.
Topics: Humans; Female; Ado-Trastuzumab Emtansine; Trastuzumab; Receptor, ErbB-2; Antibodies, Monoclonal, Humanized; Maytansine; Treatment Outcome; Breast Neoplasms
PubMed: 37437610
DOI: 10.1016/j.radonc.2023.109805 -
Journal of the National Cancer Institute Mar 2023In advanced HER2-positive (HER2+) breast cancer, the new antibody-drug conjugate trastuzumab deruxtecan is more effective compared with trastuzumab emtansine (T-DM1)....
In advanced HER2-positive (HER2+) breast cancer, the new antibody-drug conjugate trastuzumab deruxtecan is more effective compared with trastuzumab emtansine (T-DM1). However, trastuzumab deruxtecan can have considerable toxicities, and the right treatment sequence is unknown. Biomarkers to guide the use of anti-HER2 therapies beyond HER2 status are needed. Here, we evaluated if preestablished levels of ERBB2 mRNA expression according to the HER2DX standardized assay are associated with response and survival following T-DM1. In ERBB2 low, medium, and high groups, the overall response rate was 0%, 29%, and 56%, respectively (P < .001). ERBB2 mRNA was statistically significantly associated with better progression-free survival (P = .002) and overall survival (OS; P = .02). These findings were independent of HER2 immunohistochemistry (IHC) levels, hormone receptor, age, brain metastasis, and line of therapy. The HER2DX risk score (P = .04) and immunoglobulin signature (P = .04) were statistically significantly associated with overall survival since diagnosis. HER2DX provides prognostic and predictive information following T-DM1 in advanced HER2+ breast cancer.
Topics: Humans; Female; Ado-Trastuzumab Emtansine; Breast Neoplasms; Maytansine; Antibodies, Monoclonal, Humanized; Trastuzumab; Receptor, ErbB-2; RNA, Messenger
PubMed: 36576009
DOI: 10.1093/jnci/djac227