There have been significant improvements in the detection and treatment of breast cancer in recent decades. However, there is still a need to develop more effective therapeutic techniques that are patient specific wit...There have been significant improvements in the detection and treatment of breast cancer in recent decades. However, there is still a need to develop more effective therapeutic techniques that are patient specific with reduced toxicity leading to further increases in patients' overall survival; the ongoing progress in understanding recurrence, resistant and spread also needs to be maintained. Better understanding of breast cancer pathology, molecular biology and progression as well as identification of some of the underlying factors involved in breast cancer tumourgenesis and metastasis has led to the identification of novel therapeutic targets. Over a number of years interest has risen in breast tumour kinase(Brk) also known as protein tyrosine kinase 6; the research field has grown and Brk has been described as a desirable therapeutic target in relation to tyrosine kinase inhibition as well as disruption of its kinase independent activity. This review will outline the current "state of play" with respect to targeted therapy for breast cancer, as well as discussing Brk's role in the processes underlying tumour development and metas-tasis and its potential as a therapeutic target in breast cancer.展开更多
Our understanding about the epidemiological aspects,pathogenesis,molecular diagnosis,and targeted therapies of neuroendocrine neoplasms(NENs)have drastically advanced in the past decade.Gastroenteropancreatic(GEP)NENs...Our understanding about the epidemiological aspects,pathogenesis,molecular diagnosis,and targeted therapies of neuroendocrine neoplasms(NENs)have drastically advanced in the past decade.Gastroenteropancreatic(GEP)NENs originate from the enteroendocrine cells of the embryonic gut which share common endocrine and neural differentiation factors.Most NENs are welldifferentiated,and slow growing.Specific neuroendocrine biomarkers that are used in the diagnosis of functional NENs include insulin,glucagon,vasoactive intestinal polypeptide,gastrin,somatostatin,adrenocorticotropin,growth hormone releasing hormone,parathyroid hormone-related peptide,serotonin,histamine,and 5-hydroxy indole acetic acid(5-HIAA).Biomarkers such as pancreatic polypeptide,human chorionic gonadotrophin subunits,neurotensin,ghrelin,and calcitonin are used in the diagnosis of non-functional NENs.5-HIAA levels correlate with tumour burden,prognosis and development of carcinoid heart disease and mesenteric fibrosis,however several diseases,medications and edible products can falsely elevate the 5-HIAA levels.Organ-specific transcription factors are useful in the differential diagnosis of metastasis from an unknown primary of well-differentiated NENs.Emerging novel biomarkers include circulating tumour cells,circulating tumour DNA,circulating micro-RNAs,and neuroendocrine neoplasms test(NETest)(simultaneous measurement of 51 neuroendocrine-specific marker genes in the peripheral blood).NETest has high sensitivity(85%-98%)and specificity(93%-97%)for the detection of gastrointestinal NENs,and is useful for monitoring treatment response,recurrence,and prognosis.In terms of management,surgery,radiofrequency ablation,symptom control with medications,chemotherapy and molecular targeted therapies are all considered as options.Surgery is the mainstay of treatment,but depends on factors including age of the individual,location,stage,grade,functional status,and the heredity of the tumour(sporadic vs inherited).Medical management is helpful to alleviate the symptoms,manage inoperable lesions,suppress postoperative tumour growth,and manage recurrences.Several molecular-targeted therapies are considered second line to somatostatin analogues.This review is a clinical update on the pathophysiological aspects,diagnostic algorithm,and management of GEP NENs.展开更多
2013年美国癌症基因组图谱(The Cancer Genome Atlas,TCGA)完成了子宫内膜癌(endometrial carcinoma,EC)分子分型,将患者分为POLE(DNA polymerase epsilon)突变型、微卫星不稳定高突变(microsatellite instability-high,MSI-H)型、低拷...2013年美国癌症基因组图谱(The Cancer Genome Atlas,TCGA)完成了子宫内膜癌(endometrial carcinoma,EC)分子分型,将患者分为POLE(DNA polymerase epsilon)突变型、微卫星不稳定高突变(microsatellite instability-high,MSI-H)型、低拷贝数(copy number low,CN-L)型和高拷贝数(copy number high,CN-H)型,后西方学者改良为更贴合临床应用的ProMisE及Trans-PORTEC分型。POLE突变型患者预后较好,复发率较低,可合理减少患者手术范围,术后降级治疗,当患者合并MSI-H或CN-H时仍归为POLE突变型;MSI-H型患者肿瘤突变负荷高,免疫治疗临床获益显著;CN-L型患者最常见,预后仅次于POLE突变型患者,该类患者为保留生育功能行激素治疗缓解率较高;CN-H型患者预后最差,肿瘤具有侵袭性特征及高复发风险,对于该类患者术后需积极补充治疗,避免治疗不足,此外靶向治疗对CN-H患者疗效较好。TCGA分子分型突破了子宫内膜癌传统病理组织学分型评估预后的局限性,为子宫内膜癌的病理特征、预后及临床诊疗决策提供了全新见解。展开更多
Head and neck squamous cell cancer(HNSCC) is the sixth most common cancer in the world. Effective therapeutic modalities such as surgery, radiation, chemotherapy and combinations of each are used in the management of ...Head and neck squamous cell cancer(HNSCC) is the sixth most common cancer in the world. Effective therapeutic modalities such as surgery, radiation, chemotherapy and combinations of each are used in the management of the disease. In most cases, treatment fails to obtain total cancer cure. In recent years, it appears that one of the key determinants of treatment failure may be the presence of cancer stem cells(CSCs) that escape currently available therapies. CSCs form a small portion of the total tumor burden but may play a disproportionately important role in determining outcomes. CSCs have stem features such as self-renewal, high migration capacity, drug resistance, high proliferation abilities. A large body of evidence points to the fact that CSCs are particularly resistant to radiotherapy and chemotherapy. In HNSCC, CSCs have been increasingly shown to have an integral role in tumor initiation, disease progression, metastasis and treatment resistance. In the light of such observations, the present review summarizes biological characteristics of CSCs in HNSCC, outlines targeted strategies for the successful eradication of CSCs in HNSCC including targeting the self-renewal controlling pathways, blocking epithelial mesenchymal transition, niche targeting, immunotherapy approaches and highlights the need to better understand CSCs biology for new treatments modalities.展开更多
The receptor protein tyrosine kinase RON belongs to the c-MET proto-oncogene family.Research has shown that RON has a role in cancer pathogenesis,which places RON on the frontline of the development of novel cancer th...The receptor protein tyrosine kinase RON belongs to the c-MET proto-oncogene family.Research has shown that RON has a role in cancer pathogenesis,which places RON on the frontline of the development of novel cancer therapeutic strategies.Hepatobiliary and pancreatic(HBP)cancers have a poor prognosis,being reported as having higher rates of cancer-related death.Therefore,to combat these malignant diseases,the mechanism underlying the aberrant expression and signaling of RON in HBP cancer pathogenesis,and the development of RON as a drug target for therapeutic intervention should be investigated.Abnormal RON expression and signaling have been identified in HBP cancers,and also act as tumorigenic determinants for HBP cancer malignant behaviors.In addition,RON is emerging as an important mediator of the clinical prognosis of HBP cancers.Thus,not only is RON significant in HBP cancers,but also RON-targeted therapeutics could be developed to treat these cancers,for example,therapeutic monoclonal antibodies and small-molecule inhibitors.Among them,antibody-drug conjugates have become increasingly popular in current research and their potential as novel anti-cancer biotherapeutics will be determined in future clinical trials.展开更多
The abnormal activation of HER family kinase activity is closely related to the development of human malignancies.In this study,we used HER kinases as targets for the treatment of nasopharyngeal carcinoma(NPC)and expl...The abnormal activation of HER family kinase activity is closely related to the development of human malignancies.In this study,we used HER kinases as targets for the treatment of nasopharyngeal carcinoma(NPC)and explored the anti-tumor effects of the novel pan-HER inhibitor HM781-36B,alone or in combination with cisplatin.We found that HER family proteins were positively expressed in tumor tissues of some NPC patients,and the high levels of those proteins were significantly related to poor prognosis.HM781-36B inhibited NPC in vitro and in vivo.HM781-36B exerted synergistic effects with cisplatin on inhibiting proliferation and promoting apoptosis of NPC cells.In NPC xenograft models in nude mice,HM781-36B and cisplatin synergistically inhibited tumor growth.Downregulating the activity of HER family proteins and their downstream signaling pathways and regulating tumor microenvironment may explain the synergistic anti-tumor effects of HM781-36B and cisplatin.In conclusion,our study provides evidence for HER family proteins as prognostic biomarkers and potential therapeutic targets for NPC.The pan-HER inhibitor HM781-36B alone or in combination with cisplatin represents promising therapeutic effects for the treatment of NPC patients,which provides a new idea for the comprehensive treatment of NPC.展开更多
Neuroendocrine neoplasms(NENs)are a heterogeneous group of rare tumours often producing high levels of hormones and causing symptoms.There are a number of different types of NENs.They usually arise as advanced and low...Neuroendocrine neoplasms(NENs)are a heterogeneous group of rare tumours often producing high levels of hormones and causing symptoms.There are a number of different types of NENs.They usually arise as advanced and low/intermediate grade only in a minority of cases,as high grade.Treatment depends on which type and may include surgery,interventional radiology,and systemic treatment,including chemotherapy,somatostatin analogs,interferonα2b,peptide receptor radionuclide therapy,and only for pancreatic neuroendocrine tumors,molecular targeted agents,including everolimus and sunitinib.The aim of the article is to review the medical approaches with somatostatin analogs and chemotherapy.The treatment of NENs is mainly based on their biological characteristics of aggressiveness and functional features,such as symptoms and endocrine markers.展开更多
文摘There have been significant improvements in the detection and treatment of breast cancer in recent decades. However, there is still a need to develop more effective therapeutic techniques that are patient specific with reduced toxicity leading to further increases in patients' overall survival; the ongoing progress in understanding recurrence, resistant and spread also needs to be maintained. Better understanding of breast cancer pathology, molecular biology and progression as well as identification of some of the underlying factors involved in breast cancer tumourgenesis and metastasis has led to the identification of novel therapeutic targets. Over a number of years interest has risen in breast tumour kinase(Brk) also known as protein tyrosine kinase 6; the research field has grown and Brk has been described as a desirable therapeutic target in relation to tyrosine kinase inhibition as well as disruption of its kinase independent activity. This review will outline the current "state of play" with respect to targeted therapy for breast cancer, as well as discussing Brk's role in the processes underlying tumour development and metas-tasis and its potential as a therapeutic target in breast cancer.
文摘Our understanding about the epidemiological aspects,pathogenesis,molecular diagnosis,and targeted therapies of neuroendocrine neoplasms(NENs)have drastically advanced in the past decade.Gastroenteropancreatic(GEP)NENs originate from the enteroendocrine cells of the embryonic gut which share common endocrine and neural differentiation factors.Most NENs are welldifferentiated,and slow growing.Specific neuroendocrine biomarkers that are used in the diagnosis of functional NENs include insulin,glucagon,vasoactive intestinal polypeptide,gastrin,somatostatin,adrenocorticotropin,growth hormone releasing hormone,parathyroid hormone-related peptide,serotonin,histamine,and 5-hydroxy indole acetic acid(5-HIAA).Biomarkers such as pancreatic polypeptide,human chorionic gonadotrophin subunits,neurotensin,ghrelin,and calcitonin are used in the diagnosis of non-functional NENs.5-HIAA levels correlate with tumour burden,prognosis and development of carcinoid heart disease and mesenteric fibrosis,however several diseases,medications and edible products can falsely elevate the 5-HIAA levels.Organ-specific transcription factors are useful in the differential diagnosis of metastasis from an unknown primary of well-differentiated NENs.Emerging novel biomarkers include circulating tumour cells,circulating tumour DNA,circulating micro-RNAs,and neuroendocrine neoplasms test(NETest)(simultaneous measurement of 51 neuroendocrine-specific marker genes in the peripheral blood).NETest has high sensitivity(85%-98%)and specificity(93%-97%)for the detection of gastrointestinal NENs,and is useful for monitoring treatment response,recurrence,and prognosis.In terms of management,surgery,radiofrequency ablation,symptom control with medications,chemotherapy and molecular targeted therapies are all considered as options.Surgery is the mainstay of treatment,but depends on factors including age of the individual,location,stage,grade,functional status,and the heredity of the tumour(sporadic vs inherited).Medical management is helpful to alleviate the symptoms,manage inoperable lesions,suppress postoperative tumour growth,and manage recurrences.Several molecular-targeted therapies are considered second line to somatostatin analogues.This review is a clinical update on the pathophysiological aspects,diagnostic algorithm,and management of GEP NENs.
文摘2013年美国癌症基因组图谱(The Cancer Genome Atlas,TCGA)完成了子宫内膜癌(endometrial carcinoma,EC)分子分型,将患者分为POLE(DNA polymerase epsilon)突变型、微卫星不稳定高突变(microsatellite instability-high,MSI-H)型、低拷贝数(copy number low,CN-L)型和高拷贝数(copy number high,CN-H)型,后西方学者改良为更贴合临床应用的ProMisE及Trans-PORTEC分型。POLE突变型患者预后较好,复发率较低,可合理减少患者手术范围,术后降级治疗,当患者合并MSI-H或CN-H时仍归为POLE突变型;MSI-H型患者肿瘤突变负荷高,免疫治疗临床获益显著;CN-L型患者最常见,预后仅次于POLE突变型患者,该类患者为保留生育功能行激素治疗缓解率较高;CN-H型患者预后最差,肿瘤具有侵袭性特征及高复发风险,对于该类患者术后需积极补充治疗,避免治疗不足,此外靶向治疗对CN-H患者疗效较好。TCGA分子分型突破了子宫内膜癌传统病理组织学分型评估预后的局限性,为子宫内膜癌的病理特征、预后及临床诊疗决策提供了全新见解。
文摘Head and neck squamous cell cancer(HNSCC) is the sixth most common cancer in the world. Effective therapeutic modalities such as surgery, radiation, chemotherapy and combinations of each are used in the management of the disease. In most cases, treatment fails to obtain total cancer cure. In recent years, it appears that one of the key determinants of treatment failure may be the presence of cancer stem cells(CSCs) that escape currently available therapies. CSCs form a small portion of the total tumor burden but may play a disproportionately important role in determining outcomes. CSCs have stem features such as self-renewal, high migration capacity, drug resistance, high proliferation abilities. A large body of evidence points to the fact that CSCs are particularly resistant to radiotherapy and chemotherapy. In HNSCC, CSCs have been increasingly shown to have an integral role in tumor initiation, disease progression, metastasis and treatment resistance. In the light of such observations, the present review summarizes biological characteristics of CSCs in HNSCC, outlines targeted strategies for the successful eradication of CSCs in HNSCC including targeting the self-renewal controlling pathways, blocking epithelial mesenchymal transition, niche targeting, immunotherapy approaches and highlights the need to better understand CSCs biology for new treatments modalities.
基金National Natural Sciences Foundation of China,No.81872883Zhejiang Major Medical Health&Sciences Technology Foundation Projects,No.WKJ-ZJ-13.
文摘The receptor protein tyrosine kinase RON belongs to the c-MET proto-oncogene family.Research has shown that RON has a role in cancer pathogenesis,which places RON on the frontline of the development of novel cancer therapeutic strategies.Hepatobiliary and pancreatic(HBP)cancers have a poor prognosis,being reported as having higher rates of cancer-related death.Therefore,to combat these malignant diseases,the mechanism underlying the aberrant expression and signaling of RON in HBP cancer pathogenesis,and the development of RON as a drug target for therapeutic intervention should be investigated.Abnormal RON expression and signaling have been identified in HBP cancers,and also act as tumorigenic determinants for HBP cancer malignant behaviors.In addition,RON is emerging as an important mediator of the clinical prognosis of HBP cancers.Thus,not only is RON significant in HBP cancers,but also RON-targeted therapeutics could be developed to treat these cancers,for example,therapeutic monoclonal antibodies and small-molecule inhibitors.Among them,antibody-drug conjugates have become increasingly popular in current research and their potential as novel anti-cancer biotherapeutics will be determined in future clinical trials.
基金supported by the National Science Foundation for Excellent Young Scholars(No.32122052)National Natural Science Regional Innovation and Development Foundation(No.U19A2003).
文摘The abnormal activation of HER family kinase activity is closely related to the development of human malignancies.In this study,we used HER kinases as targets for the treatment of nasopharyngeal carcinoma(NPC)and explored the anti-tumor effects of the novel pan-HER inhibitor HM781-36B,alone or in combination with cisplatin.We found that HER family proteins were positively expressed in tumor tissues of some NPC patients,and the high levels of those proteins were significantly related to poor prognosis.HM781-36B inhibited NPC in vitro and in vivo.HM781-36B exerted synergistic effects with cisplatin on inhibiting proliferation and promoting apoptosis of NPC cells.In NPC xenograft models in nude mice,HM781-36B and cisplatin synergistically inhibited tumor growth.Downregulating the activity of HER family proteins and their downstream signaling pathways and regulating tumor microenvironment may explain the synergistic anti-tumor effects of HM781-36B and cisplatin.In conclusion,our study provides evidence for HER family proteins as prognostic biomarkers and potential therapeutic targets for NPC.The pan-HER inhibitor HM781-36B alone or in combination with cisplatin represents promising therapeutic effects for the treatment of NPC patients,which provides a new idea for the comprehensive treatment of NPC.
文摘Neuroendocrine neoplasms(NENs)are a heterogeneous group of rare tumours often producing high levels of hormones and causing symptoms.There are a number of different types of NENs.They usually arise as advanced and low/intermediate grade only in a minority of cases,as high grade.Treatment depends on which type and may include surgery,interventional radiology,and systemic treatment,including chemotherapy,somatostatin analogs,interferonα2b,peptide receptor radionuclide therapy,and only for pancreatic neuroendocrine tumors,molecular targeted agents,including everolimus and sunitinib.The aim of the article is to review the medical approaches with somatostatin analogs and chemotherapy.The treatment of NENs is mainly based on their biological characteristics of aggressiveness and functional features,such as symptoms and endocrine markers.
