Pub Date : 2016-11-23DOI: 10.18632/oncoscience.326
H. Bid, S. Kerk
Angiogenesis is one of the most critical multi-step biological essentials affecting the development and progression of cancer. It has been explored for decades as a potential target for therapy after endless preclinical and clinical studies. Currently, conceptually promising FDA-approved agents, such as bevacizumab (Avastin, Genentech/Roche), sorafenib (Nexavar, Bayer), and sunitinib (Sutent, Pfizer), have twisted only modest effects in the clinic and do not result in lasting responses of cancer treatment [1]. Tumors have proven to be either intrinsic resistant or acquired resistance through evasion via mutation or recruitment of surplus pro-angiogenic factors [1]. Molecular targeted therapies comprising anti-antiangiogenic potential are becoming more widely accepted in drug discovery era as compared to established anticancer treatment approaches and have more promising results in numerous types of cancers. JQ1, a bromodomain inhibitor produced by James Bradner, (Tensha Therapeutics acquired by Roche) has direct antitumor and antiangiogenic properties. This small molecule inhibitor targets BRD4, a member of the bromodomain and extra-terminal (BET) family of transcription factors. BRD4 binds to acetylated lysine residues within chromatin, and recruits positive transcription elongation factor (P-TEFb) and other super enhancers involved in transcription. JQ-1 prevents the BRD4-acetylated lysine interaction by competitively binding to BRD4 and inhibiting transcription. In multiple myeloma (MM), a disease frequently associated with dysregulated BET activity, a direct interaction between BRD4 and IgH enhancers located within the MYC locus was observed. JQ1 prohibited this interaction, suppressed MYC transcription, and reduced the levels of downstream effectors. JQ1 treatment induced cell senescence and apoptosis in multiple MM cell lines, and slowed tumor growth and in orthotopic MM mouse models leading to increased survival [2]. The ability of JQ-1 to inhibit MYC transcription has important implications in angiogenesis via blocking VEGF, notch pathway, etc (Figure 1). One study observed that c-Myc knockout mice displayed dysfunctional endothelial cell activity and impaired vascular development in embryonic yolk sacs. Furthermore, the loss of c-Myc reduced the tumorogenicity and differentiation ability of embryonic stem (ES) cells. Reintroducing VEGF reversed the effects of c-Myc knockout. C-Myc also increased the expression of other pro-angiogenic factors such as angiopoietin-2 (ANG-2) and down-regulated anti-angiogenic factors like ANG-1 and thrombospondin-1 (TSP-1) [3]. Indeed, in a study with a transgenic mouse model of Myc oncogenesis, overexpressing Myc in pancreatic β cells quickly increased the expression of the inflammatory cytokine IL-1β, activating matrix metalloproteases (MMP) that in turn released VEGF-A sequestered in the extracellular matrix (ECM). VEGF-A localized to its …
{"title":"BET bromodomain inhibitor (JQ1) and tumor angiogenesis","authors":"H. Bid, S. Kerk","doi":"10.18632/oncoscience.326","DOIUrl":"https://doi.org/10.18632/oncoscience.326","url":null,"abstract":"Angiogenesis is one of the most critical multi-step biological essentials affecting the development and progression of cancer. It has been explored for decades as a potential target for therapy after endless preclinical and clinical studies. Currently, conceptually promising FDA-approved agents, such as bevacizumab (Avastin, Genentech/Roche), sorafenib (Nexavar, Bayer), and sunitinib (Sutent, Pfizer), have twisted only modest effects in the clinic and do not result in lasting responses of cancer treatment [1]. Tumors have proven to be either intrinsic resistant or acquired resistance through evasion via mutation or recruitment of surplus pro-angiogenic factors [1]. Molecular targeted therapies comprising anti-antiangiogenic potential are becoming more widely accepted in drug discovery era as compared to established anticancer treatment approaches and have more promising results in numerous types of cancers. JQ1, a bromodomain inhibitor produced by James Bradner, (Tensha Therapeutics acquired by Roche) has direct antitumor and antiangiogenic properties. This small molecule inhibitor targets BRD4, a member of the bromodomain and extra-terminal (BET) family of transcription factors. BRD4 binds to acetylated lysine residues within chromatin, and recruits positive transcription elongation factor (P-TEFb) and other super enhancers involved in transcription. JQ-1 prevents the BRD4-acetylated lysine interaction by competitively binding to BRD4 and inhibiting transcription. In multiple myeloma (MM), a disease frequently associated with dysregulated BET activity, a direct interaction between BRD4 and IgH enhancers located within the MYC locus was observed. JQ1 prohibited this interaction, suppressed MYC transcription, and reduced the levels of downstream effectors. JQ1 treatment induced cell senescence and apoptosis in multiple MM cell lines, and slowed tumor growth and in orthotopic MM mouse models leading to increased survival [2]. The ability of JQ-1 to inhibit MYC transcription has important implications in angiogenesis via blocking VEGF, notch pathway, etc (Figure 1). One study observed that c-Myc knockout mice displayed dysfunctional endothelial cell activity and impaired vascular development in embryonic yolk sacs. Furthermore, the loss of c-Myc reduced the tumorogenicity and differentiation ability of embryonic stem (ES) cells. Reintroducing VEGF reversed the effects of c-Myc knockout. C-Myc also increased the expression of other pro-angiogenic factors such as angiopoietin-2 (ANG-2) and down-regulated anti-angiogenic factors like ANG-1 and thrombospondin-1 (TSP-1) [3]. Indeed, in a study with a transgenic mouse model of Myc oncogenesis, overexpressing Myc in pancreatic β cells quickly increased the expression of the inflammatory cytokine IL-1β, activating matrix metalloproteases (MMP) that in turn released VEGF-A sequestered in the extracellular matrix (ECM). VEGF-A localized to its …","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"3 1","pages":"316 - 317"},"PeriodicalIF":0.0,"publicationDate":"2016-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87776969","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 : 2016-11-23DOI: 10.18632/oncoscience.325
R. C. Poulos, J. W. Wong
In recent years, somatic mutations in cis-regulatory elements of cancer genomes have become a focus of much research. A landmark discovery occurred in 2013, in which recurrent somatic mutations were identified in the promoter of the key cancer-associated gene, TERT (reviewed in [1]). In the search for other highly recurrent cis-regulatory mutations which may serve as novel driver events, two papers, published in 2014 [2, 3], revealed somewhat surprising results. These studies investigated large cohorts of cancer genomes and found that, despite identifying many recurrent promoter mutations, few could be associated with gene expression changes. Of those that did alter gene expression, many of their target genes did not have strong links to cancer development. We also published similar unexpected findings in a genomewide survey of promoter mutations in the melanoma cellline, COLO829 [4]. The study showed that while some regulatory mutations can alter promoter activity (~17% of mutant promoter regions surveyed), one such mutation that was recurrent (~4.4%) in other melanomas was not associated with altered gene expression in actual cancer samples [4]. Remarkably, we additionally observed that of the 14 remaining promoter mutations surveyed to not alter promoter activity, five mutations were also recurrent in melanoma samples. Together these articles raised the question of why there are such high rates of recurrence among promoter mutations if many do not appear to arise due to their oncogenic ability to alter gene expression.
{"title":"Mutation hotspots in cis-regulatory regions in cancer","authors":"R. C. Poulos, J. W. Wong","doi":"10.18632/oncoscience.325","DOIUrl":"https://doi.org/10.18632/oncoscience.325","url":null,"abstract":"In recent years, somatic mutations in cis-regulatory elements of cancer genomes have become a focus of much research. A landmark discovery occurred in 2013, in which recurrent somatic mutations were identified in the promoter of the key cancer-associated gene, TERT (reviewed in [1]). In the search for other highly recurrent cis-regulatory mutations which may serve as novel driver events, two papers, published in 2014 [2, 3], revealed somewhat surprising results. These studies investigated large cohorts of cancer genomes and found that, despite identifying many recurrent promoter mutations, few could be associated with gene expression changes. Of those that did alter gene expression, many of their target genes did not have strong links to cancer development. We also published similar unexpected findings in a genomewide survey of promoter mutations in the melanoma cellline, COLO829 [4]. The study showed that while some regulatory mutations can alter promoter activity (~17% of mutant promoter regions surveyed), one such mutation that was recurrent (~4.4%) in other melanomas was not associated with altered gene expression in actual cancer samples [4]. Remarkably, we additionally observed that of the 14 remaining promoter mutations surveyed to not alter promoter activity, five mutations were also recurrent in melanoma samples. Together these articles raised the question of why there are such high rates of recurrence among promoter mutations if many do not appear to arise due to their oncogenic ability to alter gene expression.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"4 1","pages":"318 - 319"},"PeriodicalIF":0.0,"publicationDate":"2016-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83056216","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 : 2016-11-21DOI: 10.18632/oncoscience.328
K. Kataoka, S. Ogawa
Immune checkpoint blockade therapy using antibodies against programmed cell death 1 (PD-1) and PD-1 ligand 1 (PD-L1) is revolutionizing cancer treatment (1-3). These antibodies provide long-term durable responses for patients with various types of advanced cancers, such as melanoma, non–small-cell lung cancer, kidney cancer, and Hodgkin lymphoma (1-3). Accumulating evidence suggests that these agents convey their therapeutic effects through targeting the PD-1/PD-L1 immune checkpoint to unleash anti-tumor immune responses. In turn, it is supposed that cancer cells depend critically on evading immune surveillance for their malignant growth. As immune checkpoint blockade therapy has benefited only a subset of patients, defining biomarkers that can predict therapeutic efficacy and adverse effects is of urgent importance, which is substantiated by recent approvals for PD-L1 diagnostic tests (2). Here we provide a brief overview of the recent development of genetic biomarkers for PD-1/PD-L1 blockade therapies, with special focus on PD-L1 genetic abnormalities, including its 3′-UTR disruption. Early studies demonstrated the potential value of immunological biomarkers, such as intratumoral lymphoid infiltrates and PD-L1 expression on tumor or infiltrating immune cells, for predicting response to PD-1/PD-L1 blockade (1, 2). However, subsequent studies have revealed a lower but significant response rate in patients with PD-L1-tumors, raising questions about the utility of these immunological markers as an ideal selection criterion for PD-1/PD-L1 blockade therapy (2). Indeed, estimated from the results across 15 studies including various solid cancer types, the overall response rate to PD-1/PD-L1 blockade was 48% in patients with PD-L1 + tumors, in contrast to 15% in those with PD-L1-tumors. In addition, especially in clinical setting, accurate measurement and scoring of PD-L1 protein expression are hampered by a variety of technical and biological pitfalls (2). Genomics-based approaches have the potential to complement immunological biomarkers. In particular, Rizvi et al. demonstrated that a higher load of nonsynonymous mutations and neoantigens detected by whole-exome sequencing positively correlated with clinical response to an anti-PD-1 antibody (pembrolizumab) in non-small cell lung cancer (NSCLC) patients. Moreover, candidate neoantigens were experimentally validated using a high-throughput multimer screening to identify neoantigen-specific T cells. In one responder, neoantigen-specific T-cell reactivity paralleled tumor regression (4). In addition to neoantigen load, the extent of neoantigen intratumoral heterogeneity (ITH) within single tumors affects the sensitivity to immune modulation. An integrated analysis of ITH and neoantigen burden showed that the response to PD-1 blockade in patients with NSCLC was enhanced in tumors enriched for clonal neoantigens, i.e., those shared …
{"title":"Genetic biomarkers for PD-1/PD-L1 blockade therapy","authors":"K. Kataoka, S. Ogawa","doi":"10.18632/oncoscience.328","DOIUrl":"https://doi.org/10.18632/oncoscience.328","url":null,"abstract":"Immune checkpoint blockade therapy using antibodies against programmed cell death 1 (PD-1) and PD-1 ligand 1 (PD-L1) is revolutionizing cancer treatment (1-3). These antibodies provide long-term durable responses for patients with various types of advanced cancers, such as melanoma, non–small-cell lung cancer, kidney cancer, and Hodgkin lymphoma (1-3). Accumulating evidence suggests that these agents convey their therapeutic effects through targeting the PD-1/PD-L1 immune checkpoint to unleash anti-tumor immune responses. In turn, it is supposed that cancer cells depend critically on evading immune surveillance for their malignant growth. As immune checkpoint blockade therapy has benefited only a subset of patients, defining biomarkers that can predict therapeutic efficacy and adverse effects is of urgent importance, which is substantiated by recent approvals for PD-L1 diagnostic tests (2). Here we provide a brief overview of the recent development of genetic biomarkers for PD-1/PD-L1 blockade therapies, with special focus on PD-L1 genetic abnormalities, including its 3′-UTR disruption. Early studies demonstrated the potential value of immunological biomarkers, such as intratumoral lymphoid infiltrates and PD-L1 expression on tumor or infiltrating immune cells, for predicting response to PD-1/PD-L1 blockade (1, 2). However, subsequent studies have revealed a lower but significant response rate in patients with PD-L1-tumors, raising questions about the utility of these immunological markers as an ideal selection criterion for PD-1/PD-L1 blockade therapy (2). Indeed, estimated from the results across 15 studies including various solid cancer types, the overall response rate to PD-1/PD-L1 blockade was 48% in patients with PD-L1 + tumors, in contrast to 15% in those with PD-L1-tumors. In addition, especially in clinical setting, accurate measurement and scoring of PD-L1 protein expression are hampered by a variety of technical and biological pitfalls (2). Genomics-based approaches have the potential to complement immunological biomarkers. In particular, Rizvi et al. demonstrated that a higher load of nonsynonymous mutations and neoantigens detected by whole-exome sequencing positively correlated with clinical response to an anti-PD-1 antibody (pembrolizumab) in non-small cell lung cancer (NSCLC) patients. Moreover, candidate neoantigens were experimentally validated using a high-throughput multimer screening to identify neoantigen-specific T cells. In one responder, neoantigen-specific T-cell reactivity paralleled tumor regression (4). In addition to neoantigen load, the extent of neoantigen intratumoral heterogeneity (ITH) within single tumors affects the sensitivity to immune modulation. An integrated analysis of ITH and neoantigen burden showed that the response to PD-1 blockade in patients with NSCLC was enhanced in tumors enriched for clonal neoantigens, i.e., those shared …","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"1987 1","pages":"311 - 312"},"PeriodicalIF":0.0,"publicationDate":"2016-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82275313","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 : 2016-11-17DOI: 10.18632/oncoscience.323
Stefanie B. Marquez-Vilendrer, S. Rai, Sarah J B Gramling, Li Lu, D. Reisman
Inactivation of Brg1 and Brm accelerated lung tumor development, shortened tumor latency, and caused a loss of differentiation. Tumors with Brg1 and/or Brm loss recapitulated the evolution of human lung cancer as observed by the development of local tumor invasion as well as distal tumor metastasis, thereby making this model useful in lung cancer studies. Brg1 loss contributed to metastasis in part by driving E-cadherin loss and Vimentin up-regulation. By changing more than 6% of the murine genome with the down-regulation of tumor suppressors, DNA repair, differentiation and cell adhesion genes, and the concomitant up-regulation of oncogenes, angiogenesis, metastasis and antiapoptosis genes, caused by the dual loss of Brg1/Brm further accelerated tumor development. Additionally, this Brg1/Brm-driven change in gene expression resulted in a nearly two-fold increase in tumorigenicity in Brg1/Brm knockout mice compared with wild type mice. Most importantly, Brg1/Brm-driven lung cancer development histologically and clinically reflects human lung cancer development thereby making this GEMM model potentially useful.
{"title":"Loss of the SWI/SNF ATPase subunits BRM and BRG1 drives lung cancer development","authors":"Stefanie B. Marquez-Vilendrer, S. Rai, Sarah J B Gramling, Li Lu, D. Reisman","doi":"10.18632/oncoscience.323","DOIUrl":"https://doi.org/10.18632/oncoscience.323","url":null,"abstract":"Inactivation of Brg1 and Brm accelerated lung tumor development, shortened tumor latency, and caused a loss of differentiation. Tumors with Brg1 and/or Brm loss recapitulated the evolution of human lung cancer as observed by the development of local tumor invasion as well as distal tumor metastasis, thereby making this model useful in lung cancer studies. Brg1 loss contributed to metastasis in part by driving E-cadherin loss and Vimentin up-regulation. By changing more than 6% of the murine genome with the down-regulation of tumor suppressors, DNA repair, differentiation and cell adhesion genes, and the concomitant up-regulation of oncogenes, angiogenesis, metastasis and antiapoptosis genes, caused by the dual loss of Brg1/Brm further accelerated tumor development. Additionally, this Brg1/Brm-driven change in gene expression resulted in a nearly two-fold increase in tumorigenicity in Brg1/Brm knockout mice compared with wild type mice. Most importantly, Brg1/Brm-driven lung cancer development histologically and clinically reflects human lung cancer development thereby making this GEMM model potentially useful.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"52 1","pages":"322 - 336"},"PeriodicalIF":0.0,"publicationDate":"2016-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75892238","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 : 2016-11-15DOI: 10.18632/oncoscience.324
F. Bertucci, A. Gonçalves, P. Viens
Inflammatory breast cancer (IBC) is a rare (~5%) but aggressive form of breast cancer with high metastatic potential [1]. Despite the successful introduction of neoadjuvant anthracycline/taxane-based chemotherapy, combined with neoadjuvant/adjuvant trastuzumab in case of HER2-positivity and adjuvant hormone therapy in case of hormone receptor (HR)-positivity, the 5-year survival ranges from 50 to 60% as compared to more than 85% in non-IBC. Besides its aggressiveness and frequent resistance to treatment, IBC displays other characteristics that make progresses difficult. The disease is rare and the diagnosis challenging, based on clinical signs including rapid (no more than 6 months) onset of breast erythema and oedema, with or without underlying palpable mass. Such features exclude IBC from mass screening, lead to frequent misdiagnosis and delayed diagnosis, and complicate the setup of IBC-specific clinical trials. However, IBC is biologically different from non-IBC [2]. Notably, IBCs are more angiogenic tumours than non-IBC, displaying higher microvessel density, and showing presence of dermal lymphovascular tumour emboli. Combined with the negative prognostic value of VEGF expression, these observations made IBC attractive for testing anti-angiogenic drugs. Based on these observations, and with the intent to continue to study IBC as a separate entity as we did previously [3, 4], we launched in 2008 the BEVERLY-1 trial, a French, multicentric, single arm, prospective phase 2 trial assessing the benefit of neoadjuvant/ adjuvant bevacizumab in patients with HER2-negative (BEVERLY-1) non-metastatic IBC. Bevacizumab is a monoclonal antibody that inhibits tumour angiogenesis by targeting VEGF, approved in 2008 by the US Food and Drug Administration under an accelerated plan in combination with chemotherapy in metastatic breast cancer. During the neo-adjuvant phase, the patients received four cycles of FEC100 plus bevacizumab every three weeks, followed by four cycles of docetaxel plus bevacizumab every three weeks. Then, the surgery included total mastectomy and axillary lymph node dissection, and was followed by adjuvant radiation therapy plus 10 cycles of bevacizumab (every 3 weeks), and hormone therapy if the tumour was HR-positive. Each patient theoretically received 8 cycles of neo-adjuvant chemotherapy and 18 cycles of neo-adjuvant/adjuvant bevacizumab. The primary endpoint was the pathological complete response (pCR) rate in breast and axillary lymph nodes after neo-adjuvant treatment, centrally assessed using the Sataloff classification: the regimen was regarded as efficacious if 30% or more patients had a pCR. Secondary endpoints included disease-free survival (DFS), overall survival (OS), safety, and analysis of circulating tumour cells and endothelial cells. BEVERLY-1 was the …
{"title":"Bevacizumab in HER2-negative inflammatory breast cancer","authors":"F. Bertucci, A. Gonçalves, P. Viens","doi":"10.18632/oncoscience.324","DOIUrl":"https://doi.org/10.18632/oncoscience.324","url":null,"abstract":"Inflammatory breast cancer (IBC) is a rare (~5%) but aggressive form of breast cancer with high metastatic potential [1]. Despite the successful introduction of neoadjuvant anthracycline/taxane-based chemotherapy, combined with neoadjuvant/adjuvant trastuzumab in case of HER2-positivity and adjuvant hormone therapy in case of hormone receptor (HR)-positivity, the 5-year survival ranges from 50 to 60% as compared to more than 85% in non-IBC. Besides its aggressiveness and frequent resistance to treatment, IBC displays other characteristics that make progresses difficult. The disease is rare and the diagnosis challenging, based on clinical signs including rapid (no more than 6 months) onset of breast erythema and oedema, with or without underlying palpable mass. Such features exclude IBC from mass screening, lead to frequent misdiagnosis and delayed diagnosis, and complicate the setup of IBC-specific clinical trials. However, IBC is biologically different from non-IBC [2]. Notably, IBCs are more angiogenic tumours than non-IBC, displaying higher microvessel density, and showing presence of dermal lymphovascular tumour emboli. Combined with the negative prognostic value of VEGF expression, these observations made IBC attractive for testing anti-angiogenic drugs. Based on these observations, and with the intent to continue to study IBC as a separate entity as we did previously [3, 4], we launched in 2008 the BEVERLY-1 trial, a French, multicentric, single arm, prospective phase 2 trial assessing the benefit of neoadjuvant/ adjuvant bevacizumab in patients with HER2-negative (BEVERLY-1) non-metastatic IBC. Bevacizumab is a monoclonal antibody that inhibits tumour angiogenesis by targeting VEGF, approved in 2008 by the US Food and Drug Administration under an accelerated plan in combination with chemotherapy in metastatic breast cancer. During the neo-adjuvant phase, the patients received four cycles of FEC100 plus bevacizumab every three weeks, followed by four cycles of docetaxel plus bevacizumab every three weeks. Then, the surgery included total mastectomy and axillary lymph node dissection, and was followed by adjuvant radiation therapy plus 10 cycles of bevacizumab (every 3 weeks), and hormone therapy if the tumour was HR-positive. Each patient theoretically received 8 cycles of neo-adjuvant chemotherapy and 18 cycles of neo-adjuvant/adjuvant bevacizumab. The primary endpoint was the pathological complete response (pCR) rate in breast and axillary lymph nodes after neo-adjuvant treatment, centrally assessed using the Sataloff classification: the regimen was regarded as efficacious if 30% or more patients had a pCR. Secondary endpoints included disease-free survival (DFS), overall survival (OS), safety, and analysis of circulating tumour cells and endothelial cells. BEVERLY-1 was the …","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"19 1","pages":"297 - 298"},"PeriodicalIF":0.0,"publicationDate":"2016-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91553967","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 : 2016-10-31DOI: 10.18632/oncoscience.322
Marta Cardoso, S. Maia, P. Paulo, M. Teixeira
The recurrent germline mutation HOXB13 p.(Gly84Glu) (G84E) has recently been identified as a risk factor for prostate cancer. In a recent study, we have performed full sequencing of the HOXB13 gene in 462 Portuguese prostate cancer patients with early-onset and/or familial/hereditary disease, and identified two novel missense mutations, p.(Ala128Asp) (A128D) and p.(Phe240Leu) (F240L), that were predicted to be damaging to protein function. In the present work we aimed to investigate the potential oncogenic role of these mutations, comparing to that of the recurrent G84E mutation and wild-type HOXB13. We induced site-directed mutagenesis in a HOXB13 expression vector and established in vitro cell models of prostate carcinogenesis with stable overexpression of either the wild-type or the mutated HOXB13 variants. By performing in vitro assays we observed that, while the wild-type promotes proliferation, also observed with the F240L variant along with a decrease in apoptosis, the A128D mutation decreases apoptosis and promotes anchorage independent growth. No phenotypic impact was observed for the G84E mutation in the cell line model used. Our data show that specific HOXB13 mutations are involved in the acquisition of different cancer-associated capabilities and further support an oncogenic role for HOXB13 in prostate carcinogenesis.
{"title":"Oncogenic mechanisms of HOXB13 missense mutations in prostate carcinogenesis","authors":"Marta Cardoso, S. Maia, P. Paulo, M. Teixeira","doi":"10.18632/oncoscience.322","DOIUrl":"https://doi.org/10.18632/oncoscience.322","url":null,"abstract":"The recurrent germline mutation HOXB13 p.(Gly84Glu) (G84E) has recently been identified as a risk factor for prostate cancer. In a recent study, we have performed full sequencing of the HOXB13 gene in 462 Portuguese prostate cancer patients with early-onset and/or familial/hereditary disease, and identified two novel missense mutations, p.(Ala128Asp) (A128D) and p.(Phe240Leu) (F240L), that were predicted to be damaging to protein function. In the present work we aimed to investigate the potential oncogenic role of these mutations, comparing to that of the recurrent G84E mutation and wild-type HOXB13. We induced site-directed mutagenesis in a HOXB13 expression vector and established in vitro cell models of prostate carcinogenesis with stable overexpression of either the wild-type or the mutated HOXB13 variants. By performing in vitro assays we observed that, while the wild-type promotes proliferation, also observed with the F240L variant along with a decrease in apoptosis, the A128D mutation decreases apoptosis and promotes anchorage independent growth. No phenotypic impact was observed for the G84E mutation in the cell line model used. Our data show that specific HOXB13 mutations are involved in the acquisition of different cancer-associated capabilities and further support an oncogenic role for HOXB13 in prostate carcinogenesis.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"1 1","pages":"288 - 296"},"PeriodicalIF":0.0,"publicationDate":"2016-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88635477","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 : 2016-09-12DOI: 10.18632/oncoscience.319
Maurice Pasternak, A. Sadeghi-Naini, Shawn Ranieri, A. Giles, M. Oelze, Michael C. Kolios, G. Czarnota
High frequency quantitative ultrasound techniques were investigated to characterize different forms of cell death in vitro. Suspension-grown acute myeloid leukemia cells were treated to cause apoptosis, oncosis, mitotic arrest, and heat-induced death. Samples were scanned with 20 and 40 MHz ultrasound and assessed histologically in terms of cellular structure. Frequency-domain analysis of 20 MHz ultrasound data demonstrated midband fit changes of 6.0 ± 0.7 dBr, 6.2 ± 1.8 dBr, 4.0 ± 1.0 dBr and −4.6 ± 1.7 dBr after 48-hour cisplatinum-induced apoptosis, 48-hour oncotic decay, 36-hour colchicine-induced mitotic arrest, and heat treatment compared to control, respectively. Trends from 40 MHz ultrasound were similar. Spectral slope changes obtained from 40 MHz ultrasound data were reflective of alterations in cell and nucleus size. Chromatin pyknosis or lysis trends suggested that the density of nuclear material may be responsible for observed changes in ultrasound backscatter. Flow cytometry analysis confirmed the modes of cell death and supported midband fit trends in ultrasound data. Scatterer-size and concentration estimates obtained from a fluid-filled sphere form factor model further corresponded with spectral analysis and histology. Results indicate quantitative ultrasound spectral analysis may be used for probing anti-cancer response and distinguishing various modes of cell death in vitro.
{"title":"High-frequency ultrasound detection of cell death: Spectral differentiation of different forms of cell death in vitro","authors":"Maurice Pasternak, A. Sadeghi-Naini, Shawn Ranieri, A. Giles, M. Oelze, Michael C. Kolios, G. Czarnota","doi":"10.18632/oncoscience.319","DOIUrl":"https://doi.org/10.18632/oncoscience.319","url":null,"abstract":"High frequency quantitative ultrasound techniques were investigated to characterize different forms of cell death in vitro. Suspension-grown acute myeloid leukemia cells were treated to cause apoptosis, oncosis, mitotic arrest, and heat-induced death. Samples were scanned with 20 and 40 MHz ultrasound and assessed histologically in terms of cellular structure. Frequency-domain analysis of 20 MHz ultrasound data demonstrated midband fit changes of 6.0 ± 0.7 dBr, 6.2 ± 1.8 dBr, 4.0 ± 1.0 dBr and −4.6 ± 1.7 dBr after 48-hour cisplatinum-induced apoptosis, 48-hour oncotic decay, 36-hour colchicine-induced mitotic arrest, and heat treatment compared to control, respectively. Trends from 40 MHz ultrasound were similar. Spectral slope changes obtained from 40 MHz ultrasound data were reflective of alterations in cell and nucleus size. Chromatin pyknosis or lysis trends suggested that the density of nuclear material may be responsible for observed changes in ultrasound backscatter. Flow cytometry analysis confirmed the modes of cell death and supported midband fit trends in ultrasound data. Scatterer-size and concentration estimates obtained from a fluid-filled sphere form factor model further corresponded with spectral analysis and histology. Results indicate quantitative ultrasound spectral analysis may be used for probing anti-cancer response and distinguishing various modes of cell death in vitro.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"234 1","pages":"275 - 287"},"PeriodicalIF":0.0,"publicationDate":"2016-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74509184","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 : 2016-09-12DOI: 10.18632/oncoscience.320
Jingxian Ding, P. Hu, Jun Chen, Xiaobo Wu, Yali Cao
Background The discrepancy of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) statuses in breast cancers has been reported. Available systemic therapy for patients with breast cancer is based on the molecular subtypes as identified by IHC and/or FISH. However, these biomarkers may change throughout tumor progression. Case presentation We report a relatively uncommon case of a 39-year-old Chinese woman with local advanced breast cancer (LABC) treated with 6 cycles of docetaxel, doxorubicin and cyclophosphamide (TAC) regimen neoadjuvant chemotherapy, and subsequently mastectomy, intensity-modulated radiation therapy (IMRT) and tamoxifen followed as regularly. Brain metastatic event appeared in 6 months after mastectomy. Treatment for brain metastasis was surgical resection and followed by whole brain radiotherapy (WBRT) approved by multidisciplinary team (MDT). Initial pathological diagnosis was IDC, cT4N1M0, luminal B (ER+ 90%, PR+90%, HER2 0, Ki67+ 70%) based on ultrasound-guided core needle biopsy. Surgical pathology revealed IDC, pT2N3M0 luminal B (ER+ 20%, PR+20%, HER2 0, Ki67+ 20%). Histological response to neoadjuvant chemotherapy is grade 3 according to the Miller/Payne grading system. Final pathology of brain metastasis showed a HER2 overexpression metastatic breast cancer luminal B (ER+ 70%, PR+ 70%, HER2 2+, Ki67+ 30%), FISH confirmed HER2 overexpression. Weekly paclitaxel plus trastuzumab was given for 12 weeks, then trastuzumab every 3 weeks for a whole year. Patient follow-up is still ongoing, no new events appear yet. Conclusions The determination of hormone receptors and HER2 status should be routinely performed in all involved tissues, if possible, and systemic therapy should be tailored following the latest finding.
{"title":"The importance of tissue confirmation of metastatic disease in patients with breast cancer: lesson from a brain metastasis case","authors":"Jingxian Ding, P. Hu, Jun Chen, Xiaobo Wu, Yali Cao","doi":"10.18632/oncoscience.320","DOIUrl":"https://doi.org/10.18632/oncoscience.320","url":null,"abstract":"Background The discrepancy of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) statuses in breast cancers has been reported. Available systemic therapy for patients with breast cancer is based on the molecular subtypes as identified by IHC and/or FISH. However, these biomarkers may change throughout tumor progression. Case presentation We report a relatively uncommon case of a 39-year-old Chinese woman with local advanced breast cancer (LABC) treated with 6 cycles of docetaxel, doxorubicin and cyclophosphamide (TAC) regimen neoadjuvant chemotherapy, and subsequently mastectomy, intensity-modulated radiation therapy (IMRT) and tamoxifen followed as regularly. Brain metastatic event appeared in 6 months after mastectomy. Treatment for brain metastasis was surgical resection and followed by whole brain radiotherapy (WBRT) approved by multidisciplinary team (MDT). Initial pathological diagnosis was IDC, cT4N1M0, luminal B (ER+ 90%, PR+90%, HER2 0, Ki67+ 70%) based on ultrasound-guided core needle biopsy. Surgical pathology revealed IDC, pT2N3M0 luminal B (ER+ 20%, PR+20%, HER2 0, Ki67+ 20%). Histological response to neoadjuvant chemotherapy is grade 3 according to the Miller/Payne grading system. Final pathology of brain metastasis showed a HER2 overexpression metastatic breast cancer luminal B (ER+ 70%, PR+ 70%, HER2 2+, Ki67+ 30%), FISH confirmed HER2 overexpression. Weekly paclitaxel plus trastuzumab was given for 12 weeks, then trastuzumab every 3 weeks for a whole year. Patient follow-up is still ongoing, no new events appear yet. Conclusions The determination of hormone receptors and HER2 status should be routinely performed in all involved tissues, if possible, and systemic therapy should be tailored following the latest finding.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"1 1","pages":"268 - 274"},"PeriodicalIF":0.0,"publicationDate":"2016-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85275499","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 : 2016-08-28DOI: 10.18632/oncoscience.316
Yizhen Xie, F. Yang, W. Tan, Xiangmin Li, C. Jiao, Ren Huang, Burton B. Yang
To examine the role of oral Ganoderma spore oil in cardiovascular disease, we used transverse aortic constriction (TAC) in mice to model pressure overload-induced cardiomyopathy. Our preliminary results demonstrated a potential cardioprotective role for spore oil extracted from Ganoderma. We found that Ganoderma treatment normalized ejection fraction and corrected the fractional shortening generated by TAC. We also found evidence of reduced left ventricular hypertrophy as assessed by left ventricular end diastolic diameter. Analysis of total RNA expression using cardiac tissue samples from these mice corroborated our findings. We found reduced expression of genes associated with heart failure, including a novel circular RNA circ-Foxo3. Thus our data provides evidence for Ganoderma lucidum as a potential cardioprotective agent, warranting further preclinical exploration.
{"title":"The anti-cancer components of Ganoderma lucidum possesses cardiovascular protective effect by regulating circular RNA expression","authors":"Yizhen Xie, F. Yang, W. Tan, Xiangmin Li, C. Jiao, Ren Huang, Burton B. Yang","doi":"10.18632/oncoscience.316","DOIUrl":"https://doi.org/10.18632/oncoscience.316","url":null,"abstract":"To examine the role of oral Ganoderma spore oil in cardiovascular disease, we used transverse aortic constriction (TAC) in mice to model pressure overload-induced cardiomyopathy. Our preliminary results demonstrated a potential cardioprotective role for spore oil extracted from Ganoderma. We found that Ganoderma treatment normalized ejection fraction and corrected the fractional shortening generated by TAC. We also found evidence of reduced left ventricular hypertrophy as assessed by left ventricular end diastolic diameter. Analysis of total RNA expression using cardiac tissue samples from these mice corroborated our findings. We found reduced expression of genes associated with heart failure, including a novel circular RNA circ-Foxo3. Thus our data provides evidence for Ganoderma lucidum as a potential cardioprotective agent, warranting further preclinical exploration.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"19 1","pages":"203 - 207"},"PeriodicalIF":0.0,"publicationDate":"2016-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80280753","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 : 2016-07-27DOI: 10.18632/oncoscience.315
N. Sundahl, Dorien Clarisse, M. Bracke, F. Offner, W. V. Berghe, I. Beck
Although adverse effects and glucocorticoid resistance cripple their chronic use, glucocorticoids form the mainstay therapy for acute and chronic inflammatory disorders, and play an important role in treatment protocols of both lymphoid malignancies and as adjuvant to stimulate therapy tolerability in various solid tumors. Glucocorticoid binding to their designate glucocorticoid receptor (GR), sets off a plethora of cell-specific events including therapeutically desirable effects, such as cell death, as well as undesirable effects, including chemotherapy resistance, systemic side effects and glucocorticoid resistance. In this context, selective GR agonists and modulators (SEGRAMs) with a more restricted GR activity profile have been developed, holding promise for further clinical development in anti-inflammatory and potentially in cancer therapies. Thus far, the research into the prospective benefits of selective GR modulators in cancer therapy limped behind. Our review discusses how selective GR agonists and modulators could improve the therapy regimens for lymphoid malignancies, prostate or breast cancer. We summarize our current knowledge and look forward to where the field should move to in the future. Altogether, our review clarifies novel therapeutic perspectives in cancer modulation via selective GR targeting.
{"title":"Selective glucocorticoid receptor-activating adjuvant therapy in cancer treatments","authors":"N. Sundahl, Dorien Clarisse, M. Bracke, F. Offner, W. V. Berghe, I. Beck","doi":"10.18632/oncoscience.315","DOIUrl":"https://doi.org/10.18632/oncoscience.315","url":null,"abstract":"Although adverse effects and glucocorticoid resistance cripple their chronic use, glucocorticoids form the mainstay therapy for acute and chronic inflammatory disorders, and play an important role in treatment protocols of both lymphoid malignancies and as adjuvant to stimulate therapy tolerability in various solid tumors. Glucocorticoid binding to their designate glucocorticoid receptor (GR), sets off a plethora of cell-specific events including therapeutically desirable effects, such as cell death, as well as undesirable effects, including chemotherapy resistance, systemic side effects and glucocorticoid resistance. In this context, selective GR agonists and modulators (SEGRAMs) with a more restricted GR activity profile have been developed, holding promise for further clinical development in anti-inflammatory and potentially in cancer therapies. Thus far, the research into the prospective benefits of selective GR modulators in cancer therapy limped behind. Our review discusses how selective GR agonists and modulators could improve the therapy regimens for lymphoid malignancies, prostate or breast cancer. We summarize our current knowledge and look forward to where the field should move to in the future. Altogether, our review clarifies novel therapeutic perspectives in cancer modulation via selective GR targeting.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"50 1","pages":"188 - 202"},"PeriodicalIF":0.0,"publicationDate":"2016-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88357972","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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