targeted therapy
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2023 ◽  
Vol 83 ◽  
Y. Lan ◽  
Y. Liang ◽  
X. Xiao ◽  
Y. Shi ◽  
M. Zhu ◽  

Abstract Hypoxia is a prominent feature of head and neck cancer. However, the oxygen element characteristics of proteins and how they adapt to hypoxia microenvironments of head and neck cancer are still unknown. Human genome sequences and proteins expressed data of head and neck cancer were retrieved from pathology atlas of Human Protein Atlas project. Then compared the oxygen and carbon element contents between proteomes of head and neck cancer and normal oral mucosa-squamous epithelial cells, genome locations, pathways, and functional dissection associated with head and neck cancer were also studied. A total of 902 differentially expressed proteins were observed where the average oxygen content is higher than that of the lowly expressed proteins in head and neck cancer proteins. Further, the average oxygen content of the up regulated proteins was 2.54% higher than other. None of their coding genes were distributed on the Y chromosome. The up regulated proteins were enriched in endocytosis, apoptosis and regulation of actin cytoskeleton. The increased oxygen contents of the highly expressed and the up regulated proteins might be caused by frequent activity of cytoskeleton and adapted to the rapid growth and fast division of the head and neck cancer cells. The oxygen usage bias and key proteins may help us to understand the mechanisms behind head and neck cancer in targeted therapy, which lays a foundation for the application of stoichioproteomics in targeted therapy and provides promise for potential treatments for head and neck cancer.

2022 ◽  
Vol 12 (5) ◽  
pp. 1065-1070
Jin Song ◽  
Jiahan Chang ◽  
Xue Lin ◽  
Cibo Fan ◽  
Lili Han ◽  

Triple-negative breast cancer (TNBC) remains a threat to women’s life with a lack of targeted therapy. This study aimed to explore the role of PTEN derived from BMSCs in TNBC. We carried out a retrospective analysis of 65 TNBC patients and 30 healthy subjects from October 2016 to January 2021 with a 10-year follow up. PTEN expression in TNBC tissues and cells was determined by RTqPCR. Functional experiments were conducted to evaluate PTEN’s effect on TNBC cell biological behaviors using MTT assay and Transwell assay, as well as on PI3K-Akt-HIF-1α-VEGF signaling transduction. PTEN was up-regulated in TNBC tissues relative to healthy controls and it was negatively associated with the survival rate. In in vitro experiments, PTEN overexpression increased cell viability and invasion and knocking down of PTEN exerted opposite effect. The expression of PI3K was directly regulated by PTEN. Up-regulation of PTEN resulted in a decline in HIF-1α, Akt and VEGF expressions, which were elevated after knocking down of PTEN. In conclusion, PTEN derived from BMSCs promotes TNBC cell development through blocking PI3K-Akt-HIF-1α-VEGF signaling pathway, providing a new theoretical basis for targeted therapy of TNBC.

Reinhard Dummer ◽  
Georgina V. Long ◽  
Caroline Robert ◽  
Hussein A. Tawbi ◽  
Keith T. Flaherty ◽  

PURPOSE Preclinical data suggest the combination of an anti–programmed death receptor 1 antibody plus dabrafenib and trametinib to have superior antitumor activity compared with dabrafenib plus trametinib alone. These observations are supported by translational evidence suggesting that immune checkpoint inhibitors plus targeted therapy may improve treatment outcomes in patients with BRAF V600–mutant metastatic melanoma. COMBI-i is a phase III trial evaluating spartalizumab, an anti–programmed death receptor 1 antibody, in combination with dabrafenib and trametinib (sparta-DabTram), versus placebo plus dabrafenib and trametinib (placebo-DabTram) in patients with BRAF V600–mutant unresectable or metastatic melanoma. METHODS Patients received spartalizumab 400 mg intravenously every 4 weeks plus dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily or placebo-DabTram. Participants were age ≥ 18 years with unresectable or metastatic BRAF V600–mutant melanoma. The primary end point was investigator-assessed progression-free survival. Overall survival was a key secondary end point ( identifier: NCT02967692 ). RESULTS At data cutoff (July 1, 2020), the median progression-free survival was 16.2 months (95% CI, 12.7 to 23.9 months) in the sparta-DabTram arm versus 12.0 months (95% CI, 10.2 to 15.4 months) in the placebo-DabTram arm (hazard ratio, 0.82 [95% CI, 0.66 to 1.03]; P = .042 [one-sided; nonsignificant]). The objective response rates were 69% (183 of 267 patients) versus 64% (170 of 265 patients), respectively. Grade ≥ 3 treatment-related adverse events occurred in 55% (146 of 267) of patients in the sparta-DabTram arm and 33% (88 of 264) in the placebo-DabTram arm. CONCLUSION The study did not meet its primary end point; broad first-line use of sparta-DabTram is not supported by these results. Further biomarker-driven investigation may identify patient subpopulations who could benefit from checkpoint inhibitor plus targeted therapy combinations.

2022 ◽  
Vol 11 ◽  
Jianzheng Wang ◽  
Hongle Li ◽  
Hui Wang ◽  
Qingli Li ◽  
Xuanye Bai ◽  

Desmoid tumor is a rare disease, which is histologically characterized by local invasion, monoclonality, and fibroblast proliferation; and clinically characterized by a variable and often unpredictable course. The treatment of desmoid tumor is mainly surgical resection, but the recurrence rate is high. In recent years, a variety of treatment methods, including endocrine therapy, surgery, radiotherapy, chemotherapy, non-steroidal anti-inflammatory drugs, targeted drugs, interferon and more, have been used and achieved certain curative effects. In addition, in view of the inertia characteristics of desmoid tumor, observation is also a first-line scheme recommended by multiple guidelines. In the past, the research progress of targeted therapy for desmoid tumor is relatively slow and the curative effect is limited. Thus, targeted therapy is usually used as a remedial treatment after the failure of other conventional treatment methods. However, in recent years, with the rapid progress in the basic research of targeted therapy, some new targeted drugs are increasingly used for the clinical treatment of desmoid tumor and have achieved good results. Herein, we described a patient with aggressive fibromatosis in the abdominal cavity. Following a combined treatment using anlotinib and celecoxib, the patient achieved a partial response with mild toxicity. Simultaneously, the patient’s pain symptoms completely disappeared. This case indicates that the combination of anlotinib and NSAIDs could be an effective treatment for desmoid tumor.

2022 ◽  
Vol 20 (6) ◽  
pp. 134-140
K. A. Garipov ◽  
Z. A. Afanaseva ◽  
Z. I. Abramova

The aim of the study was to analyze and summarize available literature data on the role of autophagy in thyroid cancer. Material and methods. We analyzed 34 publications available from pubmed and elibrary. Ru databases concerning thyroid cancer and autophagy. Results. The review discussed the role of autophagy in the progression of thyroid cancer. The development of autophagy-targeted therapy was shown can improve treatment for thyroid cancer. Differentiated thyroid cancer (dtc) is the most common endocrine malignancy. Treatment of dtc patients who are resistant to radioactive iodine therapy is a major challenge. Molecular targeted therapy using tyrosine kinase inhibitors significantly improves treatment outcomes. Conclusion. To enhance the therapeutic effect of treatment with multi-target tyrosine kinase inhibitors, as well as to overcome drug resistance, it is necessary to study the role of autophagy in the development and progression of thyroid cancer.

2022 ◽  
hamid abbaszadeh ◽  
Mahdieh Rajabi-Moghaddam

Abstract Advanced head and neck squamous cell carcinoma (HNSCC) is treated with radiotherapy, chemotherapy, targeted therapy or a combination of these treatments. Variations in toxicity and response to therapy are observed among patients despite similar clinicopathologic characteristics which are attributed to single nucleotide polymorphisms (SNPs). The aim of this review was to evaluate the impact of SNPs on toxicity and response to therapy in HNSCCs. A web-based search of all original articles about the impact of gene polymorphisms on toxicity and response to therapy in HNSCCs was done until September 2021 using international English language databases including Google Scholar, Scopus, PubMed and Web of science. Findings were categorized by type of treatment (radiotherapy, chemotherapy, targeted therapy, or combination therapy). In each category, studies related to growth control genes, cell proliferation, apoptosis, DNA repair genes, antioxidant and drug detoxification genes, genes of drug metabolizing enzymes, tissue remodeling genes and genes of antibody-dependent cellular cytotoxicity were discussed separately. Among studied SNPs with probable impact on toxicity and response to therapy are XRCC1, XRCC3, RAD51, Ku70, NBN, CAT, GSTP1, GSTT1, GSTM1, XPD, XPC, ERCC1, MMP3, ACSL6, EXO1, CXP2D6, FcγRIIIa, AurkA, and EGFR. Understanding gene polymorphisms will help us move toward personalized medicine and determine which patients will actually benefit from therapies for HNSCCs. By examining the SNPs, it is possible to make predictions about the patient's response to treatment or development of toxicity after treatment, and if necessary, make changes in the patient's treatment regimen.

Blood ◽  
2022 ◽  
Nikolaos Trasanidis ◽  
Alexia Katsarou ◽  
Kanagaraju Ponnusamy ◽  
Yao-An Shen ◽  
Ioannis V Kostopoulos ◽  

Understanding the biological and clinical impact of copy number aberrations (CNA) for the development of precision therapies in cancer remains an unmet challenge. Genetic amplification of chromosome 1q (chr1q-amp) is a major CNA conferring adverse prognosis in several types of cancer, including in the blood cancer multiple myeloma (MM). Although several genes across chr1q portend high-risk MM disease, the underpinning molecular aetiology remains elusive. Here, with reference to the 3D chromatin structure, we integrate MM patient multi-omics datasets with genetic variables to obtain an associated clinical risk map across chr1q and to identify 103 adverse prognosis genes in chr1q-amp MM. Prominent amongst these genes, the transcription factor PBX1 is ectopically expressed by genetic amplification and epigenetic activation of its own preserved 3D regulatory domain. By binding to reprogrammed super-enhancers, PBX1 directly regulates critical oncogenic pathways and a FOXM1-dependent transcriptional programme. Together, PBX1 and FOXM1 activate a proliferative gene signature which predicts adverse prognosis across multiple types of cancer. Notably, pharmacological disruption of the PBX1-FOXM1 axis with existing agents (thiostrepton) and a novel PBX1 small-molecule inhibitor (T417) is selectively toxic against chr1q-amplified myeloma and solid tumour cells. Overall, our systems medicine approach successfully identifies CNA-driven oncogenic circuitries, links them to clinical phenotypes and proposes novel CNA-targeted therapy strategies in multiple myeloma and other types of cancer.

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