Breast Cancer Therapeutics Research Articles

Abstract P4-07-04: STX-478, a mutant-selective PI3Kα H1047X inhibitor clinical candidate with a best-in-class profile: Pharmacology and therapeutic activity as monotherapy and in combination in breast cancer xenograft models

Abstract PI3Kα is highly mutated in cancer resulting in hyperactivation of lipid kinase activity and downstream AKT signaling. H1047 is the most common site of oncogenic mutation and occurs in ~14% of all breast cancers. Initial therapeutic benefit of targeting PI3Kα was established with alpelisib, an alpha-selective PI3K inhibitor that is equipotent against wild-type and mutant forms. However, wild-type PI3Kα inhibition results in frequent dose-limiting toxicities including hyperglycemia, restricting the full potential of this drug. Selective targeting of H1047X-mutant PI3Kα is expected to both improve anti-tumor activity and reduce toxicity. STX-478 is an allosteric, CNS-penetrant, selective PI3Kα H1047X inhibitor, having excellent drug-like properties and exceptional kinome selectivity. STX-478 demonstrated minimal inhibition of CYP enzymes in vitro, supporting the potential for combinations with a wide range of therapeutics in breast cancer and a variety of other tumor types. STX-478 selectivity extended to the inhibition of other activating kinase domain mutations in biochemical assays. In a diverse panel of PI3Kα H1047X mutant cell lines, STX-478 selectively reduced the cellular levels of pAKT (S473) with a strong correlation between pAKT inhibition and cell viability (R = 0.8). In a high-throughput viability screen of 467 cancer cell lines, the presence of PIK3CA H1047X and other kinase domain mutations were the single strongest predictor of STX-478 sensitivity with potency superior to alpelisib. STX-478 also selectively inhibited the proliferation of cell lines with PI3Kα helical domain mutations, potentially due to the selective dependency of these cells on mutant PI3Kα. When combined with fulvestrant, lapatinib, or abemaciclib, STX-478 demonstrated synergistic anti-proliferative activity in cell lines with relevant ER/HER2 status. Unlike alpelisib, STX-478 did not impair glucose metabolism or cause insulin resistance at efficacious doses. In the T47D (PI3Kα H1047R) breast cancer model, STX-478 (100 mg/kg) monotherapy caused tumor regression whereas alpelisib caused only stasis. STX-478 combination with fulvestrant was well-tolerated, with more consistent and deeper tumor regression. Similar results were observed in a PI3Kα H1047R mutant ER+/HER2- PDX model, where fulvestrant monotherapy showed minimal activity, while combination with STX-478 yielded tumor regressions. In an ER+/HER2+ PDX model (PI3Kα H1047R/R108H), palbociclib and STX-478 (100 mg/kg) monotherapy resulted in similar efficacy while the combination was well tolerated and yielded tumor regression. Together these data indicate robust STX-478 monotherapy activity that was well tolerated and improved when dosed in combination with fulvestrant or CDK4/6 inhibitors. Finally, we investigated the effect of STX-478 treatment in an ER+ PDX model carrying a helical domain mutation. STX-478 treatment resulted in tumor growth inhibition at doses that did not result in metabolic dysfunction, suggesting that STX-478 may also be efficacious in treating PIK3CA mutant tumors with helical domain mutations. In summary, STX-478 efficacy was superior to alpelisib at a dose level that exceeds the clinically relevant exposure in mice without causing metabolic dysfunction. STX- 478 has a predicted low human dose, CNS exposure, low risk of DDI, and a predicted long half-life with minimal variation in peak-to-trough plasma concentrations which further supports a favorable therapeutic index. STX-478 has the potential to provide a best-in-class profile to improve outcomes in patients harboring tumors with prevalent PI3Kα H1047X mutations as well as other kinase and helical domain mutant tumors. The significant CNS exposure of STX-478 is expected to enable this treatment for patients with brain tumors and brain metastases not afforded by existing options. STX-478 is currently in IND enabling studies and is expected to enter human clinical trials in 2023. Citation Format: Leonard Buckbinder, David J. St. Jean, Brendon Ladd, Trang Tieu, Philip Jonsson, Jacob Alltucker, Samantha Manimala, Weixue Wang, Angel Guzman-Perez, Darrin D. Stuart, Gregory Dowdell. STX-478, a mutant-selective PI3Kα H1047X inhibitor clinical candidate with a best-in-class profile: Pharmacology and therapeutic activity as monotherapy and in combination in breast cancer xenograft models [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-04.

Abstract P4-08-10: Azeliragon (TTP488), an orally- available small molecule RAGE inhibitor, reduces metastasis in preclinical mouse models of breast cancer

Abstract Background: Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype with a high metastatic rate. Despite significant advances in breast cancer therapeutics, due to the lack of specific therapeutic targets in TNBC, cytotoxic chemotherapy is still the mainstay of treatment for this BC subtype. Preclinical studies have shown that the Receptor for Advanced Glycation End-products (RAGE) drives the progression and metastasis of aggressive cancer subtypes, including TNBC. RAGE plays a multifaceted role in driving tumorigenesis and metastasis through tumor cell-intrinsic mechanisms, such as cancer cell invasion, migration and epithelial-mesenchymal transition, and tumor cell-extrinsic mechanisms. This multifaceted role in cancer progression and metastasis makes RAGE a promising therapeutic target in the prevention and treatment of breast cancer. Here we tested the preclinical anti-metastasic efficacy of two small molecule RAGE inhibitors; TTP48 (Azeliragon) and FPS-ZM1. Importantly, TTP488 displays a high safety profile in human trials and has previously undergone Phase 3 clinical trials for Alzheimer’s disease. While FPS-ZM1 is a well-known RAGE inhibitor in preclinical cancer models, TTP488 has not been tested for its anti-cancer activity in breast cancer. Methods: We tested the in vitro anti-metastatic effect of TTP488 and FPS-ZM1 on cancer cell migration and invasion in Boyden chamber assays with TNBC cell lines (MDA-MB-231 and 4T-1). We used the 4175 highly metastatic MDA-MB-231 variant in xenograft studies in NSG mice to test the efficacy of the RAGE inhibitors in vivo on tumor progression and metastasis. Experimental metastasis assays were performed with tail-vein injection of 4T-1 cells into BALBc mice. We performed bulk RNA sequencing on the MDA-MB-231/4175/NSG tumors to unveil and compare the mechanism of action of the two small molecule RAGE inhibitors. Results: Our results showed that TTP488 and FPS-ZM1 impaired mechanisms of metastasis in vitro with both MDA-MB231/4175 and 4T-1 cells. TTP488 and FPS-ZM1 significantly inhibited MDA-MB231/4175 cell metastasis from the orthotopic site in NSG mice without displaying any deleterious effects on mouse health. In the syngeneic 4T-1/BALBc model, both TTP488 and FPS-ZM1 impaired metastasis in tail-vein injected experimental metastasis assays. Transcriptomic analysis of primary xenograft tumors from NSG mice revealed that TTP488 and FPS-ZM1 displayed high concordance in gene expression changes. Pathway enrichment analysis showed that both RAGE inhibitors affected metastatic pathways, including focal adhesion, ECM-receptor interaction, cell cycle, and DNA replication. Conclusions: These results show that TTP488 impairs metastasis of multiple highly aggressive TNBC models for the first time. Importantly, as TTP488 displays a high safety profile in human trials, this study provides the rationale for evaluating TTP488 in clinical trials to treat or prevent metastatic breast cancer. Citation Format: Melinda Magna, Gyong Ha Hwang, Alec McIntosh, Katherine Drews-Elger, Masaru Takabatake, Barbara Mera, Taekyoung Kwak, Philip Miller, Marc Lippman, Barry I. Hudson. Azeliragon (TTP488), an orally- available small molecule RAGE inhibitor, reduces metastasis in preclinical mouse models of breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-08-10.

Novel Synergistic Combination of Pamidronate and Temozolomide for Breast Cancer Therapeutics.

Human breast cancer is among one major health concerns with high prevalence and mortality among women worldwide. Various cellular signaling pathways are implicated in carcinogenesis. One of the major pathways that affect the downstream cellular growth cascades is Mevalonate pathway (MVA). The inhibition of MVA is therapeutically beneficial for various cancers. Pamidronate (PAM) (MVA inhibitor), a nitrogen-containing bisphosphosphonate, is an antiresorptive FDAapproved drug. The objective of our study was to explore adjuvant therapy using a combination of PAM and an alkylating agent, Temozolomide (TMZ) against breast cancer. We have examined the differential gene and protein expression in response to the combination treatment strategy. For gene expression analysis RT-qPCR and for proteomic study, twodimensional gel electrophoresis and mass spectrometry techniques were utilized. Combination treatment (PAM+TMZ) showed more pronounced cytotoxic effect as compared to single agent treatment. Our results indicate that MVA pathway regulatory genes (FDFT1, FDPS, KRAS) are significantly (p<0.05) downregulated in combination-treated breast cancer cells. The differential proteomic analysis showed lower expression of GFAP, PPA1 and TRIM68 proteins after synergistic treatment whereas, these proteins are found to be up-regulated in multiple cancers. The present study reveals that a combination of PAM and TMZ produces an effective anti-cancerous effect on breast cancer cells. Therefore, this novel therapeutic regimen is likely to provide a better treatment strategy for breast cancer.

MIR497HG-Derived miR-195 and miR-497 Mediate Tamoxifen Resistance via PI3K/AKT Signaling in Breast Cancer.

Tamoxifen is commonly used for the treatment of patients with estrogen receptor-positive (ER+) breast cancer, but the acquired resistance to tamoxifen presents a critical challenge of breast cancer therapeutics. Recently, long noncoding RNA MIR497HG and its embedded miR-497 and miR-195 are proved to play significant roles in many types of human cancers, but their roles in tamoxifen-resistant breast cancer remain unknown. The results indicate that MIR497HG deficiency induces breast cancer progression and tamoxifen resistance by inducing downregulation of miR-497/195. miR-497/195 coordinately represses five positive PI3K-AKT regulators (MAP2K1, AKT3, BCL2, RAF1, and CCND1), resulting in inhibition of PI3K-AKT signaling, and PI3K-AKT inhibition in tamoxifen-resistant cells restored tamoxifen responsiveness. Furthermore, ER α binds the MIR497HG promoter to activate its transcription in an estrogen-dependent manner. ZEB1 interacts with HDAC1/2 and DNMT3B at the MIR497HG promoter, resulting in promoter hypermethylation and histone deacetylation. The findings reveal that ZEB1-induced MIR497HG depletion contributes to breast cancer progression and tamoxifen resistance through PI3K-AKT signaling. MIR497HG can be used as a biomarker for predicting tamoxifen sensitivity in patients with ER+ breast cancer.

Triazole‐tethered boswellic acid derivatives against breast cancer: Synthesis, in vitro, and in‐silico studies

A series of new analogues of 3-O-acetyl-11-keto-β-boswellic acid (β-AKBA, 1), 3-O-acetyl-β-boswellic acid (β-ABA, 2) (3–8) and 1H-1,2,3-triazole hybrids of β-AKBA (10a-j) were synthesized by employing highly efficient “Click” chemistry reaction protocol. All synthesized compounds were characterized by 1H-, 13C NMR, and HRMS spectroscopy. The structures of compounds 5 and 6 were unambiguously confirmed by the single crystal X-ray analysis diffraction method. The cytotoxic potential of the synthesized compounds was scrutinized against the triple-negative breast cancer (MDA-MB-231) and normal (MCF-10A) cell lines. Furthermore, all the synthesized derivatives exhibited highly potent anti-proliferative activity with IC50 values ranging from 4.45 to 14.45 µM. Among them, compounds 10j, 10f, and 10i exhibited exceptional inhibitory potency and were found several times more potent than the parent compounds 1 and 2. Additionally, the cheminformatics method was used to identify the potential drug target of the most potent compounds (10j, 10f, and 10i) and their binding mechanism with the selected drug target was predicted through molecular docking. The combined 2D-similarity searching, and structure-based binding investigation predict that these compounds can target CHK1 to produce anti-cancer effects in TNBC. This study lays a good foundation for new triterpenic triazole analogues of boswellic acids and could be effective anticancer leads in breast cancer therapeutics.

Integrative competing endogenous RNA network analyses identify novel lncRNA and genes implicated in metastatic breast cancer

Competing endogenous RNAs (ceRNAs) have gained attention in cancer research owing to their involvement in microRNA-mediated gene regulation. Previous studies have identified ceRNA networks of individual cancers. Nevertheless, none of these studies has investigated different cancer stages. We identify stage-specific ceRNAs in breast cancer using the cancer genome atlas data. Moreover, we investigate the molecular functions and prognostic ability of ceRNAs involved in stage I–IV networks. We identified differentially expressed candidate ceRNAs using edgeR and limma R packages. A three-step analysis was used to identify statistically significant ceRNAs of each stage. Survival analysis and functional enrichment analysis were conducted to identify molecular functions and prognostic ability. We found five genes and one long non-coding RNA unique to the stage IV ceRNA network. These genes have been described in previous breast cancer studies. Genes acted as ceRNAs are enriched in cancer-associated pathways. Two, three, and three microRNAs from stages I, II, and III were prognostic from the Kaplan–Meier survival analysis. Our results reveal a set of unique ceRNAs in metastatic breast cancer. Further experimental work is required to evaluate their role in metastasis. Moreover, identifying stage-specific ceRNAs will improve the understanding of personalised therapeutics in breast cancer.

Liver X Receptor Inverse Agonist GAC0001E5 Impedes Glutaminolysis and Disrupts Redox Homeostasis in Breast Cancer Cells.

Liver X receptors (LXRs) are members of the nuclear receptor family of ligand-dependent transcription factors which regulate the expression of lipid and cholesterol metabolism genes. Moreover, LXRs and their ligands have been shown to inhibit tumor growth in a variety of cancers. We have previously identified the small molecule compound GAC0001E5 (1E5) as an LXR inverse agonist and a potent inhibitor of pancreatic cancer cells. Transcriptomic and metabolomic studies showed that 1E5 disrupts glutamine metabolism, an essential metabolic pathway commonly reprogrammed during malignant transformation, including in breast cancers. To determine the role of LXRs and potential application of 1E5 in breast cancer, we examined LXR expression in publicly available clinical samples, and found that LXR expression is elevated in breast tumors as compared to normal tissues. In luminal A, endocrine therapy-resistant, and triple-negative breast cancer cells, 1E5 exhibited LXR inverse agonist and "degrader" activity and strongly inhibited cell proliferation and colony formation. Treatments with 1E5 downregulated the transcription of key glutaminolysis genes, and, correspondingly, biochemical assays indicated that 1E5 lowered intracellular glutamate and glutathione levels and increased reactive oxygen species. These results indicate that novel LXR ligand 1E5 is an inhibitor of glutamine metabolism and redox homeostasis in breast cancers and suggest that modulating LXR activity and expression in tumor cells is a promising strategy for targeting metabolic reprogramming in breast cancer therapeutics.

MiRNA let-7a inhibits invasion, migration, anchorage-independent growth by suppressing EZH2 and promotes mesenchymal to epithelial transition in MDAMB-231

Enhancer of zeste homolog 2 (EZH2) is a transcriptional repressor belonging to the polycomb group protein family (PRC) and is frequently linked with aggressive breast cancer. Micro RNAs (miRNAs) are single-stranded 19–25 nucleotide long RNAs that control gene expression at the post-transcriptional level. Previous reports indicated that epigenetic modulation through EZH2-mediated histone methylation can silence the miR-200 cluster. Therefore, we attempted to identify the miRNAs that regulate the expression of EZH2 in metastatic breast cancer. Our results with microarray studies showed that upon knock-down of EZH2 lead to enhanced expression of tumor-suppressive miRNAs including miR-203, miR-200a, miR-200b, and let-7a in MDAMB-231, a metastatic breast cancer cell line. Further studies to confirm the expression of EZH2 upon overexpression of the mentioned miRNAs showed that only let-7a could post-transcriptionally regulate EZH2 expression significantly. Luciferase-based 3′UTR (untranslated region) reporter assay of EZH2 confirmed a significant reduction in the reporter activity upon co-transfection of let-7a and reporter construct 3′UTR of EZH2. Interestingly, overexpression of let-7a leads to decreased expression of another PRC2 group of protein SUZ12 and produced a lowered expression of H3K27me3 methylation. Additionally, let-7a miRNA promoted mesenchymal to epithelial transition i.e., by downregulating the key metastatic markers including Vimentin, Zeb, N-cadherin, and Snail, thus leading to reduced migration and invasion ability in MDA-MB-231 cells. This data poses an impact on understanding and developing therapeutics for breast cancer.

Docking and Molecular Dynamics Simulation Revealed the Potential Inhibitory Activity of Amygdalin in Triple-Negative Breast Cancer Therapeutics Targeting the BRCT Domain of BARD1 Receptor.

Triple-negative breast cancer (TNBC), is diagnosed as the most lethal molecular subtype of breast cancer (BC) preceded by an extremely poor prognosis. For enabling effective TNBC therapy, the identification of novel druggable biomarkers is an earnest need. Multigene paneling and genomewide association studies identify multiple genes with high-to-moderate penetrance in TNBC. Modern computer-aided drug designing techniques, thus aim to design more cost-effective natural small molecule inhibitors for TNBC prevention and diagnosis. Here Amygdalin, a natural glycosidic inhibitor is docked and simulated against three such high-to-moderate penetrance genes identified in TNBC, BARD1, RAD51, and PALB2. The preliminary result of the analysis, reports a highest, intermediate, and least binding energy score of -6.69kcal/mol, -5.09kcal/mol, and -4.89kcal/mol in BARD1, RAD51, and PALB2, respectively. The best-docked protein-ligand complex (BARD1-Amygdalin) was then simulated and compared with an approved drug for TNBC treatment, Olaparib. A comparable binding energy score of -8.53kcal/mol was obtained by docking olaparib with BARD1. A 100ns MD simulation revealed, Amygdalin forms more H-bonds, providing more stable and compact protein-ligand complex with BARD1 than compared to Olaparib. The result was also supported by calculation of solvent accessible surface area and analysis of radius of gyration. Thus, our findings suggest that role of Amygdalin can further be studied in details for TNBC therapeutics, which was found to target the BRCT domain of the BARD1 receptor in stable manner. Please check and confirm that the authors and their respective affiliations have been correctly identified and amend if necessary. Name and affiliations are correctly identified.

Clinicopathological characteristics and features of molecular subtypes of breast cancer at high altitudes.

Breast cancer is one of the major malignancies threatening women's health worldwide. The incidence of breast cancer at high altitudes increased over the years. But few studies focused on the characteristics of clinicopathology and molecular subtypes among breast cancer at high altitudes, which are still unknown. Tibet, with an average altitude over 4000 meters, is a representative city at high altitudes, lying in the Qinghai-Tibetan Plateau in southwestern China. This study aimed to identify the clinicopathological characteristics and features of molecular subtypes among Tibetan women with breast cancer, and provide evidence for cancer prevention and personalized therapeutics in high-altitude regions. Between May 2013 and March 2022, 104 Tibetan women from high-altitude regions (Tibetan-group) and 34 Han Chinese women from low-altitude regions (Han-group), consecutively diagnosed with breast cancer in the Hospital of Chengdu Office of People's Government of Tibetan Autonomous Region, were included in the study. We retrospectively reviewed the clinical character, altitudes of residence, tumor size, lymph nodes metastasis, distant metastasis, pathological type, immunohistochemical index, and molecular subtype. In the study, we calculated the patient delay, equal to the period from symptoms onset to hospital visits. The patient delay of Tibetan-group was 7.47 ± 11.53 months, which was significantly longer than that of Han-group, 7.22 ± 22.96 months (p<0.05). Body Mass Index (BMI) was significantly different (p<0.05). Tumors in Tibetan-group were significantly larger than those in Han-group, 4.13 ± 2.98cm and 2.51 ± 0.82cm in diameter, respectively (p<0.05). According to ordinal logistic regression analysis, exposure to high altitudes might result in more advanced T stage (OR=2.45 95%CI 1.10-5.44). 41.3% (43/104) of cases in Tibetan-group had lymph node positive disease, whereas the percentage was found in 38.26% (13/34) in Han-group(p<0.05). The distribution of molecular subtypes was quite significantly different between two groups (p<0.05), according to the comparison of constituent ratios. Our study verified that breast cancer at high altitudes possessed its own unique clinicopathological characteristics and distinct features of molecular subtypes. It broadened the understanding of this heterogenous disease and also provided valuable evidence for cancer prevention and personalized therapeutics of breast cancer at high altitudes.

A New Direction in Membranolytic Anticancer Peptides classification: Combining Spaced k-mers with Chaos Game Representation.

The role of Membranolytic Anticancer Peptides (ACPs) as breast cancer therapeutics is gaining popularity because of their capacity to delay cellular resistance development and eliminate some common chemotherapy challenges, like cytotoxicity, aftereffect, etc. As breast cancer is a leading cause of death among women globally and designing effective treatment mechanisms for it is a crucial step, identifying the potent ACPs is a vital contribution towards cancer treatment. Since ACPs are small protein sequences, it is essential to devise efficient and effective sequence analysis methods for them. In this regard, Chaos game representation (CGR) is a popular technique used to visualize protein sequences as 2D images. In CGR, amino acids of a sequence are projected on a pre-defined axis, and the resulting image is used as input for machine learning/deep learning models. The traditional method of projecting amino acids uses the sine and cosine functions, but in this study, we explore the use of secant and cosecant functions as an alternative. Moreover, we use Spaced k-mers of a sequence as an alternate way to manipulate its amino acids rather than the original sequence, which is proven to show better results than traditional methods which deal with each amino acid within the sequence separately. In this study, we propose a new approach for ACP classification based on the concept of CGR and spaced k-mers. We generate images of the peptide sequences and use them as input to the deep learning (DL) models to perform classification. The results show that our proposed approach achieves high predictive performance for ACP classification, and provides a new direction for identifying the potent ACPs which can be used for breast cancer treatment.

Molecular docking and ADMET studies to predict the anti-breast cancer effect of aloin by targeting estrogen and progesterone receptors

The existing anti-cancer drugs are known for their adverse effects. Hence, it calls for an urgent need to explore the alternative therapies that are safer and efficient with no or minimal side effects. This approach points towards the utilization of traditional medicinal herbs to formulate naturally-derived drugs. So, aloin is a bioactive compound of Aloe Vera and known to exhibit an anticancerous effect on different cancer types. However, limited studies are indicating its possible interaction with estrogen receptors (ER) and progesterone receptors (PGR), that are the most targeted receptors in breast cancer therapeutics. Our study aims to predict the possible interactions of ER and PGR with aloin. We also analysed the drug likeliness properties of aloin for its anti-breast cancer activity. Hence, we performed molecular docking study of aloin against both these receptors using AutodockVina. Drug-like properties and bioactivity score for aloin was also predicted, using Molinspiration tool. The results suggest that aloin exhibit better interaction with ER than PGR with a binding affinity of −8.0 Kcal/mol. Molinspiration assay further suggested the aloin to carry drug-like property and behave as a good ligand for nuclear receptors. Our study indicates that aloin may behave as a potential anti-breast cancer agent by targeting the ER in breast cancer cells.

3-deazaadenosine: A promising novel p38γ antagonist with potential as a breast cancer therapeutic agent

Human p38γ protein kinase, or MAPK12, is a crucial signaling protein that is important in channelizing membrane signals to the nucleus in the MAPK cascade pathway, associated with breast and colorectal cancer, besides other forms of malignancies and atherosclerotic lesions too. P38γ has a significant contribution to the progression of breast carcinoma due to its multifaceted functions. Targeting p38γ for defining potent antagonists against p38γ can turn out to be an attractive and novel means of breast cancer therapeutics. Novel and potent lead molecules were designed utilizing computational drug design methodologies. Using high-throughput virtual screening, 1909 geometrically similar analogs of known inhibitors were generated, primarily using BIRB796, SB202190, ANP, CHEBI: 620708, and CHEBI: 524699. Chemical correctness was ensured using LigPrep for the standalone library, and Prep Wizard for p38γ using Maestro v.11.5. Using the Glide v5.5 flexible docking procedure on a standalone library of p38γ binding sites, we defined 18 potential leads and assessed their ADMET properties. Lead "1", among the proposed four p38γ antagonists with high-scoring and favorable interactions, was considered for 100 ns molecular dynamics simulations. Among the four proposed leads, Lead '1′ displayed consistent and stable bonding interactions with p38γ throughout the 100 ns molecular dynamics (MD) simulations. Additionally, it formed water bridges, contributing to its strong association with the protein. Notably, Lead '1′ (3-deazaadenosine) exhibited favorable root-mean-square deviation (RMSD) and root-mean-square fluctuation (RMSF) within the acceptable range of pharmacological properties. Thus, 3-deazaadenosine and its mimetic might be promising new directions for developing a novel class of antagonists for breast cancer treatment.

Gold nanoparticles in triple-negative breast cancer therapeutics.

Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer with enhanced metastasis and poor survival. Though chemotherapy, radiotherapy, photothermal therapy (PTT), photodynamic therapy (PDT), and gene delivery are used to treat TNBC, various side effects limit these therapeutics against TNBC. In this review article, we have focused on the mechanism of action of gold nanoparticles (AuNPs) to enhance the efficacy of therapeutics with targeted delivery on TNBC cells. Research data were accumulated from PubMed, Scopus, Web of Science, and Google Scholar using searching criteria "gold nanoparticles and triple-negative breast cancer" and "gold nanoparticles and cancer". Though we reviewed many old papers, most cited papers were from the last ten years. Various studies indicate that AuNPs can enhance bioavailability, site-specific drug delivery, and efficacy of chemotherapy, radiotherapy, PTT, and PDT as well as modulate gene expression. The role of AuNPs in the modulation of TNBC therapeutics through the inhibition of cell proliferation, progression, and metastasis has been proved in vitro and in vivo studies. As these mechanistic actions of AuNPs are most desirable to develop drugs with enhanced therapeutic efficacy against TNBC, it might be a promising approach to apply AuNPs for TNBC therapeutics. This article reviewed the mechanism of action of AuNPs and their application in the enhancement of therapeutics against TNBC. Much more attention is required for studying the role of AuNPs in developing them either as a single or synergistic anti-cancer agent against TNBC.

Two-dimensional speckle tracking echocardiography help identify breast cancer therapeutics–related cardiac dysfunction

BackgroundCancer therapeutics–related cardiac dysfunction (CTRCD) from different chemotherapy strategies are underdetermined by echocardiography. As an imaging marker of subclinical cardiac dysfunction, two-dimensional speckle tracking echocardiography (2D-STE) may assist in identifying the impact patterns of different CTRCD.MethodsA total of 67 consecutive patients with invasive ductal breast carcinoma who will undertake neoadjuvant chemotherapy were enrolled and grouped according to their different chemotherapy regimens based on their biopsy results. Group A included 34 patients who received anthracycline without trastuzumab, whereas Group B had 33 patients who received trastuzumab without anthracycline. Echocardiography was performed at three time-points, i.e., baseline (T0), cycle-2 (T2), and cycle-4 (T4) of chemotherapy. Conventional echocardiographic measurements and 2D-STE strain values, and myocardial work (MW) parameters, were compared between different groups at different time-points.ResultsThe mean age had no statistical difference between the two groups. E/e′ was the only conventional echocardiographic parameter that had variation in group A (P < 0.05). Compared with baseline, GLS in group A decreased at T2, and GCS decreased at T4 (P < 0.05). GLS and GCS in group B both decreased at T4 (P < 0.05). More patients in group A had a more than 15% fall of baseline GLS rather than GCS at T2 (P < 0.05), however, there was no difference of either GLS or GCS decline rate at T4 between the two groups. All the MW parameters in group A had variations overtime, whereas only GCW in group B (P < 0.05).ConclusionEarly subclinical myocardial dysfunction can be identified by 2D-STE in breast cancer patients with chemotherapy, and GLS provides profound value in demonstrating the temporal changes in early myocardial damage induced by anthracycline. LV contractility injury in patients with trastuzumab may be mild at first but increases in severity with exposure time as early as cycle-4. Awareness of these differences may help to stratify the prevention of late cardiovascular events caused by different CTRCDs. In addition, GCW may be the most sensitive myocardial work parameter of CTRCD.

Towards Sensing of Breast Cancer Biomarkers: Engineering Glucose Dehydrogenase As an Estrogenic Regulated Protein

Breast cancer is the second leading cause of cancer-related death in women. Approximately 50% of mortalities arise from estrogen receptor (ER)-positive tumors.[1] The major therapeutics for breast cancer are estrogen antagonists, like tamoxifen. Closely monitoring the antagonist in a patient would increase the efficacy of endocrine therapeutics while alleviating side effects during treatment. However, existing methods such as routine immunohistochemistry cannot effectively monitor estrogen antagonists because of their low throughput and high cost. To address these issues, we have devised a bioelectronic sensor of estrogen antagonists by grafting ER to the point of care (POC) glucometer.Glucometers use a test strip containing glucose dehydrogenase (GDH), an enzyme that reacts with glucose in blood droplets and generates electric signals. To obtain an estrogenic regulated GDH, we inserted the ligand-binding domain of ER at all the 456 amino acids of the GDH. More than 7000 colonies were screened to identify the allosteric insertion sites globally. We find that the estrogenic regulated GDH can electrochemically detect a series of ER modulators as low as 1 nM with ≥40% dynamic range. Successful engineering of the classical glucose dehydrogenase yields a self-power antagonist sensor and establishes a platform for designing personalized diagnostics in a POC fashion.[1] Torre, Lindsey A., et al. "Ovarian cancer statistics, 2018." CA: a cancer journal for clinicians 68.4 (2018): 284-296.

Nanomaterial-assisted CRISPR gene-engineering - A hallmark for triple-negative breast cancer therapeutics advancement.

Triple-negative breast cancer (TNBC) is the most violent class of tumor and accounts for 20–24% of total breast carcinoma, in which frequently rare mutation occurs in high frequency. The poor prognosis, recurrence, and metastasis in the brain, heart, liver and lungs decline the lifespan of patients by about 21 months, emphasizing the need for advanced treatment. Recently, the adaptive immunity mechanism of archaea and bacteria, called clustered regularly interspaced short palindromic repeats (CRISPR) combined with nanotechnology, has been utilized as a potent gene manipulating tool with an extensive clinical application in cancer genomics due to its easeful usage and cost-effectiveness. However, CRISPR/Cas are arguably the efficient technology that can be made efficient via organic material-assisted approaches. Despite the efficacy of the CRISPR/Cas@nano complex, problems regarding successful delivery, biodegradability, and toxicity remain to render its medical implications. Therefore, this review is different in focus from past reviews by (i) detailing all possible genetic mechanisms of TNBC occurrence; (ii) available treatments and gene therapies for TNBC; (iii) overview of the delivery system and utilization of CRISPR-nano complex in TNBC, and (iv) recent advances and related toxicity of CRISPR-nano complex towards clinical trials for TNBC.

Trop-2-Cells, Their Exosomal Cargo, and the Potential Impact on Diagnostics and Therapeutics in Breast Cancer: The Expanding Frontiers

Recently, an anti-trophoblast surface antigen-2 (Trop-2) antibody-drug conjugate targeting Trop-2 positive cancer cells has been approved for treating patients with unresectable locally advanced or metastatic triple-negative breast cancer, who have failed two or more lines of systemic chemotherapy. This has renewed the interest in translational research of Trop-2 positive breast cancer, the gene TACSTD2 and microRNAs that interact with it, and the signaling networks sparked by Trop-2 mediated signaling. In addition, this opinion paper argues that exosomes, extracellular vesicles that are released from Trop-2 positive cancer cells, could play a significant role in cancer progression. Furthermore, diagnostic applications using Trop-2-released exosomes, the cargo exosomes carry, which could be any genetic information such as specific miRNAs, adhesion molecules such as integrins, and metabolites, are yet to be explored in breast cancer patients. Most of the evidence and data are obtained from studies in epithelial cancers other than breast cancers, which have been introduced in the current paper. Therefore, this article briefly summarizes previously published data on other cancer types, forms some hypotheses, and proposes research questions and directions that may be explored further.

Sensor Technology for Opening New Pathways in Diagnosis and Therapeutics of Breast, Lung, Colorectal and Prostate Cancer

This study analyzes the interaction between sensor research and technology and different types of cancer (breast, lung, colorectal, and prostate) with the goal of detecting new directions for improving diagnosis and therapeutics in medicine. This study develops an approach to computational scientometrics based on data from the Web of Science from the 1991 to 2021 period. The results of this analysis show the vital role of biosensors and electrochemical biosensors applied in breast cancer, lung cancer, and prostate cancer research. Instead, scientific research of optical sensors is developing main technological trajectories in breast, prostate, and colorectal cancer for improving diagnostics. Finally, oxygen sensor research has a main technological development in breast and lung cancer for new applications in breath analysis directed to treatment processes. Preliminary results presented here clearly illustrate the evolutionary paths of sensor research and technologies that have great potential for developing incremental and radical innovations in cancer diagnosis and therapies. These conclusions are, of course, tentative. There is a need for much more detailed research based on other aspects and factors for detecting stable technological trajectories that can foster the technology transfer of new sensor in cancer research for improving diagnosis and therapeutics, reducing, whenever possible, world-wide mortality of cancer in society.JEL Classification: I10, O30, O31, O32; O33. Doi: 10.28991/HIJ-2022-03-03-010 Full Text: PDF

Advances of Epigenetic Biomarkers and Epigenome Editing for Early Diagnosis in Breast Cancer.

Epigenetic modifications are known to regulate cell phenotype during cancer progression, including breast cancer. Unlike genetic alterations, changes in the epigenome are reversible, thus potentially reversed by epi-drugs. Breast cancer, the most common cause of cancer death worldwide in women, encompasses multiple histopathological and molecular subtypes. Several lines of evidence demonstrated distortion of the epigenetic landscape in breast cancer. Interestingly, mammary cells isolated from breast cancer patients and cultured ex vivo maintained the tumorigenic phenotype and exhibited aberrant epigenetic modifications. Recent studies indicated that the therapeutic efficiency for breast cancer regimens has increased over time, resulting in reduced mortality. Future medical treatment for breast cancer patients, however, will likely depend upon a better understanding of epigenetic modifications. The present review aims to outline different epigenetic mechanisms including DNA methylation, histone modifications, and ncRNAs with their impact on breast cancer, as well as to discuss studies highlighting the central role of epigenetic mechanisms in breast cancer pathogenesis. We propose new research areas that may facilitate locus-specific epigenome editing as breast cancer therapeutics.