Luminespib plus pemetrexed in patients with non-squamous non-small cell lung cancer

Noor, Zorawar S.; Goldman, Jonathan W.; Lawler, W; Telivala, Bijoy; Braiteh, Fadi; DiCarlo, Brian; Kennedy, Kathleen; Adams, Brad; Wang, Xiaoyan; Jones, Benjamin; Slamon, Dennis J.; Garon, Edward B.

doi:10.1016/j.lungcan.2019.05.022

Cited by 9 publications

(2 citation statements)

References 32 publications

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“…If other organ diseases are combined at the same time, the chemotherapy tolerability of elderly lung cancer patients will decrease. The continuous updating of chemotherapy drugs in recent years has brought good clinical effects for the treatment of elderly lung cancer patients [ 16 ]. Therefore, this study used a comprehensive approach of chemotherapy combined with radiotherapy for patients with advanced NSCLC.…”

Section: Discussionmentioning

confidence: 99%

Computed Tomography Image under Artificial Intelligence Algorithm to Evaluate the Nursing and Treatment Effect of Pemetrexed Combined Platinum‐Based Chemotherapy on Elderly Lung Cancer

Gu¹,

Li²

2022

Contrast Media & Molecular Imaging

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This study was to evaluate the clinical efficacy of pemetrexed combined with platinum-based chemotherapy in the treatment of elderly lung cancer using electronic computed tomography (CT) images based on artificial intelligence algorithms. In this study, 80 elderly patients with lung cancer treated were selected and randomly divided into two groups: patients treated with pemetrexed combined with cisplatin were included in the pemetrexed group and patients treated with docetaxel combined with cisplatin were included in the docetaxel group, with 40 cases in each group. The DenseNet network was compared with the Let Net-5 and ResNet model and applied to the CT images of 80 elderly patients with lung cancer. The diagnosis accuracy of the DenseNet network (97.4%) was higher than that of the Let Net-5 network (80.1%) and ResNet model (95.5%). Carcinoembryonic antigen (CEA), cytokeratin fragment antigen 21–1 (CYFRA 21–1), and squamous cell-associated antigen (SCC) after chemotherapy in the pemetrexed group and docetaxel group were all lower than those before chemotherapy, showing statistically obvious differences (P < 0.05). The satisfaction degree of nursing care in the pemetrexed group (92.67%) was significantly higher than that in the docetaxel group (85.62%), and the difference was statistically significant (P < 0.05). Adverse reactions such as fatigue, diarrhea, and neutrophils in the pemetrexed group were lower than those in the docetaxel group, and the difference was statistically great (P < 0.05). The DenseNet convolutional neural network has high diagnostic accuracy; methotrexate combined with platinum chemotherapy can improve the chemotherapy effect in elderly patients with lung cancer, with low degree of adverse reactions and good overall tolerance, which can be used as the first-line treatment for elderly patients with lung cancer.

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Section: Discussionmentioning

confidence: 99%

Computed Tomography Image under Artificial Intelligence Algorithm to Evaluate the Nursing and Treatment Effect of Pemetrexed Combined Platinum‐Based Chemotherapy on Elderly Lung Cancer

Gu¹,

Li²

2022

Contrast Media & Molecular Imaging

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“…The biological consequence of AUY922, a potent anti-cancer drug, on suppressing cell growth is well documented in vitro and in vivo. Clinically, AUY922 as a single regimen or in combination with other compounds has been evaluated in many types of human cancers and reported to induce ocular AEs [16][17][18][19][56][57][58][59][60]. AUY922induced cell apoptosis has been reported in retinas from albino Sprague Dawley rats intravenously treated with 10.0 mg/kg/3qw for 2 weeks [21].…”

Section: Discussionmentioning

confidence: 99%

AUY922 induces retinal toxicity through attenuating TRPM1

et al. 2021

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Background Ocular adverse events are common dose-limiting toxicities in cancer patients treated with HSP90 inhibitors, such as AUY922; however, the pathology and molecular mechanisms that mediate AUY922-induced retinal toxicity remain undescribed. Methods The impact of AUY922 on mouse retinas and cell lines was comprehensively investigated using isobaric tags for relative and absolute quantitation (iTRAQ)‑based proteomic profiling and pathway enrichment analysis, immunohistochemistry and immunofluorescence staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, MTT assay, colony formation assay, and western blot analysis. The effect of AUY922 on the Transient Receptor Potential cation channel subfamily M member 1 (TRPM1)-HSP90 chaperone complex was characterized by coimmunoprecipitation. TRPM1-regulated gene expression was analyzed by RNAseq analysis and gene set enrichment analysis (GSEA). The role of TRPM1 was assessed using both loss-of-function and gain-of-function approaches. Results Here, we show that the treatment with AUY922 induced retinal damage and cell apoptosis, dysregulated the photoreceptor and retinal pigment epithelium (RPE) layers, and reduced TRPM1 expression. Proteomic profiling and functional annotation of differentially expressed proteins reveals that those related to stress responses, protein folding processes, regulation of apoptosis, cell cycle and growth, reactive oxygen species (ROS) response, cell junction assembly and adhesion regulation, and proton transmembrane transport were significantly enriched in AUY922-treated cells. We found that AUY922 triggered caspase-3-dependent cell apoptosis, increased ROS production and inhibited cell growth. We determined that TRPM1 is a bona fide HSP90 client and characterized that AUY922 may reduce TRPM1 expression by disrupting the CDC37-HSP90 chaperone complex. Additionally, GSEA revealed that TRPM1-regulated genes were associated with retinal morphogenesis in camera-type eyes and the JAK-STAT cascade. Finally, gain-of-function and loss-of-function analyses validated the finding that TRPM1 mediated the cell apoptosis, ROS production and growth inhibition induced by AUY922. Conclusions Our study demonstrates the pathology of AUY922-induced retinal toxicity in vivo. TRPM1 is an HSP90 client, regulates photoreceptor morphology and function, and mediates AUY922-induced cytotoxicity.

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Design and Synthesis of Novel 6,7‐Dihydrobenzo[d]isoxazol‐4(5H)‐one Derivatives Bearing 1,2,3‐Triazole Moiety as Potential Hsp90 Inhibitors and their Evaluation as Antiproliferative Agents

Varabyeva,

Salnikova,

Krymov

et al. 2024

ChemistrySelect

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An effective approach to 5‐triazolyl‐substituted 6,7‐dihydrobenzo[d]isoxazol‐4(5H)‐ones and 4,5,6,7‐tetrahydrobenzo[d]isoxazoles was developed. The approach included α‐keto bromination of 6,7‐dihydrobenzo[d]isoxazol‐4(5H)‐one followed by nucleophilic substitution of bromine with the azide group. For the preparation of 5‐azido‐6,7‐dihydrobenzo[d]isoxazol‐4(5H)‐one, the carbonyl group at position 4 was reduced to a methylene group under ionic hydrogenation conditions using triethylsilane as a reducing agent. Cu(I)‐catalyzed [2+3] cycloaddition of terminal alkynes to both obtained azides was used for the synthesis of two series of triazolyl derivatives. Compounds, which contain in their structures common for some Hsp90 inhibitors 2,4‐dihydroxy‐5‐isopropylphenyl fragment, were evaluated as antiproliferative agents against two breast cancer cell lines: hormone‐dependent MCF7 and HER2‐positive HCC1954. The lead compound showed half‐maximal inhibitory concentration (IC50) values below 5 μM and induced significant changes in the Hsp90 signaling pathways in HER2‐positive HCC1954 cells. It increased the expression of Hsp70 (used as a pharmacodynamic marker of Hsp90 inhibition) and inhibited the expression of HER2, p‐c‐Met, c‐Met, and p‐AKT. The combination of the selected isoxazole‐triazole hybrid molecule and the earlier described apoptosis inducer LCTA‐3344 demonstrated a significant antiproliferative effect against HCC1954 cells. The lead compound was revealed to be a promising candidate for future anticancer drug design, particularly against aggressive breast cancer positive for HER2.

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Luminespib plus pemetrexed in patients with non-squamous non-small cell lung cancer

Cited by 9 publications

References 32 publications

Computed Tomography Image under Artificial Intelligence Algorithm to Evaluate the Nursing and Treatment Effect of Pemetrexed Combined Platinum‐Based Chemotherapy on Elderly Lung Cancer

Computed Tomography Image under Artificial Intelligence Algorithm to Evaluate the Nursing and Treatment Effect of Pemetrexed Combined Platinum‐Based Chemotherapy on Elderly Lung Cancer

AUY922 induces retinal toxicity through attenuating TRPM1

Design and Synthesis of Novel 6,7‐Dihydrobenzo[d]isoxazol‐4(5H)‐one Derivatives Bearing 1,2,3‐Triazole Moiety as Potential Hsp90 Inhibitors and their Evaluation as Antiproliferative Agents

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