Pub Date : 2017-07-01Epub Date: 2017-08-14DOI: 10.4103/ctm.ctm_7_17
Jeremy A Hengst, Taryn E Dick, Arati Sharma, Kenichiro Doi, Shailaja Hegde, Su-Fern Tan, Laura M Geffert, Todd E Fox, Arun K Sharma, Dhimant Desai, Shantu Amin, Mark Kester, Thomas P Loughran, Robert F Paulson, David F Claxton, Hong-Gang Wang, Jong K Yun
Aim: To further characterize the selectivity, mechanism-of-action and therapeutic efficacy of the novel small molecule inhibitor, SKI-178.
Methods: Using the state-of-the-art Cellular Thermal Shift Assay (CETSA) technique to detect "direct target engagement" of proteins intact cells, in vitro and in vivo assays, pharmacological assays and multiple mouse models of acute myeloid leukemia (AML).
Results: Herein, we demonstrate that SKI-178 directly target engages both Sphingosine Kinase 1 and 2. We also present evidence that, in addition to its actions as a Sphingosine Kinase Inhibitor, SKI-178 functions as a microtubule network disrupting agent both in vitro and in intact cells. Interestingly, we separately demonstrate that simultaneous SphK inhibition and microtubule disruption synergistically induces apoptosis in AML cell lines. Furthermore, we demonstrate that SKI-178 is well tolerated in normal healthy mice. Most importantly, we demonstrate that SKI-178 has therapeutic efficacy in several mouse models of AML.
Conclusion: SKI-178 is a multi-targeted agent that functions both as an inhibitor of the SphKs as well as a disruptor of the microtubule network. SKI-178 induced apoptosis arises from a synergistic interaction of these two activities. SKI-178 is safe and effective in mouse models of AML, supporting its further development as a multi-targeted anti-cancer therapeutic agent.
{"title":"SKI-178: A Multitargeted Inhibitor of Sphingosine Kinase and Microtubule Dynamics Demonstrating Therapeutic Efficacy in Acute Myeloid Leukemia Models.","authors":"Jeremy A Hengst, Taryn E Dick, Arati Sharma, Kenichiro Doi, Shailaja Hegde, Su-Fern Tan, Laura M Geffert, Todd E Fox, Arun K Sharma, Dhimant Desai, Shantu Amin, Mark Kester, Thomas P Loughran, Robert F Paulson, David F Claxton, Hong-Gang Wang, Jong K Yun","doi":"10.4103/ctm.ctm_7_17","DOIUrl":"https://doi.org/10.4103/ctm.ctm_7_17","url":null,"abstract":"<p><strong>Aim: </strong>To further characterize the selectivity, mechanism-of-action and therapeutic efficacy of the novel small molecule inhibitor, SKI-178.</p><p><strong>Methods: </strong>Using the state-of-the-art Cellular Thermal Shift Assay (CETSA) technique to detect \"direct target engagement\" of proteins intact cells, <i>in vitro</i> and <i>in vivo</i> assays, pharmacological assays and multiple mouse models of acute myeloid leukemia (AML).</p><p><strong>Results: </strong>Herein, we demonstrate that SKI-178 directly target engages both Sphingosine Kinase 1 and 2. We also present evidence that, in addition to its actions as a Sphingosine Kinase Inhibitor, SKI-178 functions as a microtubule network disrupting agent both <i>in vitro</i> and in intact cells. Interestingly, we separately demonstrate that simultaneous SphK inhibition and microtubule disruption synergistically induces apoptosis in AML cell lines. Furthermore, we demonstrate that SKI-178 is well tolerated in normal healthy mice. Most importantly, we demonstrate that SKI-178 has therapeutic efficacy in several mouse models of AML.</p><p><strong>Conclusion: </strong>SKI-178 is a multi-targeted agent that functions both as an inhibitor of the SphKs as well as a disruptor of the microtubule network. SKI-178 induced apoptosis arises from a synergistic interaction of these two activities. SKI-178 is safe and effective in mouse models of AML, supporting its further development as a multi-targeted anti-cancer therapeutic agent.</p>","PeriodicalId":9428,"journal":{"name":"Cancer Translational Medicine","volume":"3 4","pages":"109-121"},"PeriodicalIF":0.0,"publicationDate":"2017-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5590228/pdf/nihms900433.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35390565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Y. Ahmed, N. Osman, R. Sheikh, S. Picardo, G. Watson
Aim: To evaluate abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: This is a multicenter retrospective analysis, involving 44 consecutive abiraterone-treated mCRPC patients, in either chemotherapy-naive or postdocetaxel setting. Results: The study cohort's median age was 68.7 (50–88) years, and the median duration of abiraterone treatment was 8 (1–36) months. Of the 44 patients, 23 (52%) and 21 (47%) patients were in chemotherapy- naive and postdocetaxel groups, respectively. Eastern Cooperative Oncology Group performance status score was 0–1 and 2–3 in 65% and 34% of chemotherapy-naive and 85% and 15% of postdocetaxel patients, respectively. Prostate-specific antigen (PSA) response was achieved in 13 (56.5%) chemotherapy-naive and 14 (66.6%) postdocetaxel patients. The median time to PSA progression was 12 (10.5–13.5) months. Objective radiological response was achieved in 11 (34.6%) patients, stable disease in 16 (55.1%) patients, and progressive disease in 3 (6.8%) patients. Median time to radiographic progression was 10.8 (10.3–11.4) months. Median overall survival was not reached (mean = 17 [14–20.5] months). The most common adverse events related to mineralocorticoid excess include hypokalemia (12%), fluid retention/edema (28%), and hypertension (8%). Conclusion: This study supports the safety and efficacy of abiraterone for mCRPC patients in the real-world setting.
{"title":"Real-world experience with abiraterone in metastatic castration-resistant prostate cancer","authors":"Y. Ahmed, N. Osman, R. Sheikh, S. Picardo, G. Watson","doi":"10.4103/ctm.ctm_5_17","DOIUrl":"https://doi.org/10.4103/ctm.ctm_5_17","url":null,"abstract":"Aim: To evaluate abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: This is a multicenter retrospective analysis, involving 44 consecutive abiraterone-treated mCRPC patients, in either chemotherapy-naive or postdocetaxel setting. Results: The study cohort's median age was 68.7 (50–88) years, and the median duration of abiraterone treatment was 8 (1–36) months. Of the 44 patients, 23 (52%) and 21 (47%) patients were in chemotherapy- naive and postdocetaxel groups, respectively. Eastern Cooperative Oncology Group performance status score was 0–1 and 2–3 in 65% and 34% of chemotherapy-naive and 85% and 15% of postdocetaxel patients, respectively. Prostate-specific antigen (PSA) response was achieved in 13 (56.5%) chemotherapy-naive and 14 (66.6%) postdocetaxel patients. The median time to PSA progression was 12 (10.5–13.5) months. Objective radiological response was achieved in 11 (34.6%) patients, stable disease in 16 (55.1%) patients, and progressive disease in 3 (6.8%) patients. Median time to radiographic progression was 10.8 (10.3–11.4) months. Median overall survival was not reached (mean = 17 [14–20.5] months). The most common adverse events related to mineralocorticoid excess include hypokalemia (12%), fluid retention/edema (28%), and hypertension (8%). Conclusion: This study supports the safety and efficacy of abiraterone for mCRPC patients in the real-world setting.","PeriodicalId":9428,"journal":{"name":"Cancer Translational Medicine","volume":"3 1","pages":"133 - 138"},"PeriodicalIF":0.0,"publicationDate":"2017-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81978164","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 : 2017-05-01Epub Date: 2017-06-08DOI: 10.4103/ctm.ctm_12_17
Poonam Sonawane, Young A Choi, Hetal Pandya, Denise M Herpai, Izabela Fokt, Waldemar Priebe, Waldemar Debinski
A multifunctional fusion protein, IL-13.E13K-D2-NLS, effectively recognizes glioblastoma (GBM) cells and delivers its portion to the cell nucleus. IL-13.E13K-D2-NLS is composed of a cancer cell targeting ligand (IL-13.E13K), specialized cytosol translocation bacterial toxin domain 2 of Pseudomonas exotoxin A (D2) and SV40 T antigen nuclear localization signal (NLS). We have now tested whether we can produce proteins that would serve as a delivery vehicle to lysosomes and mitochondria as well. Moreover, we examined whether IL-13.E13K-D2-NLS can deliver anti-cancer drugs like doxorubicin to their nuclear site of action in cancer cells. We have thus constructed two novel proteins: IL-13.E13K-D2-LLS which incorporates lysosomal localization signal (LLS) of a human lysosomal associated membrane protein (LAMP-1) for targeting to lysosomes and IL-13-D2-KK2, which incorporates a pro-apoptotic peptide (KLAKLAK)2 (KK2) exerting its action in mitochondria. Furthermore, we have produced IL-13.E13K-D2-NLS and IL-13.E13K-D2-LLS versions containing a cysteine for site-specific conjugation with a modified doxorubicin, WP936. We found that single-chain recombinant proteins IL-13.E13K-D2-LLS and IL-13-D2-KK2 are internalized and localized mostly to the lysosomal and mitochondrial compartments, respectively, without major trafficking to cells' nuclei. We also determined that IL-13.E13K-D2-NLS-cys[WP936], IL-13.E13K-D2-LAMP-cys[WP936] and IL-13-D2-KK2 were cytotoxic to GBM cells overexpressing IL-13RA2, while much less cytotoxic to GBM cell lines expressing low levels of the receptor. IL-13.E13K-D2-NLS-cys[WP936] was the most potent of the tested anti-tumor agents including free WP936. We believe that our receptor-directed intracellular organelle-targeted proteins can be employed for numerous specific and safer treatment applications when drugs have specific intracellular sites of their action.
{"title":"Novel Molecular Multilevel Targeted Antitumor Agents.","authors":"Poonam Sonawane, Young A Choi, Hetal Pandya, Denise M Herpai, Izabela Fokt, Waldemar Priebe, Waldemar Debinski","doi":"10.4103/ctm.ctm_12_17","DOIUrl":"10.4103/ctm.ctm_12_17","url":null,"abstract":"<p><p>A multifunctional fusion protein, IL-13.E13K-D2-NLS, effectively recognizes glioblastoma (GBM) cells and delivers its portion to the cell nucleus. IL-13.E13K-D2-NLS is composed of a cancer cell targeting ligand (IL-13.E13K), specialized cytosol translocation bacterial toxin domain 2 of <i>Pseudomonas</i> exotoxin A (D2) and SV40 T antigen nuclear localization signal (NLS). We have now tested whether we can produce proteins that would serve as a delivery vehicle to lysosomes and mitochondria as well. Moreover, we examined whether IL-13.E13K-D2-NLS can deliver anti-cancer drugs like doxorubicin to their nuclear site of action in cancer cells. We have thus constructed two novel proteins: IL-13.E13K-D2-LLS which incorporates lysosomal localization signal (LLS) of a human lysosomal associated membrane protein (LAMP-1) for targeting to lysosomes and IL-13-D2-KK2, which incorporates a pro-apoptotic peptide (KLAKLAK)<sub>2</sub> (KK2) exerting its action in mitochondria. Furthermore, we have produced IL-13.E13K-D2-NLS and IL-13.E13K-D2-LLS versions containing a cysteine for site-specific conjugation with a modified doxorubicin, WP936. We found that single-chain recombinant proteins IL-13.E13K-D2-LLS and IL-13-D2-KK2 are internalized and localized mostly to the lysosomal and mitochondrial compartments, respectively, without major trafficking to cells' nuclei. We also determined that IL-13.E13K-D2-NLS-cys[WP936], IL-13.E13K-D2-LAMP-cys[WP936] and IL-13-D2-KK2 were cytotoxic to GBM cells overexpressing IL-13RA2, while much less cytotoxic to GBM cell lines expressing low levels of the receptor. IL-13.E13K-D2-NLS-cys[WP936] was the most potent of the tested anti-tumor agents including free WP936. We believe that our receptor-directed intracellular organelle-targeted proteins can be employed for numerous specific and safer treatment applications when drugs have specific intracellular sites of their action.</p>","PeriodicalId":9428,"journal":{"name":"Cancer Translational Medicine","volume":"3 3","pages":"69-79"},"PeriodicalIF":0.0,"publicationDate":"2017-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5558462/pdf/nihms894528.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35336217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gastric cancer is the fifth most common cancer worldwide, with most cases presenting in the form of primary tumors. In this paper, we performed a literature review on the incidence and particularities of extragastric metastases. These lesions are rare in clinical practice and can be misdiagnosed as primary undifferentiated gastric carcinomas as the differential diagnosis between primary and secondary malignancy is difficult to make. As per the literature, the most common malignancies which can present gastric metastases are lung cancer, followed by carcinoma of the breast, esophagus, kidney, and head and neck carcinomas. Malignant melanoma, ovarian cancer, prostate cancer, and adrenal gland carcinomas are rarely described as presenting metastases in the stomach. In most cases, the literature addressed poorly differentiated tumors with high-grade malignancy. The most common feature was the ulcerated tumor with depressed area, associated with identifiable extragastric tumor cells in the gastric submucosa. The linitis plastica-like feature is unusual and is more characteristic of breast lobular carcinoma. The accurate diagnosis of such rare extragastric metastatic cases depends on the appropriate clinical history and precise pathological diagnosis, which is mandatory for initiating the best therapeutic options.
{"title":"Gastric metastases mimicking primary gastric cancer: A brief literature review","authors":"S. Gurzu, M. Beleaua, L. Banias, I. Jung","doi":"10.4103/ctm.ctm_67_16","DOIUrl":"https://doi.org/10.4103/ctm.ctm_67_16","url":null,"abstract":"Gastric cancer is the fifth most common cancer worldwide, with most cases presenting in the form of primary tumors. In this paper, we performed a literature review on the incidence and particularities of extragastric metastases. These lesions are rare in clinical practice and can be misdiagnosed as primary undifferentiated gastric carcinomas as the differential diagnosis between primary and secondary malignancy is difficult to make. As per the literature, the most common malignancies which can present gastric metastases are lung cancer, followed by carcinoma of the breast, esophagus, kidney, and head and neck carcinomas. Malignant melanoma, ovarian cancer, prostate cancer, and adrenal gland carcinomas are rarely described as presenting metastases in the stomach. In most cases, the literature addressed poorly differentiated tumors with high-grade malignancy. The most common feature was the ulcerated tumor with depressed area, associated with identifiable extragastric tumor cells in the gastric submucosa. The linitis plastica-like feature is unusual and is more characteristic of breast lobular carcinoma. The accurate diagnosis of such rare extragastric metastatic cases depends on the appropriate clinical history and precise pathological diagnosis, which is mandatory for initiating the best therapeutic options.","PeriodicalId":9428,"journal":{"name":"Cancer Translational Medicine","volume":"35 1","pages":"101 - 105"},"PeriodicalIF":0.0,"publicationDate":"2017-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90084755","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}
Men who intake high ratios of fish oil or omega-3 fatty acids (FAs), especially docosahexaenoic acid and eicosapentaenoic acid, relative to omega-6 arachidonic acid have been found to have a decreased risk of prostate cancer compared to those with low ratios in some but not all case-control and cohort studies. Primary prevention trials with either risk biomarkers or cancer incidence as endpoints regarding the association between omega-3 FA consumption and risk of prostate cancer are studded with controversial results. However, many clinical trials have shown that fish oil could decrease the risk of developing prostate cancer. The anticancer properties of anticancer drugs could be greatly improved when combined with fish oil. We briefly reviewed fish oil and relevant omega-3 FAs as well as early investigations in prostate cancer prevention and treatment.
{"title":"Fish oil and prostate cancer: Effects and clinical relevance","authors":"P. Liang, Michael Gao","doi":"10.4103/ctm.ctm_63_16","DOIUrl":"https://doi.org/10.4103/ctm.ctm_63_16","url":null,"abstract":"Men who intake high ratios of fish oil or omega-3 fatty acids (FAs), especially docosahexaenoic acid and eicosapentaenoic acid, relative to omega-6 arachidonic acid have been found to have a decreased risk of prostate cancer compared to those with low ratios in some but not all case-control and cohort studies. Primary prevention trials with either risk biomarkers or cancer incidence as endpoints regarding the association between omega-3 FA consumption and risk of prostate cancer are studded with controversial results. However, many clinical trials have shown that fish oil could decrease the risk of developing prostate cancer. The anticancer properties of anticancer drugs could be greatly improved when combined with fish oil. We briefly reviewed fish oil and relevant omega-3 FAs as well as early investigations in prostate cancer prevention and treatment.","PeriodicalId":9428,"journal":{"name":"Cancer Translational Medicine","volume":"6 1","pages":"80 - 86"},"PeriodicalIF":0.0,"publicationDate":"2017-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90634734","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}
The ultimate goal of cancer therapy is to establish a treatment regimen that will ensure complete eradication of cancers with minimal toxicity to the surrounding normal tissues. Protein toxins are highly efficient when they are used as treatment reagents of cancer but are associated with toxicity in normal tissues. Given that specialized promoters have been widely investigated for specific expressions, we speculated that tumor-specialized promoters would play an important role in protein toxin tumor therapy. Therefore, we hypothesize that a tumor-specialized promoter can be inserted into a truncated protein toxin expression vector. Then, the vector can be introduced into the human body by either a viral or nonviral vector. These protein toxin genes would be specifically expressed in tumor cells, but not in normal tissue cells. The proposition may provide a new strategy with the development of protein toxins for specific targeting to neoplastic tumors.
{"title":"Possibility of specific expression of the protein toxins at the tumor site with tumor-specialized promoter","authors":"Liyuan Zhou, Yujun Li, Changchen Hu, Binquan Wang","doi":"10.4103/ctm.ctm_50_16","DOIUrl":"https://doi.org/10.4103/ctm.ctm_50_16","url":null,"abstract":"The ultimate goal of cancer therapy is to establish a treatment regimen that will ensure complete eradication of cancers with minimal toxicity to the surrounding normal tissues. Protein toxins are highly efficient when they are used as treatment reagents of cancer but are associated with toxicity in normal tissues. Given that specialized promoters have been widely investigated for specific expressions, we speculated that tumor-specialized promoters would play an important role in protein toxin tumor therapy. Therefore, we hypothesize that a tumor-specialized promoter can be inserted into a truncated protein toxin expression vector. Then, the vector can be introduced into the human body by either a viral or nonviral vector. These protein toxin genes would be specifically expressed in tumor cells, but not in normal tissue cells. The proposition may provide a new strategy with the development of protein toxins for specific targeting to neoplastic tumors.","PeriodicalId":9428,"journal":{"name":"Cancer Translational Medicine","volume":"5 1","pages":"106 - 108"},"PeriodicalIF":0.0,"publicationDate":"2017-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88928361","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}
Breast cancer is the most common cancer in women worldwide. Endocrine therapy is the cornerstone of treatment for patients with hormone receptor-positive advanced breast cancer. Unfortunately, although most patients initially respond to endocrine treatment, they will eventually acquire resistance to endocrine therapy. The mechanisms of endocrine resistance are complicated. In particular, the estrogen receptor-1 (ESR1) mutation has been recognized as an important topic in recent years. Mutation of ESR1 leads to complete aromatase inhibitor resistance and partial resistance to estrogen receptor agonists and antagonists. Therefore, during clinical treatment, it is of great importance to continuously monitor ESR1 mutations before and after endocrine therapy. Conventional tissue biopsies have unavoidable disadvantages, and therefore, the use of circulating tumor DNA (ctDNA) has become more prevalent because it is noninvasive and convenient, has excellent sensitivity, and can quickly assess the overall situation of the tumor. The current methods for detecting ctDNA ESR1 mutations mainly include droplet digital polymerase chain reaction and next-generation sequencing techniques. Based on their advantages and disadvantages, we can establish an initial ESR1 mutation monitoring system. However, developing robust methods to monitor ESR1 mutation, detecting endocrine drug resistance, and evaluating prognoses for guiding clinical treatment strategies require long-term exploration. In this review, we will summarize recent concepts and advancements regarding ESR1 mutation monitoring, ctDNA detection technology, and their application in endocrine therapy of breast cancer.
{"title":"The application of estrogen receptor-1 mutations' detection through circulating tumor dna in breast cancer","authors":"Binliang Liu, Yalan Yang, Z. Yi, X. Guan, F. Ma","doi":"10.4103/ctm.ctm_10_17","DOIUrl":"https://doi.org/10.4103/ctm.ctm_10_17","url":null,"abstract":"Breast cancer is the most common cancer in women worldwide. Endocrine therapy is the cornerstone of treatment for patients with hormone receptor-positive advanced breast cancer. Unfortunately, although most patients initially respond to endocrine treatment, they will eventually acquire resistance to endocrine therapy. The mechanisms of endocrine resistance are complicated. In particular, the estrogen receptor-1 (ESR1) mutation has been recognized as an important topic in recent years. Mutation of ESR1 leads to complete aromatase inhibitor resistance and partial resistance to estrogen receptor agonists and antagonists. Therefore, during clinical treatment, it is of great importance to continuously monitor ESR1 mutations before and after endocrine therapy. Conventional tissue biopsies have unavoidable disadvantages, and therefore, the use of circulating tumor DNA (ctDNA) has become more prevalent because it is noninvasive and convenient, has excellent sensitivity, and can quickly assess the overall situation of the tumor. The current methods for detecting ctDNA ESR1 mutations mainly include droplet digital polymerase chain reaction and next-generation sequencing techniques. Based on their advantages and disadvantages, we can establish an initial ESR1 mutation monitoring system. However, developing robust methods to monitor ESR1 mutation, detecting endocrine drug resistance, and evaluating prognoses for guiding clinical treatment strategies require long-term exploration. In this review, we will summarize recent concepts and advancements regarding ESR1 mutation monitoring, ctDNA detection technology, and their application in endocrine therapy of breast cancer.","PeriodicalId":9428,"journal":{"name":"Cancer Translational Medicine","volume":"21 1","pages":"46 - 52"},"PeriodicalIF":0.0,"publicationDate":"2017-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77308394","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}
M. Dietrich, C. Rolfo, Pablo Reclusa, M. Giallombardo, A. Valentino, L. Raez
Lung cancer is the most common malignancy in the United States, totaling 225,000 cases per year. In recent years, several new treatment options have become available based on the molecular and cellular characterization of the disease. More recently, "liquid biopsies" have received attention to complement traditional tissue biopsies and to enhance the spectrum of analysis for tumor-derived factors. As one of these tumor characteristics, extracellular vesicles (EVs) are lipid bilayered EVs that can cargo a variety of factors, including growth factors and their receptors, RNA transcripts, microRNAs, and DNA, among others. Initial acceptance as mere physiological products has been attributed to the presence of exosomes in healthy individuals, and the large diversity of exosomes that have made the assignment of distinct pathophysiological roles difficult. While their role in clinical application has not yet been established, they have emerged from their once thought innocent role as a bystander to a critical mediator of intratumoral signaling, tumor progression, chemotherapy resistance, and metastasis. In this review, we have summarized the structure and biology of EVs, their role in lung cancer, and the potential diagnostic and therapeutic implications for the treatment of this complex disease.
{"title":"Exosomes biology: Function and clinical implications in lung cancer","authors":"M. Dietrich, C. Rolfo, Pablo Reclusa, M. Giallombardo, A. Valentino, L. Raez","doi":"10.4103/ctm.ctm_32_16","DOIUrl":"https://doi.org/10.4103/ctm.ctm_32_16","url":null,"abstract":"Lung cancer is the most common malignancy in the United States, totaling 225,000 cases per year. In recent years, several new treatment options have become available based on the molecular and cellular characterization of the disease. More recently, \"liquid biopsies\" have received attention to complement traditional tissue biopsies and to enhance the spectrum of analysis for tumor-derived factors. As one of these tumor characteristics, extracellular vesicles (EVs) are lipid bilayered EVs that can cargo a variety of factors, including growth factors and their receptors, RNA transcripts, microRNAs, and DNA, among others. Initial acceptance as mere physiological products has been attributed to the presence of exosomes in healthy individuals, and the large diversity of exosomes that have made the assignment of distinct pathophysiological roles difficult. While their role in clinical application has not yet been established, they have emerged from their once thought innocent role as a bystander to a critical mediator of intratumoral signaling, tumor progression, chemotherapy resistance, and metastasis. In this review, we have summarized the structure and biology of EVs, their role in lung cancer, and the potential diagnostic and therapeutic implications for the treatment of this complex disease.","PeriodicalId":9428,"journal":{"name":"Cancer Translational Medicine","volume":"46 1","pages":"58 - 63"},"PeriodicalIF":0.0,"publicationDate":"2017-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91173679","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 : 2017-03-01DOI: 10.4103/2395-3977.202228
Aaron Chen, Glenn Braunstein, M. Anselmo, Jair Jaboni, Fernando T. Viloria, J. Neidich, Xiang Li, A. Kammesheidt
Aim: Detection of circulating tumor DNA (ctDNA) holds promise as an adjunct to traditional cancer screening methods. To determine the sensitivity and specificity of ctDNA measurements, levels were measured in plasma from patients with a cancer diagnosis and a low-risk, healthy population. Methods: We validated a plasma assay for detection of 96 ctDNA mutations in nine cancer genes (BRAF, CTNNB1, EGFR, FOXL2, GNAS, KRAS, NRAS, PIK3CA, and TP53). The assay reliably detects low levels of ctDNA, >2 copies. A total of 183 plasma samples from cancer patients were obtained along with plasma from 102 healthy individuals. Results: ctDNA was detected in 24.0% of cancer patients (14.7% stage I, 18.8% II, 33.3% III, and 50.0% IV). ctDNA was not detected in 96% of low-risk subjects. Three subjects tested positive for one mutation and one subject tested positive for two mutations. ctDNA levels in positive subjects were followed for a year, and levels remained steady with small fluctuation. Multiple lung nodules found in the subject with two mutations have remained stable for 1 year. None of the healthy individuals was diagnosed with cancer in the year following study entry. Conclusion: The sensitivity of the ctDNA assay was 24.0% in the mixture of cancers. The specificity was 96.1%. In the low cancer risk population, the apparent false positive detection rate for ctDNA at 1 year is 3.9%.
{"title":"Mutation detection with a liquid biopsy 96 mutation assay in cancer patients and healthy donors","authors":"Aaron Chen, Glenn Braunstein, M. Anselmo, Jair Jaboni, Fernando T. Viloria, J. Neidich, Xiang Li, A. Kammesheidt","doi":"10.4103/2395-3977.202228","DOIUrl":"https://doi.org/10.4103/2395-3977.202228","url":null,"abstract":"Aim: Detection of circulating tumor DNA (ctDNA) holds promise as an adjunct to traditional cancer screening methods. To determine the sensitivity and specificity of ctDNA measurements, levels were measured in plasma from patients with a cancer diagnosis and a low-risk, healthy population. Methods: We validated a plasma assay for detection of 96 ctDNA mutations in nine cancer genes (BRAF, CTNNB1, EGFR, FOXL2, GNAS, KRAS, NRAS, PIK3CA, and TP53). The assay reliably detects low levels of ctDNA, >2 copies. A total of 183 plasma samples from cancer patients were obtained along with plasma from 102 healthy individuals. Results: ctDNA was detected in 24.0% of cancer patients (14.7% stage I, 18.8% II, 33.3% III, and 50.0% IV). ctDNA was not detected in 96% of low-risk subjects. Three subjects tested positive for one mutation and one subject tested positive for two mutations. ctDNA levels in positive subjects were followed for a year, and levels remained steady with small fluctuation. Multiple lung nodules found in the subject with two mutations have remained stable for 1 year. None of the healthy individuals was diagnosed with cancer in the year following study entry. Conclusion: The sensitivity of the ctDNA assay was 24.0% in the mixture of cancers. The specificity was 96.1%. In the low cancer risk population, the apparent false positive detection rate for ctDNA at 1 year is 3.9%.","PeriodicalId":9428,"journal":{"name":"Cancer Translational Medicine","volume":"32 1","pages":"39 - 45"},"PeriodicalIF":0.0,"publicationDate":"2017-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82724753","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}
Ting Chen, Rongzhang He, Xinglin Hu, Weihao Luo, Z. Hu, Jia Li, L. Duan, Yali Xie, Wenna Luo, T. Tan, Dixian Luo
Circulating tumor DNA (ctDNA) in the peripheral blood is a liquid biopsy that contains representative tumor information including gene mutations. ctDNA is a promising new avenue for real-time monitoring of tumor progression. As a noninvasive biomarker and potential surrogate for the entire tumor genome, it has been applied to the detection of driver gene mutations and epigenetic alteration as well as monitoring of tumor burden, acquired resistance, tumor heterogeneity, and early diagnosis. Since precise therapy is a strategy that optimal therapy is decided based on simultaneous tumor genome information, ctDNA may help perform dynamic genetic surveillance. Dynamic marker surveillance may provide critical information to identify disease progression and guide therapeutic options. This review provides an overview on related articles about ctDNA, with a focus on monitoring response of solid tumors to anticancer therapies.
{"title":"Circulating tumor DNA: A potential biomarker from solid tumors' monitor to anticancer therapies","authors":"Ting Chen, Rongzhang He, Xinglin Hu, Weihao Luo, Z. Hu, Jia Li, L. Duan, Yali Xie, Wenna Luo, T. Tan, Dixian Luo","doi":"10.4103/ctm.ctm_6_17","DOIUrl":"https://doi.org/10.4103/ctm.ctm_6_17","url":null,"abstract":"Circulating tumor DNA (ctDNA) in the peripheral blood is a liquid biopsy that contains representative tumor information including gene mutations. ctDNA is a promising new avenue for real-time monitoring of tumor progression. As a noninvasive biomarker and potential surrogate for the entire tumor genome, it has been applied to the detection of driver gene mutations and epigenetic alteration as well as monitoring of tumor burden, acquired resistance, tumor heterogeneity, and early diagnosis. Since precise therapy is a strategy that optimal therapy is decided based on simultaneous tumor genome information, ctDNA may help perform dynamic genetic surveillance. Dynamic marker surveillance may provide critical information to identify disease progression and guide therapeutic options. This review provides an overview on related articles about ctDNA, with a focus on monitoring response of solid tumors to anticancer therapies.","PeriodicalId":9428,"journal":{"name":"Cancer Translational Medicine","volume":"26 1","pages":"64 - 67"},"PeriodicalIF":0.0,"publicationDate":"2017-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79113131","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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