-
World Journal of Clinical Oncology Aug 2014Although more widespread screening and routine adjuvant therapy has improved the outcome for breast cancer patients in recent years, there remains considerable scope for... (Review)
Review
Although more widespread screening and routine adjuvant therapy has improved the outcome for breast cancer patients in recent years, there remains considerable scope for improving the efficacy, safety and tolerability of adjuvant therapy in the early stage disease and the treatment of advanced disease. Toremifene is a selective estrogen receptor modifier (SERM) that has been widely used for decades in hormone receptor positive breast cancer both in early and late stage disease. Its efficacy has been well established in nine prospective randomized phase III trials compared to tamoxifen involving more than 5500 patients, as well as in several large uncontrolled and non-randomized studies. Although most studies show therapeutic equivalence between the two SERMs, some show an advantage for toremifene. Several meta-analyses have also confirmed that the efficacy of toremifene is at least as good as that of tamoxifen. In terms of safety and tolerability toremifene is broadly similar to tamoxifen although there is some evidence that toremifene is less likely to cause uterine neoplasms, serious vascular events and it has a more positive effect on serum lipids than does tamoxifen. Toremifene is therefore effective and safe in the treatment of breast cancer. It provides not only a useful therapeutic alternative to tamoxifen, but may bring specific benefits.
PubMed: 25114854
DOI: 10.5306/wjco.v5.i3.393 -
International Journal of Molecular... Jun 2020Breast cancer (BCa) is one of the most predominantly diagnosed cancers in women. Notably, 70% of BCa diagnoses are Estrogen Receptor α positive (ERα+) making it a... (Review)
Review
Breast cancer (BCa) is one of the most predominantly diagnosed cancers in women. Notably, 70% of BCa diagnoses are Estrogen Receptor α positive (ERα+) making it a critical therapeutic target. With that, the two subtypes of ER, ERα and ERβ, have contrasting effects on BCa cells. While ERα promotes cancerous activities, ERβ isoform exhibits inhibitory effects on the same. ER-directed small molecule drug discovery for BCa has provided the FDA approved drugs tamoxifen, toremifene, raloxifene and fulvestrant that all bind to the estrogen binding site of the receptor. These ER-directed inhibitors are non-selective in nature and may eventually induce resistance in BCa cells as well as increase the risk of endometrial cancer development. Thus, there is an urgent need to develop novel drugs with alternative ERα targeting mechanisms that can overcome the limitations of conventional anti-ERα therapies. Several functional sites on ERα, such as Activation Function-2 (AF2), DNA binding domain (DBD), and F-domain, have been recently considered as potential targets in the context of drug research and discovery. In this review, we summarize methods of computer-aided drug design (CADD) that have been employed to analyze and explore potential targetable sites on ERα, discuss recent advancement of ERα inhibitor development, and highlight the potential opportunities and challenges of future ERα-directed drug discovery.
Topics: Binding Sites; Breast Neoplasms; Computer Simulation; Computer-Aided Design; Drug Resistance; Estrogen Receptor alpha; Female; Humans; Ligands; Small Molecule Libraries
PubMed: 32545494
DOI: 10.3390/ijms21124193 -
Frontiers in Endocrinology 2023Despite the promising efficacy of the novel antibody-drug conjugate trastuzumab deruxtecan in treating Hormone Receptor (HoR)-positive/Human Epidermal Growth Factor...
OBJECTIVE
Despite the promising efficacy of the novel antibody-drug conjugate trastuzumab deruxtecan in treating Hormone Receptor (HoR)-positive/Human Epidermal Growth Factor Receptor 2 (HER2)-low metastatic breast cancer (MBC), its categorization as a distinct entity remains disputed, as does the divergence in its endocrine and chemotherapy outcomes. This study aimed to elucidate the clinical characteristics, primary/metastatic lesion HER2 expression, and treatment outcomes of HoR-positive/HER2-low patients.
METHODS
We included HoR-positive/HER2-negative MBC patients who underwent 1 and 2 line endocrine treatment from July 2010 to October 2022 at the Fudan University Shanghai Cancer Center, comparing the clinical pathological characteristics, HER2 expression in primary/metastatic lesions, treatment, and therapeutic effects of the HER2-low and HER2-zero groups.
RESULTS
Among the 458 HoR-positive/HER2-negative MBC patients, 54.37% (249/458) were HER2-low. The HER2-low group and the HER2-zero group had similar clinical pathological characteristics and similar progression-free survival (PFS) of 1 and 2 line endocrine treatment (median PFS: 8.05 months vs 10.12 months, p=0.114, HR 1.257, 95% CI 0.771 to 1.028). The PFS of the HER2-low and HER2-zero groups was also similar, treated with different endocrine drugs (including aromatase inhibitors, tamoxifen/toremifene, fulvestrant, palbociclib, and everolimus). However, the HER2-low group had significantly shorter PFS during 1 and 2 line chemotherapy compared to the HER2-zero group (median PFS: 8.64 vs 9.03 months, p=0.027, HR 0.841, 95% CI 0.721-0.980). Additionally, 41.18% (63/153) of patients exhibited a change in HER2 expression between primary and metastatic lesions. Notably, patients whose HER2 status changed from zero to low expression had significantly prolonged PFS during chemotherapy compared to those who maintained low HER2 expression (median PFS: 14.29 vs 11.27 months, p=0.048, HR 0.597, 95% CI 0.358-0.996).
CONCLUSION
In HoR-positive MBC, patients with low and zero HER2 expression have similar clinical characteristics and respond similarly to endocrine treatment, but the chemotherapy effect is worse in the HER2-low patients. Moreover, the transformation of HER2 status from primary to metastatic lesions may have potential influence on chemotherapy outcomes. Therefore, the expression and heterogeneity of HER2 should be considered in clinical decisions.
Topics: Humans; Female; Breast Neoplasms; Antineoplastic Combined Chemotherapy Protocols; China; Treatment Outcome; Progression-Free Survival
PubMed: 37881502
DOI: 10.3389/fendo.2023.1270453 -
MBio Dec 2018The concept of repurposing previously approved medications to the treatment of new indications by taking advantage of off-target effects has gained traction in recent... (Review)
Review
The concept of repurposing previously approved medications to the treatment of new indications by taking advantage of off-target effects has gained traction in recent years, particularly in areas of medicine that do not offer large profits to pharmaceutical firms. As infectious disease discovery research has declined among large pharmaceutical companies, the potential payoff of repurposing has become attractive. From these efforts, the triphenylethylene class of selective estrogen receptor modulators related to tamoxifen has shown activity against a wide range of medically important human pathogens, including bacteria, fungi, parasites, and viruses. Because it has activity against many pathogens affecting people in resource-limited areas of the world, TAM and related drugs may be particularly useful. Here, we review the , , and mechanistic studies of the anti-infective activity of tamoxifen, toremifene, clomiphene, and their analogs. We also discuss the pharmacologic properties of this privileged scaffold and its potential utility in treating infectious diseases.
Topics: Animals; Bacteria; Communicable Diseases; Drug Repositioning; Estrogen Receptor Antagonists; Female; Humans; Mice; Parasites; Stilbenes; Tamoxifen; Toremifene; Viruses
PubMed: 30563895
DOI: 10.1128/mBio.02272-18 -
Nature Jul 2016Ebola viruses (EBOVs) are responsible for repeated outbreaks of fatal infections, including the recent deadly epidemic in West Africa. There are currently no approved...
Ebola viruses (EBOVs) are responsible for repeated outbreaks of fatal infections, including the recent deadly epidemic in West Africa. There are currently no approved therapeutic drugs or vaccines for the disease. EBOV has a membrane envelope decorated by trimers of a glycoprotein (GP, cleaved by furin to form GP1 and GP2 subunits), which is solely responsible for host cell attachment, endosomal entry and membrane fusion. GP is thus a primary target for the development of antiviral drugs. Here we report the first, to our knowledge, unliganded structure of EBOV GP, and high-resolution complexes of GP with the anticancer drug toremifene and the painkiller ibuprofen. The high-resolution apo structure gives a more complete and accurate picture of the molecule, and allows conformational changes introduced by antibody and receptor binding to be deciphered. Unexpectedly, both toremifene and ibuprofen bind in a cavity between the attachment (GP1) and fusion (GP2) subunits at the entrance to a large tunnel that links with equivalent tunnels from the other monomers of the trimer at the three-fold axis. Protein–drug interactions with both GP1 and GP2 are predominately hydrophobic. Residues lining the binding site are highly conserved among filoviruses except Marburg virus (MARV), suggesting that MARV may not bind these drugs. Thermal shift assays show up to a 14 °C decrease in the protein melting temperature after toremifene binding, while ibuprofen has only a marginal effect and is a less potent inhibitor. These results suggest that inhibitor binding destabilizes GP and triggers premature release of GP2, thereby preventing fusion between the viral and endosome membranes. Thus, these complex structures reveal the mechanism of inhibition and may guide the development of more powerful anti-EBOV drugs.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Antiviral Agents; Binding Sites; Cell Line; Conserved Sequence; Ebolavirus; Endosomes; Humans; Hydrophobic and Hydrophilic Interactions; Ibuprofen; Ligands; Marburgvirus; Membrane Fusion; Models, Molecular; Protein Binding; Protein Stability; Protein Structure, Quaternary; Protein Subunits; Temperature; Toremifene; Viral Envelope Proteins; Virus Attachment
PubMed: 27362232
DOI: 10.1038/nature18615 -
Journal of the Advanced Practitioner in... Mar 2017DE, a 31-year-old premenopausal woman with a nonsignificant medical history, noticed a right breast mass after playing basketball in September 2011. She initially... (Review)
Review
DE, a 31-year-old premenopausal woman with a nonsignificant medical history, noticed a right breast mass after playing basketball in September 2011. She initially attributed the mass to slight trauma, but after 2 weeks, she realized the mass was increasing in size. Her primary care physician ordered a bilateral screening mammogram and ultrasound. Mammography revealed no evidence of malignancy in the left breast. In the right breast, at the 7 o'clock position, a loose cluster of faint calcifications spanned a 2.2-cm area. Ultrasound confirmed an irregular hypoechoic mass in the right breast measuring 3.5 × 2.7 × 2.8 cm. Ultrasound of the right axilla identified two enlarged right axillary lymph nodes. Ultrasound core-needle biopsy of the suspicious right breast mass confirmed invasive ductal carcinoma, nuclear grade 2, Ki67 index of 55%, estrogen receptor-positive (H score of 180), progesterone receptor-positive (H score of 135), HER2-positive (3+ on immunohistochemistry). Utilizing the TNM (tumor, node, metastasis) staging system, she was clinically staged with a stage IIB (cT2, cN1, M0) invasive breast tumor. The computerized axial tomography (CT) scan of the chest, abdomen, and pelvis demonstrated the known right breast mass and two enlarged right axillary lymph nodes; however, no metastatic disease was noted. Nuclear bone scan revealed no bone metastases. Her medical oncologist recommended she receive neoadjuvant chemotherapy. The patient was treated with 6 cycles of neoadjuvant docetaxel at 75 mg/m², carboplatin at an AUC (area under the curve) of 6, and trastuzumab (Herceptin) at 6 mg/kg (TCH), which she tolerated well. She then underwent a right segmental mastectomy with axillary lymph node dissection and was found to have a residual 1.0-cm invasive ductal carcinoma, representing a 60% tumor volume reduction. None of 13 axillary lymph nodes were positive for disease. Pathologic staging confirmed a stage IA (ypT1, ypN0, M0) tumor. DE completed 33 fractions of radiation therapy to the right breast. She initiated endocrine therapy with tamoxifen at 20 mg daily and received 1 year of maintenance trastuzumab (6 mg/kg). Due to vaginal discharge and weight gain, endocrine therapy was switched from tamoxifen to toremifene (Fareston), which she tolerated relatively well. She continued routine follow-up, with no evidence of disease. In September 2014, DE presented to her primary care physician complaining of left hip pain. Magnetic resonance imaging (MRI) of the left hip revealed T2 hyperintense masses within the right anterior superior iliac crest, right sacrum, and left iliac body consistent with skeletal metastases. She was referred back to her medical oncologist, and per National Comprehensive Cancer Network (NCCN) guidelines, a biopsy of the suspicious lesion was obtained. The bone biopsy of the lytic lesion was consistent with metastatic breast cancer, which was estrogen receptor-positive, progesterone receptor-positive, and HER2-positive (3+ on immunohistochemistry). Restaging CT scan of the chest, abdomen, and pelvis revealed new 4- to 6-mm pulmonary nodules, hilar and mediastinal lymphadenopathy, new liver lesions, and bone lesions. Nuclear bone scan confirmed multiple bone metastases of the right and left iliac bones and sternum. Complete blood cell count with differential and complete metabolic panel were within normal ranges. The CA 27-29 tumor marker for breast cancer was elevated at 495 U/mL (normal range, < 37 U/mL). DE was understandably devastated by the new diagnosis. She questioned how the treatment plan was to be established. Her medical oncologist struck a somewhat optimistic tone. He explained that metastatic breast cancer was not yet considered to be curable, but periods of disease stability and chronicity were possible. He explained that the HER2 positivity was perhaps the most important factor in delineating her treatment options. He told her that current treatment options were numerous and increasing in number.
PubMed: 29900024
DOI: No ID Found -
Cell Discovery 2020Human coronaviruses (HCoVs), including severe acute respiratory syndrome coronavirus (SARS-CoV) and 2019 novel coronavirus (2019-nCoV, also known as SARS-CoV-2), lead...
Human coronaviruses (HCoVs), including severe acute respiratory syndrome coronavirus (SARS-CoV) and 2019 novel coronavirus (2019-nCoV, also known as SARS-CoV-2), lead global epidemics with high morbidity and mortality. However, there are currently no effective drugs targeting 2019-nCoV/SARS-CoV-2. Drug repurposing, representing as an effective drug discovery strategy from existing drugs, could shorten the time and reduce the cost compared to de novo drug discovery. In this study, we present an integrative, antiviral drug repurposing methodology implementing a systems pharmacology-based network medicine platform, quantifying the interplay between the HCoV-host interactome and drug targets in the human protein-protein interaction network. Phylogenetic analyses of 15 HCoV whole genomes reveal that 2019-nCoV/SARS-CoV-2 shares the highest nucleotide sequence identity with SARS-CoV (79.7%). Specifically, the envelope and nucleocapsid proteins of 2019-nCoV/SARS-CoV-2 are two evolutionarily conserved regions, having the sequence identities of 96% and 89.6%, respectively, compared to SARS-CoV. Using network proximity analyses of drug targets and HCoV-host interactions in the human interactome, we prioritize 16 potential anti-HCoV repurposable drugs (e.g., melatonin, mercaptopurine, and sirolimus) that are further validated by enrichment analyses of drug-gene signatures and HCoV-induced transcriptomics data in human cell lines. We further identify three potential drug combinations (e.g., sirolimus plus dactinomycin, mercaptopurine plus melatonin, and toremifene plus emodin) captured by the "" pattern: the targets of the drugs both hit the HCoV-host subnetwork, but target separate neighborhoods in the human interactome network. In summary, this study offers powerful network-based methodologies for rapid identification of candidate repurposable drugs and potential drug combinations targeting 2019-nCoV/SARS-CoV-2.
PubMed: 32194980
DOI: 10.1038/s41421-020-0153-3 -
Breast Cancer (Tokyo, Japan) Jan 2018In patients with hormone receptor-positive postmenopausal of early stage breast cancer, adjuvant endocrine monotherapies include letrozole, anastrozole, exemestane,... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
In patients with hormone receptor-positive postmenopausal of early stage breast cancer, adjuvant endocrine monotherapies include letrozole, anastrozole, exemestane, toremifene and tamoxifen. But the optimum regimen remains controversial.
METHODS
PubMed, Cochrane Database and ClinicalTrials.gov were systematically reviewed of abstract for randomized-controlled trials (RCTs) to assess the efficacy of tamoxifen, letrozole, exemestane, anastrozle and toremifene for postmenopausal patients with hormone-receptor positive (HR+), who have not received prior therapy for early stage breast cancer. The outcomes were measured by disease-free survival (DFS) and overall survival (OS). We evaluated relative hazard ratios (HRs) for death of different therapies by combination hazard ratios for death of included trials. The SUCRA values were used to evaluate the rankings of efficacy for these monotherapies.
RESULTS
A total of fourteen studies including 19,517 patients in our research were absorbed and estimated. The superiority of efficacy for DFS were 5-year letrozole and 10-year tamoxifen (SUCRA values 0.743/0.657) in all comparisons. A more efficient SUCRA values for OS were 5-year Exemestane, 5-year letrozole and 10-year tamoxifen (0.756/0.677/0.669).
CONCLUSIONS
Clinically important differences exist between commonly prescribed different adjuvant endocrine monotherapy regimens for both efficacy and acceptability in favor of exemestane and letrozole. 10-year tamoxifen for early breast cancer patients is noninferior to 5-year anastrozle, and might be the best choice where aromatase inhibitors (AIs) are not easy to acquire.
Topics: Aromatase Inhibitors; Breast Neoplasms; Chemotherapy, Adjuvant; Female; Humans; Network Meta-Analysis; Postmenopause; Prognosis; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone
PubMed: 28755088
DOI: 10.1007/s12282-017-0794-8