OncoTargets and therapy最新文献

Receptors coupled with G proteins (GPCRs) are expressed in large numbers in multiple systems, such as endocrine, cardiovascular, digestive, immune, and reproductive systems. As an important signal transduction mediator, in recent years, the research on GPCRs has become more and more in-depth. Many articles have verified that in the gastrointestinal, reproductive, and urinary systems, GPCRs are contributed to the development and occurrence of cancerous tumors and have been associated with the infiltration of malignant tumors and metastasis. Currently, in clinical practice, GPCRs become the target of action for about 30% of drugs. However, it should be noted that there are still over 100 GPCRs collectively referred to as orphan GPCRs (OGPCRs) due to the lack of corresponding ligands. Despite the lack of known ligands, research in animals and experiments has proved that numerous OGPCRs regulate crucial physiological functions and are intriguing and undeveloped targets for therapeutics. GPR137 is a member of OGPCRS, which promotes carcinogenesis and progression of cancers, and its expression is elevated in various malignant tumor tissues. Additionally, GPR137 has been shown to play a role in promoting tumorigenesis and metastasis in colorectal, gastric, hepatocellular, ovarian and prostate cancers. Knockdown of the GPR137 leads to cell cycle arrest within cancer cells, effectively inhibiting their proliferation and colony-forming ability while promoting apoptosis. This highlights its potential therapeutic significance as a target for numerous cancers.

Osimertinib has become the standard of care in the first-line treatment of advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. Although previous studies reported that the BRAF V600E mutation is a unique resistance mechanism to osimertinib, the treatment of lung adenocarcinoma patients harboring both EGFR and acquired BRAF-V600E comutations remains unclear. Here, we report a case of a 36-year-old woman diagnosed with stage IV lung adenocarcinoma harboring the EGFR L858R mutation. She received osimertinib for 24 months and experienced progressive disease. Rebiopsy pathology revealed that the lung lesion was still adenocarcinoma, and NGS revealed gains of BRAF V600E and TP53 mutations in addition to the EGFR L858R mutation. This patient subsequently received aumolertinib in combination with dabrafenib and trametinib and achieved a complete response for 8 months. In conclusion, acquired BRAF-V600E mutations may contribute to osimertinib resistance. Aumolertinib plus BRAF inhibitors improves outcomes in patients with EGFR-L858R and acquired BRAF-V600E comutant lung adenocarcinoma in whom osimertinib treatment has failed.

Purpose: The objective of this study was to identify biomarkers associated with immunogenic cell death (ICD) in lung squamous cell carcinoma (LUSC), focusing on subtypes with distinct immunological characteristics and prognosis. Given the heterogeneous nature of LUSC, understanding ICD's role is crucial for developing tailored therapeutic strategies.

Patients and methods: RNA sequencing data from 504 LUSC samples were analyzed using unsupervised clustering to identify ICD-related gene expression patterns. These patterns were linked to immune scores, immune cell infiltration, and clinical outcomes. A separate dataset was used to validate the association between ICD-related subtypes and immunotherapy efficacy.

Results: Unsupervised clustering revealed two distinct ICD-related subtypes with significantly different immune scores, immune cell infiltration levels, and prognosis. A prognostic model was developed based on differentially expressed ICD-related genes, which demonstrated strong predictive power for patient survival and immune response. This model may offer valuable insights for clinical decision-making, particularly for immunotherapy strategies.

Conclusion: This study identified key ICD-related biomarkers and developed a prognostic model that can enhance our understanding of ICD in LUSC, ultimately guiding personalized treatment approaches.

Regorafenib, a multikinase inhibitor, frequently induces severe hand-foot skin reactions (HFSR), often requiring dose reduction or discontinuation. This case report demonstrates the successful management of HFSR in a patient with fibromyxoid sarcoma using topical Chinese medicine "Shouzuping" soaking combined with urea ointment. It suggests the unique advantages of integrated traditional Chinese and Western medicine in managing HFSR. This article further reviews the clinical characteristics, pathogenesis, prevention and treatment strategies of HFSR caused by targeted therapies, with a view to providing valuable clinical insights.

The effectiveness of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) has been established, leading the NCCN Guidelines to recommend it as a first-line treatment for patients with advanced EGFR mutation-positive non-small cell lung cancer (NSCLC). However, there is still controversy about the use of neoadjuvant TKI treatment for patients with stage III EGFR mutation-positive NSCLC. Here, we firstly report that a stage IIIA lung adenocarcinoma patient benefited from chemotherapy and dacomitinib as neoadjuvant targeted therapy based on EGFR G719X mutation, achieving a pathological downstaging and the chance of radical surgical resection. Our case describes dacomitinib use as neoadjuvant targeted therapy for EGFR positive advanced NSCLC and highlights the application of molecular testing for the better treatment decision making.

Background: Insufficient ablation is a significant factor contributing to the recurrence of non-small cell lung cancer (NSCLC), and it is of great significance to explore the protein expression profile of lung cancer cells after insufficient ablation.

Methods: We establish an insufficient microwave ablation model of lung cancer xenograft in mice, identify differentially expressed proteins (DEPs) and involved signaling pathways through proteomic sequencing, and confirm proteins expression via immunohistochemistry (IHC). Utilizing The Cancer Genome Atlas (TCGA) dataset, we investigate proteins associated with human lung cancer prognosis.

Results: Proteomic sequencing results reveal that 99 proteins exhibited differential expression levels. Subsequent Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicate that the DEPs are significantly enriched in metabolic processes. Several DEPs are identified and subsequently confirmed through immunohistochemistry (IHC). Among these proteins, CTP synthase 1 (CTPS1) and Thymidylate synthetase (TYMS), both of which play roles in nucleotide metabolism, are found to be significantly associated with the survival outcomes of patients with lung cancer.

Conclusion: Insufficient ablation can cause alterations in nucleotide metabolism, potentially leading to recurrence and metastasis.

As hematological tumor patients are surviving long-term, the long-term toxicities of therapeutic regimens have become increasingly evident. The coexistence of two hematological tumors in the same patient is extremely rare and typically shows an aggressive clinical course and unsatisfactory prognosis. In the present case, we describe the case of a 64-year-old man who was admitted to the hospital because of fatigue. Biochemical showed an elevated monoclonal immunoglobulin M (IgM) at 37g/L. Next Generation Sequencing (NGS) analysis revealed MYD88^L265p mutation, CXCR4 wild type. In August 2020, he was diagnosed with Waldenström macroglobulinemia (WM) and underwent six cycles of chemotherapy with bendamustine, zanubrutinib, and rituximab. However, he was admitted to the hospital in December 2022 following six-month history of Leukocytosis. Bone marrow (BM) flow cytometry (FCM) showed increased MO1 monocytes. Molecular studies were positive for TET2 mutations. He was finally diagnosed with WM and chronic myelomonocytic leukemia (CMML). Then he accepted hematopoietic stem cell transplantation (HSCT). Unfortunately, after 6 months, the patient died as a consequence of severe pulmonary infection.

Background: The efficacy of Fms-like tyrosine kinase 3 (FLT3) inhibitors has been well established against acute myeloid leukemia (AML) with FLT3 internal tandem duplication (FLT3-ITD) mutations. However, comparative data on the available inhibitors are limited, and drug resistance remains a major concern.

Methods: This study examined the inhibitory effects of gilteritinib, quizartinib and midostaurin on Ba/F3 cells with FLT3-ITD mutations, or point mutations in the tyrosine kinase domain (TKD-PM) or juxtamembrane domain (JMD-PM), both in vitro and in vivo. Quizartinib and midostaurin were selected as comparators due to their clinical relevance in the AML setting and differing mechanisms of action.

Results: Gilteritinib showed similar or superior growth inhibition against the majority of FLT3-TKD-PM or FLT3-JMD-PM cells compared to FLT3-ITD-mutant cells. In contrast, the inhibitory effects of quizartinib were reduced on cells with most types of FLT3-TKD-PM, and the inhibitory effects of midostaurin were attenuated on cells with FLT3-TKD-PM N676K. Gilteritinib also effectively suppressed FLT3 autophosphorylation and phosphorylation of signal transducer and activator of transcription 5 (STAT5), AKT and extracellular signal-regulated kinase (ERK) in FLT3-TKD-PM cells, while quizartinib showed a reduced inhibitory effect on FLT3 autophosphorylation and phosphorylation of downstream signaling molecules in FLT3-TKD-PM cells. In mice xenografted with Ba/F3 cells expressing FLT3-ITD mutations or FLT3-TKD-PM, gilteritinib showed a potent antitumor effect, whereas the antitumor effect of quizartinib was significantly diminished in the FLT3-TKD-PM xenograft model.

Conclusion: These findings highlight the potent efficacy of gilteritinib against a wide range of FLT3 mutations, including TKD-PM and JMD-PM, as well as those associated with resistance to quizartinib or midostaurin. This comparative analysis underscores the need for tailored therapeutic strategies in AML treatment, emphasizing the clinical significance of gilteritinib in overcoming drug resistance.

Aim: Breast cancer remains a prevalent and challenging health issue for women globally. In the pursuit of more effective and less harmful therapies, researchers have focused on natural compounds, especially phenolic compounds found in various plants and fruits.

Purpose: This study aims to explore the potency of coumarin compounds from Citrus aurantiifolia (Christm.) Swingle peel as alternative treatment for breast cancer through in vitro and in silico studies.

Methods: Three coumarins were isolated from C. aurantiifolia peel through multiple steps of column chromatograph. Their cytotoxic activities against the MCF-7 breast cancer cell line were evaluated using the MTT assay. Additionally, in silico studies, including molecular docking and molecular dynamics simulations, were conducted to evaluate the interactions of the most potent compound with estrogen receptor alpha (ERα).

Results: Chemical investigation of C. aurantiifolia peel led to the isolation of three compounds: 5-geranyloxy-7-methoxycoumarin (1), 5-geranyloxypsoralen (2), and 8-geranyloxypsoralen (3). Cytotoxic assays revealed that compound 2 exhibited the highest cytotoxic potency against MCF-7 breast cancer cell line with an IC₅₀ of 138.51 ± 14.44 µg/mL, followed by compounds 1 and 3 with IC₅₀ values of 204.69 ± 22.91 and 478.15 ± 34.85 µg/mL, respectively. Molecular docking studies against estrogen receptor alpha (ERα) showed that 5-geranyloxypsoralen (2) had a lower docking score (-10.63 kcal/mol) compared to estradiol (-9.99 kcal/mol). Molecular dynamics simulation revealed the binding stability ERα-Compound 2 complex as evidence from the root mean square deviation (RMSD) of 2.964 ± 0.460 Å. Furthermore, pharmacokinetic predictions suggested that 5-geranyloxypsoralen may possess favourable pharmacokinetic properties, highlighting its potential as a therapeutic agent.

Conclusion: The study highlights the potential of coumarin compounds from C. aurantiifolia peel as an alternative treatment for breast cancer, particularly 5-geranyloxypsoralen could be a promising therapeutic agent in breast cancer treatment, warranting further investigation.

Purpose: Early relapsed breast cancer, characterized by recurrence within two years post-surgery, often results from drug resistance and rapid progression. The clinicopathological, prognostic and molecular features of these patients still await exploration.

Methods: In this study, 43 patients with early relapsed breast cancer were included as well as 42 advanced breast cancer patients who experienced a recurrence after two years since surgery as the control group. Clinicopathological factors and prognosis were compared among the two groups, and tumor tissue from 27 available early relapsed patients was subjected to genetic sequencing.

Results: Compared with the control group, early relapsed group exhibited more aggressive malignant biological characteristics, shorter median overall survival (27.8 vs 49.8 months, P=0.005) and lower objective response rate for the first line treatment (42.90% vs 86.8%, P<0.001). Genetic sequencing of 27 early relapsed breast cancer demonstrated with TP53 (52%), PIK3CA (22%), and MLL3 (19%) as the top three frequently mutated genes, suggesting potential therapeutic targets for personalized treatment strategies.

Conclusion: Early relapsed breast cancer patients demonstrated poor prognosis and treatment response, indicating a reagent need of effective treatment combination for disease control. Genetic sequencing may identify potential therapeutic targets, providing new therapeutic opportunities for such patients. These findings underline the urgent need for personalized therapeutic strategies informed by genetic profiling to improve outcomes for early-relapsed breast cancer patients.