Pub Date : 2023-12-11DOI: 10.37349/etat.2023.00190
Zhengwang Guo, Shuyan Han
Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype with limited treatment options. Cancer stem cells (CSCs) are thought to play a crucial role in TNBC progression and resistance to therapy. CSCs are a small subpopulation of cells within tumors that possess self-renewal and differentiation capabilities and are responsible for tumor initiation, maintenance, and metastasis. CSCs exhibit plasticity, allowing them to switch between states and adapt to changing microenvironments. Targeting CSC plasticity has emerged as a promising strategy for TNBC treatment. This review summarizes recent advances in understanding the molecular mechanisms underlying CSC plasticity in TNBC and discusses potential therapeutic approaches targeting CSC plasticity.
{"title":"Targeting cancer stem cell plasticity in triple-negative breast cancer","authors":"Zhengwang Guo, Shuyan Han","doi":"10.37349/etat.2023.00190","DOIUrl":"https://doi.org/10.37349/etat.2023.00190","url":null,"abstract":"Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype with limited treatment options. Cancer stem cells (CSCs) are thought to play a crucial role in TNBC progression and resistance to therapy. CSCs are a small subpopulation of cells within tumors that possess self-renewal and differentiation capabilities and are responsible for tumor initiation, maintenance, and metastasis. CSCs exhibit plasticity, allowing them to switch between states and adapt to changing microenvironments. Targeting CSC plasticity has emerged as a promising strategy for TNBC treatment. This review summarizes recent advances in understanding the molecular mechanisms underlying CSC plasticity in TNBC and discusses potential therapeutic approaches targeting CSC plasticity.","PeriodicalId":73002,"journal":{"name":"Exploration of targeted anti-tumor therapy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139010075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-06DOI: 10.37349/etat.2023.00189
Alexey V. Emshanov, D. Nesterov, Tatyana N. Sokolova, Priscilla S. Amankwah, E. N. Imyanitov
Early clinical trials aimed to halt cancer progression by inhibiting the growth of new blood vessels in tumors through single-agent targeted therapy with bevacizumab. These trials largely proved unsuccessful. However, bevacizumab turned out to be efficient when administered in combination with other anticancer drugs. The efficacy of this approach is explained by the ability of bevacizumab to eliminate immature blood vessels thus normalizing intratumoral blood flow and improving the delivery of cytotoxic or targeted agents. This report describes four cases of heavily pretreated patients with metastatic HER2-positive breast cancer, who had no meaningful treatment options left, and who received single-agent bevacizumab as an empirical last-resort therapy. Three of these patients had severe complaints, and they demonstrated striking symptomatic relief within the first day of this treatment. In addition to the observed “Lazarus response”, which was likely attributed to the bevacizumab-driven resolution of edema, some evidence of a direct antitumor effect was observed. These data may call for the reconsideration of bevacizumab monotherapy in patients with HER2-associated breast cancer, and perhaps in some other categories of cancer patients.
{"title":"Unexpected “Lazarus response” to single-agent bevacizumab in heavily pretreated patients with HER2-positive breast cancer","authors":"Alexey V. Emshanov, D. Nesterov, Tatyana N. Sokolova, Priscilla S. Amankwah, E. N. Imyanitov","doi":"10.37349/etat.2023.00189","DOIUrl":"https://doi.org/10.37349/etat.2023.00189","url":null,"abstract":"Early clinical trials aimed to halt cancer progression by inhibiting the growth of new blood vessels in tumors through single-agent targeted therapy with bevacizumab. These trials largely proved unsuccessful. However, bevacizumab turned out to be efficient when administered in combination with other anticancer drugs. The efficacy of this approach is explained by the ability of bevacizumab to eliminate immature blood vessels thus normalizing intratumoral blood flow and improving the delivery of cytotoxic or targeted agents. This report describes four cases of heavily pretreated patients with metastatic HER2-positive breast cancer, who had no meaningful treatment options left, and who received single-agent bevacizumab as an empirical last-resort therapy. Three of these patients had severe complaints, and they demonstrated striking symptomatic relief within the first day of this treatment. In addition to the observed “Lazarus response”, which was likely attributed to the bevacizumab-driven resolution of edema, some evidence of a direct antitumor effect was observed. These data may call for the reconsideration of bevacizumab monotherapy in patients with HER2-associated breast cancer, and perhaps in some other categories of cancer patients.","PeriodicalId":73002,"journal":{"name":"Exploration of targeted anti-tumor therapy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138596694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-06DOI: 10.37349/etat.2023.00188
Witida Laopajon, Nuchjira Takheaw, Kamonporn Kotemul, S. Pata, S. Hongeng, W. Kasinrerk
Aim: The present study aims to generate chimeric mouse single-chain variable fragment (scFv) and immunoglobulin G1 (IgG1) crystallizable fragment (Fc) antibody against disialoganglioside (GD2) for the treatment of neuroblastoma (NB). The generated scFv-IgG Fc antibody, lacking first constant domain of heavy chain (CH1), is of a smaller size than the natural antibody and has anti-tumor activity. Methods: Vector for scFv-IgG Fc antibody was constructed and scFv-IgG Fc antibody was expressed in human embryonic kidney 293T (HEK293T) cell line. Purification of scFv-IgG Fc antibody from the culture supernatant of transfected HEK293T cells was performed by Protein G affinity chromatography. The structure and binding activity of scFv-IgG Fc antibody were verified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), western blotting (WB), and immunofluorescence techniques. Anti-tumor activities by antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) were determined. Results: Using plasmid fusion-human IgG1-Fc2 tag vector (pFUSE-hIgG1-Fc2), a plasmid vector encoding chimeric mouse scFv and hIgG1 Fc antibody against GD2 was successfully constructed. This vector was transfected into human HEK293T cells to produce scFv-IgG Fc antibody. The transfected HEK293T cells could produce chimeric scFv-IgG Fc antibody against GD2, which lacks the IgG heavy chain CH1 domain but carries CH2 and CH3 domains. The chimeric antibodies could be purified from the culture supernatant of the transfected HEK293T culture in the presence of zeocin drug. The produced GD2 scFv-IgG Fc antibodies, which are smaller in size than the intact antibody, could trigger the killing of GD2 expressed NB cell line SH-SY5Y by ADCC and ADCP mechanisms. Conclusions: The results indicate that chimeric scFv-hIgG Fc antibody, lacking heavy chain CH1 domain, could mediate antibody induced anti-tumor activities. The small size of this type of chimeric antibody may be employed as anti-GD2 antibody for NB therapy.
{"title":"Chimeric single-chain variable fragment-human immunoglobulin G crystallizable fragment antibody against GD2 for neuroblastoma targeted immunotherapy","authors":"Witida Laopajon, Nuchjira Takheaw, Kamonporn Kotemul, S. Pata, S. Hongeng, W. Kasinrerk","doi":"10.37349/etat.2023.00188","DOIUrl":"https://doi.org/10.37349/etat.2023.00188","url":null,"abstract":"Aim: The present study aims to generate chimeric mouse single-chain variable fragment (scFv) and immunoglobulin G1 (IgG1) crystallizable fragment (Fc) antibody against disialoganglioside (GD2) for the treatment of neuroblastoma (NB). The generated scFv-IgG Fc antibody, lacking first constant domain of heavy chain (CH1), is of a smaller size than the natural antibody and has anti-tumor activity.\u0000Methods: Vector for scFv-IgG Fc antibody was constructed and scFv-IgG Fc antibody was expressed in human embryonic kidney 293T (HEK293T) cell line. Purification of scFv-IgG Fc antibody from the culture supernatant of transfected HEK293T cells was performed by Protein G affinity chromatography. The structure and binding activity of scFv-IgG Fc antibody were verified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), western blotting (WB), and immunofluorescence techniques. Anti-tumor activities by antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) were determined.\u0000Results: Using plasmid fusion-human IgG1-Fc2 tag vector (pFUSE-hIgG1-Fc2), a plasmid vector encoding chimeric mouse scFv and hIgG1 Fc antibody against GD2 was successfully constructed. This vector was transfected into human HEK293T cells to produce scFv-IgG Fc antibody. The transfected HEK293T cells could produce chimeric scFv-IgG Fc antibody against GD2, which lacks the IgG heavy chain CH1 domain but carries CH2 and CH3 domains. The chimeric antibodies could be purified from the culture supernatant of the transfected HEK293T culture in the presence of zeocin drug. The produced GD2 scFv-IgG Fc antibodies, which are smaller in size than the intact antibody, could trigger the killing of GD2 expressed NB cell line SH-SY5Y by ADCC and ADCP mechanisms. \u0000Conclusions: The results indicate that chimeric scFv-hIgG Fc antibody, lacking heavy chain CH1 domain, could mediate antibody induced anti-tumor activities. The small size of this type of chimeric antibody may be employed as anti-GD2 antibody for NB therapy.","PeriodicalId":73002,"journal":{"name":"Exploration of targeted anti-tumor therapy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138596020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-01DOI: 10.37349/etat.2023.00187
M. Filetti, Pasquale Lombardi, R. Falcone, Raffaele Giusti, D. Giannarelli, A. Carcagnì, V. Altamura, Giovanni Scambia, G. Daniele
Aim: This article is based on our previous research, which was presented as a post at the Congress Aiom 2022 Congress and published in Tumori Journal as Conference Abstract (Tumori J. 2022;108:1–194. doi: 10.1177/03008916221114500). In this paper, a comprehensive presentation of all the achieved results is provided. Several tyrosine kinase inhibitors (TKIs) have been investigated to treat patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). However, direct comparisons between these TKIs are lacking, with many only being compared to crizotinib. To address this gap, a network meta-analysis was conducted to compare the efficacy and safety of various first-line systemic therapies for ALK-positive NSCLC. Methods: A thorough search of PubMed, Embase, and Cochrane Library was performed to identify randomized controlled trials (RCTs) published between January 01, 2000 and April 01, 2022, and included trials that investigated upfront treatments for this molecular subgroup and reported overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs) of grade 3 or higher (grade ≥ 3 AEs). Results: The analysis included 9 RCTs with 2,443 patients receiving eight different treatments: alectinib (at two different dosages), brigatinib, ceritinib, crizotinib, ensartinib, lorlatinib, and chemotherapy. Second and third-generation TKIs significantly prolonged PFS compared to crizotinib, with lorlatinib having the highest probability of yielding the most favorable PFS, followed by alectinib (300 mg or 600 mg). However, only alectinib has been shown to significantly prolong OS compared to crizotinib to date. Lorlatinib appears superior in reducing the risk of central nervous system (CNS) progression, followed by alectinib 600 mg. Ceritinib had the highest rate of AEs, followed by lorlatinib and brigatinib. Conclusions: Based on the network meta-analysis, alectinib and lorlatinib emerged as the most promising upfront treatment options. These treatments provide prolonged disease control while maintaining an acceptable safety profile.
{"title":"Comparing efficacy and safety of upfront treatment strategies for anaplastic lymphoma kinase-positive non-small cell lung cancer: a network meta-analysis","authors":"M. Filetti, Pasquale Lombardi, R. Falcone, Raffaele Giusti, D. Giannarelli, A. Carcagnì, V. Altamura, Giovanni Scambia, G. Daniele","doi":"10.37349/etat.2023.00187","DOIUrl":"https://doi.org/10.37349/etat.2023.00187","url":null,"abstract":"Aim: This article is based on our previous research, which was presented as a post at the Congress Aiom 2022 Congress and published in Tumori Journal as Conference Abstract (Tumori J. 2022;108:1–194. doi: 10.1177/03008916221114500). In this paper, a comprehensive presentation of all the achieved results is provided. Several tyrosine kinase inhibitors (TKIs) have been investigated to treat patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). However, direct comparisons between these TKIs are lacking, with many only being compared to crizotinib. To address this gap, a network meta-analysis was conducted to compare the efficacy and safety of various first-line systemic therapies for ALK-positive NSCLC.\u0000Methods: A thorough search of PubMed, Embase, and Cochrane Library was performed to identify randomized controlled trials (RCTs) published between January 01, 2000 and April 01, 2022, and included trials that investigated upfront treatments for this molecular subgroup and reported overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs) of grade 3 or higher (grade ≥ 3 AEs).\u0000Results: The analysis included 9 RCTs with 2,443 patients receiving eight different treatments: alectinib (at two different dosages), brigatinib, ceritinib, crizotinib, ensartinib, lorlatinib, and chemotherapy. Second and third-generation TKIs significantly prolonged PFS compared to crizotinib, with lorlatinib having the highest probability of yielding the most favorable PFS, followed by alectinib (300 mg or 600 mg). However, only alectinib has been shown to significantly prolong OS compared to crizotinib to date. Lorlatinib appears superior in reducing the risk of central nervous system (CNS) progression, followed by alectinib 600 mg. Ceritinib had the highest rate of AEs, followed by lorlatinib and brigatinib.\u0000Conclusions: Based on the network meta-analysis, alectinib and lorlatinib emerged as the most promising upfront treatment options. These treatments provide prolonged disease control while maintaining an acceptable safety profile.","PeriodicalId":73002,"journal":{"name":"Exploration of targeted anti-tumor therapy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138616212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-10-31DOI: 10.37349/etat.2023.00184
Levi Arnold, Juan Pineda Gomez, Michael Barry, Marrion Yap, Laura Jackson, Thuc Ly, David Standing, Subhash B. Padhye, Bernhard Biersack, Shrikant Anant, Sufi Mary Thomas
Aim: Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide with a survival rate below fifty percent. Addressing meager therapeutic options, a series of small molecule inhibitors were screened for antitumor efficacy. The most potent analog, acryl-3,5-bis(2,4-difluorobenzylidene)-4-piperidone (DiFiD; A-DiFiD), demonstrated strong cellular JUN proto-oncogene, activator protein 1 (AP-1) transcription factor subunit (JUN, c-Jun) antagonism. c-Jun, an oncogenic transcription factor, promotes cancer progression, invasion, and adhesion; high (JUN) mRNA expression correlates with poorer HNSCC survival. Methods: Four new small molecules were generated for cytotoxicity screening in HNSCC cell lines. A-DiFiD-treated HNSCC cells were assessed for cytotoxicity, colony formation, invasion, migration, and adhesion. Dot blot array was used to identify targets. Phospho-c-Jun (p-c-Jun) expression was analyzed using immunoblotting. The Cancer Genome Atlas (TCGA) head and neck cancer datasets were utilized to determine overall patient survival. The Clinical Proteomic Tumor Analysis Consortium (CPTAC) datasets interfaced with University of Alabama at Birmingham Cancer Data Analysis Portal (UALCAN) were analyzed to determine protein levels of c-Jun in HNSCC patients and correlate levels with patient. Results: Of the small molecules tested, A-DiFiD was the most potent in HNSCC lines, while demonstrating low half-maximal drug inhibitory concentration (IC50) in non-malignant Het-1A cells. Additionally, A-DiFiD abrogated cell invasion, migration, and colony formation. Phospho-kinase in vitro array demonstrated A-DiFiD reduced p-c-Jun. Likewise, a time dependent reduction in p-c-Jun was observed starting at 3 min post A-DiFiD treatment. TCGA Firehose Legacy vs. recurrent and metastatic head and neck cancer reveal a nearly 3% DNA amplification in recurrent/metastatic tumor compared to below 1% in primary tumors that had no lymph node metastasis. CPTAC analysis show higher tumor c-Jun levels compared to normal. Patients with high JUN expression had significantly reduced 3-year survival. Conclusions: A-DiFiD targets c-Jun, a clinical HNSCC driver, with potent anti-tumor effects.
{"title":"Acryl-3,5-bis(2,4-difluorobenzylidene)-4-piperidone targeting cellular JUN proto-oncogene, AP-1 transcription factor subunit inhibits head and neck squamous cell carcinoma progression","authors":"Levi Arnold, Juan Pineda Gomez, Michael Barry, Marrion Yap, Laura Jackson, Thuc Ly, David Standing, Subhash B. Padhye, Bernhard Biersack, Shrikant Anant, Sufi Mary Thomas","doi":"10.37349/etat.2023.00184","DOIUrl":"https://doi.org/10.37349/etat.2023.00184","url":null,"abstract":"Aim: Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide with a survival rate below fifty percent. Addressing meager therapeutic options, a series of small molecule inhibitors were screened for antitumor efficacy. The most potent analog, acryl-3,5-bis(2,4-difluorobenzylidene)-4-piperidone (DiFiD; A-DiFiD), demonstrated strong cellular JUN proto-oncogene, activator protein 1 (AP-1) transcription factor subunit (JUN, c-Jun) antagonism. c-Jun, an oncogenic transcription factor, promotes cancer progression, invasion, and adhesion; high (JUN) mRNA expression correlates with poorer HNSCC survival. Methods: Four new small molecules were generated for cytotoxicity screening in HNSCC cell lines. A-DiFiD-treated HNSCC cells were assessed for cytotoxicity, colony formation, invasion, migration, and adhesion. Dot blot array was used to identify targets. Phospho-c-Jun (p-c-Jun) expression was analyzed using immunoblotting. The Cancer Genome Atlas (TCGA) head and neck cancer datasets were utilized to determine overall patient survival. The Clinical Proteomic Tumor Analysis Consortium (CPTAC) datasets interfaced with University of Alabama at Birmingham Cancer Data Analysis Portal (UALCAN) were analyzed to determine protein levels of c-Jun in HNSCC patients and correlate levels with patient. Results: Of the small molecules tested, A-DiFiD was the most potent in HNSCC lines, while demonstrating low half-maximal drug inhibitory concentration (IC50) in non-malignant Het-1A cells. Additionally, A-DiFiD abrogated cell invasion, migration, and colony formation. Phospho-kinase in vitro array demonstrated A-DiFiD reduced p-c-Jun. Likewise, a time dependent reduction in p-c-Jun was observed starting at 3 min post A-DiFiD treatment. TCGA Firehose Legacy vs. recurrent and metastatic head and neck cancer reveal a nearly 3% DNA amplification in recurrent/metastatic tumor compared to below 1% in primary tumors that had no lymph node metastasis. CPTAC analysis show higher tumor c-Jun levels compared to normal. Patients with high JUN expression had significantly reduced 3-year survival. Conclusions: A-DiFiD targets c-Jun, a clinical HNSCC driver, with potent anti-tumor effects.","PeriodicalId":73002,"journal":{"name":"Exploration of targeted anti-tumor therapy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135870010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-10-31DOI: 10.37349/etat.2023.00185
Youjun Li, Michael Karin, Edward V. Prochownik
Many human cancers carry missense mutations in or deletions of the tumor protein 53 (TP53) tumor suppressor gene. TP53’s product, p53 regulates many biological processes, including cell metabolism. Cholesterol is a key lipid needed for the maintenance of membrane function and tissue homeostasis while also serving as a precursor for steroid hormone and bile acid synthesis. An over-abundance of cholesterol can lead to its esterification and storage as cholesterol esters. The recent study has shown that the loss of p53 leads to excessive cholesterol ester biosynthesis, which promotes hepatocellular carcinoma in mice. Blocking cholesterol esterification improves treatment outcomes, particularly for liver cancers with p53 deletions/mutations that originate in a background of non-alcoholic fatty liver disease.
{"title":"Cholesterol esterification and p53-mediated tumor suppression","authors":"Youjun Li, Michael Karin, Edward V. Prochownik","doi":"10.37349/etat.2023.00185","DOIUrl":"https://doi.org/10.37349/etat.2023.00185","url":null,"abstract":"Many human cancers carry missense mutations in or deletions of the tumor protein 53 (TP53) tumor suppressor gene. TP53’s product, p53 regulates many biological processes, including cell metabolism. Cholesterol is a key lipid needed for the maintenance of membrane function and tissue homeostasis while also serving as a precursor for steroid hormone and bile acid synthesis. An over-abundance of cholesterol can lead to its esterification and storage as cholesterol esters. The recent study has shown that the loss of p53 leads to excessive cholesterol ester biosynthesis, which promotes hepatocellular carcinoma in mice. Blocking cholesterol esterification improves treatment outcomes, particularly for liver cancers with p53 deletions/mutations that originate in a background of non-alcoholic fatty liver disease.","PeriodicalId":73002,"journal":{"name":"Exploration of targeted anti-tumor therapy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135871696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-10-30DOI: 10.37349/etat.2023.00181
Christos Ladias, Pavlos Papakotoulas, Maria Papaioannou, Nikolaos A. Papanikolaou
Alternative protein-protein interactions (PPIs) arising from mutations or post-translational modifications (PTMs), termed phenotypic switching (PS), are critical for the transmission of alternative pathogenic signals and are particularly significant in cancer. In recent years, PPIs have emerged as promising targets for rational drug design, primarily because their high specificity facilitates targeting of disease-related signaling pathways. However, obstacles exist at the molecular level that arise from the properties of the interaction interfaces and the propensity of small molecule drugs to interact with more than one cleft surface. The difficulty in identifying small molecules that act as activators or inhibitors to counteract the biological effects of mutations raises issues that have not been encountered before. For example, small molecules can bind tightly but may not act as drugs or bind to multiple sites (interaction promiscuity). Another reason is the absence of significant clefts on protein surfaces; if a pocket is present, it may be too small, or its geometry may prevent binding. PS, which arises from oncogenic (alternative) signaling, causes drug resistance and forms the basis for the systemic robustness of tumors. In this review, the properties of PPI interfaces relevant to the design and development of targeting drugs are examined. In addition, the interactions between three tyrosine kinase inhibitors (TKIs) employed as drugs are discussed. Finally, potential novel targets of one of these drugs were identified in silico.
{"title":"Overcoming phenotypic switching: targeting protein-protein interactions in cancer","authors":"Christos Ladias, Pavlos Papakotoulas, Maria Papaioannou, Nikolaos A. Papanikolaou","doi":"10.37349/etat.2023.00181","DOIUrl":"https://doi.org/10.37349/etat.2023.00181","url":null,"abstract":"Alternative protein-protein interactions (PPIs) arising from mutations or post-translational modifications (PTMs), termed phenotypic switching (PS), are critical for the transmission of alternative pathogenic signals and are particularly significant in cancer. In recent years, PPIs have emerged as promising targets for rational drug design, primarily because their high specificity facilitates targeting of disease-related signaling pathways. However, obstacles exist at the molecular level that arise from the properties of the interaction interfaces and the propensity of small molecule drugs to interact with more than one cleft surface. The difficulty in identifying small molecules that act as activators or inhibitors to counteract the biological effects of mutations raises issues that have not been encountered before. For example, small molecules can bind tightly but may not act as drugs or bind to multiple sites (interaction promiscuity). Another reason is the absence of significant clefts on protein surfaces; if a pocket is present, it may be too small, or its geometry may prevent binding. PS, which arises from oncogenic (alternative) signaling, causes drug resistance and forms the basis for the systemic robustness of tumors. In this review, the properties of PPI interfaces relevant to the design and development of targeting drugs are examined. In addition, the interactions between three tyrosine kinase inhibitors (TKIs) employed as drugs are discussed. Finally, potential novel targets of one of these drugs were identified in silico.","PeriodicalId":73002,"journal":{"name":"Exploration of targeted anti-tumor therapy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136103505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-10-30DOI: 10.37349/etat.2023.00180
Marzieh Tahmasebi, Masoud Veissi, Seyed Ahmad Hosseini, Amir Jamshidnezhad
Aim: This study aimed to establish a learning system using an artificial neural network (ANN) to predict the effects of vitamin D supplementation on the serum levels of vitamin D, inflammatory factors, and total antioxidant capacity (TAC) in women with breast cancer. Methods: The data set of the current project was created from women with breast cancer who were referred to the Shafa State Hospital of Patients with Cancers in Ahvaz city, Iran. Modeling was implemented using the data set at the serum levels of vitamin D, tumor necrosis factor-α (TNF-α), transforming growth factor β (TGF-β), and TAC, before and after vitamin D3 supplement therapy. A prediction ANN model was designed to detect the effects of vitamin D3 supplementation on the serum level changes of vitamin D, inflammatory factors and TAC. Results: The results showed that the ANN model could predict the effect of vitamin D3 supplementation on the serum level changes of vitamin D, TNF-α, TGF-β1, and TAC with an accuracy average of 85%, 40%, 89.5%, and 88.1%, respectively. Conclusions: According to the findings of the study, the ANN method could accurately predict the effect of vitamin D3 supplementation on the serum levels of vitamin D, TNF-α, TGF-β1, and TAC. The results showed that the proposed ANN method can help specialists to improve the treatment process more confidently in terms of time and accuracy of predicting the influence of vitamin D supplementation on the factors affecting the progression of breast cancer (https://www.irct.ir/ identifier: IRCT2015090623924N1).
{"title":"Effect of vitamin D supplementation on inflammatory markers and total antioxidant capacity in breast cancer women using a machine learning technique","authors":"Marzieh Tahmasebi, Masoud Veissi, Seyed Ahmad Hosseini, Amir Jamshidnezhad","doi":"10.37349/etat.2023.00180","DOIUrl":"https://doi.org/10.37349/etat.2023.00180","url":null,"abstract":"Aim: This study aimed to establish a learning system using an artificial neural network (ANN) to predict the effects of vitamin D supplementation on the serum levels of vitamin D, inflammatory factors, and total antioxidant capacity (TAC) in women with breast cancer. Methods: The data set of the current project was created from women with breast cancer who were referred to the Shafa State Hospital of Patients with Cancers in Ahvaz city, Iran. Modeling was implemented using the data set at the serum levels of vitamin D, tumor necrosis factor-α (TNF-α), transforming growth factor β (TGF-β), and TAC, before and after vitamin D3 supplement therapy. A prediction ANN model was designed to detect the effects of vitamin D3 supplementation on the serum level changes of vitamin D, inflammatory factors and TAC. Results: The results showed that the ANN model could predict the effect of vitamin D3 supplementation on the serum level changes of vitamin D, TNF-α, TGF-β1, and TAC with an accuracy average of 85%, 40%, 89.5%, and 88.1%, respectively. Conclusions: According to the findings of the study, the ANN method could accurately predict the effect of vitamin D3 supplementation on the serum levels of vitamin D, TNF-α, TGF-β1, and TAC. The results showed that the proposed ANN method can help specialists to improve the treatment process more confidently in terms of time and accuracy of predicting the influence of vitamin D supplementation on the factors affecting the progression of breast cancer (https://www.irct.ir/ identifier: IRCT2015090623924N1).","PeriodicalId":73002,"journal":{"name":"Exploration of targeted anti-tumor therapy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136103676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Aim: Coronavirus disease 2019 (COVID-19) became pandemic on 11th March 2020 and it deeply stressed the healthcare system. Cancer patients represent a vulnerable population, so many recommendations have been approved to ensure optimal management. Clinical research was notably impacted by COVID too. This review aims to analyze the challenges occurred during a pandemic for the management of enrolled patients (enrollment, use of telemedicine visits, study procedures) and for the clinical trials system (from feasibility to selection visit, site initiation visit, monitorings, use of e-signature, deviations and discontinuations). Methods: The studies included in the present review were selected from PubMed/Google Scholar/ScienceDirect databases. Results: During the first phase of pandemic many clinical trials were suspended in accrual and, as the pandemic progressed, recommendations were established to guarantee the safety and the continuity of care of enrolled patients. In addition, lot of new strategies was found during the pandemic to reduce the negative consequences on clinical trial performance and to guarantee new opportunities of care in the respect of good clinical practice (GCP) in a bad scenario. Conclusions: Among all modifiers, investigators would prefer to maintain the positive ones such as pragmatic and simplified trial designs and protocols, reducing in-person visits when not necessary and to minimizing sponsor and contract research organizations (CROs) visits.
{"title":"Impact of coronavirus disease 2019 pandemic on good clinical practice trials in oncology","authors":"Veronica Agostinelli, Zelmira Ballatore, Giulia Ricci, Alessandra Lucarelli, Michela Burattini, Lorenzo Mariotti, Claudia Catani, Valentina Tarantino, Rossana Berardi","doi":"10.37349/etat.2023.00183","DOIUrl":"https://doi.org/10.37349/etat.2023.00183","url":null,"abstract":"Aim: Coronavirus disease 2019 (COVID-19) became pandemic on 11th March 2020 and it deeply stressed the healthcare system. Cancer patients represent a vulnerable population, so many recommendations have been approved to ensure optimal management. Clinical research was notably impacted by COVID too. This review aims to analyze the challenges occurred during a pandemic for the management of enrolled patients (enrollment, use of telemedicine visits, study procedures) and for the clinical trials system (from feasibility to selection visit, site initiation visit, monitorings, use of e-signature, deviations and discontinuations). Methods: The studies included in the present review were selected from PubMed/Google Scholar/ScienceDirect databases. Results: During the first phase of pandemic many clinical trials were suspended in accrual and, as the pandemic progressed, recommendations were established to guarantee the safety and the continuity of care of enrolled patients. In addition, lot of new strategies was found during the pandemic to reduce the negative consequences on clinical trial performance and to guarantee new opportunities of care in the respect of good clinical practice (GCP) in a bad scenario. Conclusions: Among all modifiers, investigators would prefer to maintain the positive ones such as pragmatic and simplified trial designs and protocols, reducing in-person visits when not necessary and to minimizing sponsor and contract research organizations (CROs) visits.","PeriodicalId":73002,"journal":{"name":"Exploration of targeted anti-tumor therapy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136103673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-10-30DOI: 10.37349/etat.2023.00182
Abrahams Ocanto, Xabier Mielgo-Rubio, Javier Luna Tirado, Nuria Linares Mesa, Marta López Valcárcel, Sara Pedraza, Victoria Vera Barragan, Patricia Valencia Nieto, Juan Zafra Martín, Felipe Couñago
Oncology patients are more susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection due to hospital contact and an immunological system that can be compromised by antineoplastic therapy and supportive treatments. Certain similarities have been described in the physiopathology of coronavirus disease 2019 (COVID-19) and lung cancer (LC) that may explain the higher probability of these patients of developing a more serious disease with more frequent hospitalizations and even death, especially with the addition of smoking, cardiovascular and respiratory comorbidities, old age and corticosteroids use. Pre-existing lesions and cancer therapies change the normal architecture of the lungs, so diagnostic scales such as COVID-19 Reporting and Data System (CO-RADS) are of vital importance for a correct diagnosis and patient homogenization, with a high inter-observer correlation. Moreover, anticancer treatments have required an adaptation to reduce the number of visits to the hospital [hypofractionated radiotherapy (RT), larger intervals between chemotherapy cycles, delay in follow-up tests, among others]. In a way, this has also caused a delay in the diagnosis of new cancers. On the other hand, vaccination has had a positive impact on the mortality of these patients, who maintain a similar seroprevalence to the rest of the population, with a similar impact in mortality.
{"title":"Coronavirus disease 2019 and lung cancer: where are we?","authors":"Abrahams Ocanto, Xabier Mielgo-Rubio, Javier Luna Tirado, Nuria Linares Mesa, Marta López Valcárcel, Sara Pedraza, Victoria Vera Barragan, Patricia Valencia Nieto, Juan Zafra Martín, Felipe Couñago","doi":"10.37349/etat.2023.00182","DOIUrl":"https://doi.org/10.37349/etat.2023.00182","url":null,"abstract":"Oncology patients are more susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection due to hospital contact and an immunological system that can be compromised by antineoplastic therapy and supportive treatments. Certain similarities have been described in the physiopathology of coronavirus disease 2019 (COVID-19) and lung cancer (LC) that may explain the higher probability of these patients of developing a more serious disease with more frequent hospitalizations and even death, especially with the addition of smoking, cardiovascular and respiratory comorbidities, old age and corticosteroids use. Pre-existing lesions and cancer therapies change the normal architecture of the lungs, so diagnostic scales such as COVID-19 Reporting and Data System (CO-RADS) are of vital importance for a correct diagnosis and patient homogenization, with a high inter-observer correlation. Moreover, anticancer treatments have required an adaptation to reduce the number of visits to the hospital [hypofractionated radiotherapy (RT), larger intervals between chemotherapy cycles, delay in follow-up tests, among others]. In a way, this has also caused a delay in the diagnosis of new cancers. On the other hand, vaccination has had a positive impact on the mortality of these patients, who maintain a similar seroprevalence to the rest of the population, with a similar impact in mortality.","PeriodicalId":73002,"journal":{"name":"Exploration of targeted anti-tumor therapy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136103579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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