Hepatocellular carcinoma(HCC)is the fifth most common cause of cancer in the world.According to Barcelona Clinic Liver Cancer modified criteria,patients with early stage disease are candidate to radiofrequency ablatio...Hepatocellular carcinoma(HCC)is the fifth most common cause of cancer in the world.According to Barcelona Clinic Liver Cancer modified criteria,patients with early stage disease are candidate to radiofrequency ablation(RFA),while patients with intermediate stage HCC are usually treated by transarterial chemoembolization(TACE).TACE and RFA induce a transient devascularisation effect followed by strong neoangiogenic stimulus.In fact,after these procedures,it has been demonstrated an up-regulation of pro-angiogenic and growth factors such as vascular endothelial growth factor-A,which might contribute to accelerated progression in patients with incomplete response.Several studies have demonstrated that MAP-kinase and AKT pathways,in addition to neo-angiogenesis,have an important role in the development of HCC.In advanced HCC,anti-angiogenic therapy and tyrosine kinases inhibitors showed potential clinical benefit.Actually,a number of clinical studies are ongoing testing these agents in combination with TACE or RFA.In this paper,we have reviewed the most recent preclinical and clinical results of such trials.展开更多
Background: The outcomes for patients with advanced hepatocellular carcinoma(HCC) receiving sorafenib are far from satisfactory because of treatment resistance to sorafenib. However, the exact mechanism of resistance ...Background: The outcomes for patients with advanced hepatocellular carcinoma(HCC) receiving sorafenib are far from satisfactory because of treatment resistance to sorafenib. However, the exact mechanism of resistance to sorafenib remains unclear and it is valuable to establish a novel mouse model to quantitatively analyze the inhibition rates of sorafenib on the invasive growth of HCC cells in the liver.Methods: HCC tissue microblocks derived from patients were cultured and mixed with hydrogel drops. Then, hydrogel drops containing microblocks of HCC tissue were attached onto the surface of the livers of nude mice to form lesions or nodules of HCC. The mice received molecular targeting agents through oral administration. Livers with tumor nodules were harvested for H&E staining(hematoxylin-eosin staining) analysis and H&E staining images were quantitatively analyzed using image J software. The invasive growth of HCC cells into the liver was calculated using the depth of the lesions compared with the total thickness of the liver.Results: Microblocks containing cells derived from HCC patients can form lesions in the liver of nude mice. Oral administration of molecular targeting agents inhibited the invasive growth of HCC cells in the liver of nude mice.Conclusions: The model established in this study involves the invasive growth of HCC cells in the liver of nude mice, and the model allows for the quantitative analysis of the inhibitory effect of molecular targeting agents on the invasion of HCC cells in vivo.展开更多
BACKGROUND Gemcitabine plus nab-paclitaxel(GA) is a commonly used first-line treatment regimen for metastatic pancreatic cancer,and many studies will add a novel targeted agent to this regimen for improving patient su...BACKGROUND Gemcitabine plus nab-paclitaxel(GA) is a commonly used first-line treatment regimen for metastatic pancreatic cancer,and many studies will add a novel targeted agent to this regimen for improving patient survival rate.However,the clinical effectiveness of GA is the most controversial issue.AIM To compare the efficacy and safety of GA regimen with a targeted agent and GA regimen.METHODS Up to 1 December 2021,the eligible randomized controlled trials(RCTs) relating to GA and GA with a targeted agent were searched on Pub Med,EMBASE and Cochrane Library for eligible data.We screened out appropriate studies for overall survival(OS),progression-free survival(PFS),objective response rate(ORR),and toxicity,which had been pooled and finally analyzed by using Stata version 15.1.In addition,we use Reference Citation Analysis(https://www.referencecitationanalysis.com/) to collect the latest related literature to improve the latest cutting-edge research results.RESULTS Seven RCTs involving 1544 patients(848 men and 696 women) were included.There were no significant differences between GA with a targeted agent and GA in PFS [hazard ratio(HR):1.18 95% confidence interval(CI):0.91-1.53],OS(HR:1.12 95%CI:0.99-1.27),and ORR(HR:0.96 95%CI:0.71-1.29).There was no notable difference in the two groups in grade 3/4 toxicity(fatigue,anemia,vomiting and neutropenia),whereas the incidence of grade 3/4 diarrhea considerably increased in GA with a targeted drug.CONCLUSION Adding a novel targeted agent to the GA regimen did not improve survival rate of patients with metastatic pancreatic cancer.展开更多
This review starts with a brief history of drug discovery & development, and the place of Asia in this worldwide effort discussed. The conditions and constraints of a successful translational R&D involving aca...This review starts with a brief history of drug discovery & development, and the place of Asia in this worldwide effort discussed. The conditions and constraints of a successful translational R&D involving academic basic research and clinical research are discussed and the Singapore model for pursuit of open R&D described. The importance of well-characterized, validated drug targets for the search for novel targeted anti-cancer agents is emphasized, as well as a structured, high quality translational R&D. Furthermore, the characteristics of an attractive preclinical development drug candidate are discussed laying the foundation of a successful preclinical development. The most frequent sources of failures are described and risk management at every stage is highly recommended. Organizational factors are also considered to play an important role. The factors to consider before starting a new drug discovery & development project are described, and an example is given of a successful clinical project that has had its roots in local universities and was carried through preclinical development into phase I clinical trials.展开更多
BACKGROUND Hepatic arterial infusion chemotherapy and camrelizumab plus apatinib(TRIPLET protocol)is promising for advanced hepatocellular carcinoma(Ad-HCC).However,the usefulness of microwave ablation(MWA)after TRIPL...BACKGROUND Hepatic arterial infusion chemotherapy and camrelizumab plus apatinib(TRIPLET protocol)is promising for advanced hepatocellular carcinoma(Ad-HCC).However,the usefulness of microwave ablation(MWA)after TRIPLET is still controversial.AIM To compare the efficacy and safety of TRIPLET alone(T-A)vs TRIPLET-MWA(TM)for Ad-HCC.METHODS From January 2018 to March 2022,217 Ad-HCC patients were retrospectively enrolled.Among them,122 were included in the T-A group,and 95 were included in the T-M group.A propensity score matching(PSM)was applied to balance bias.Overall survival(OS)was compared using the Kaplan-Meier curve with the log-rank test.The overall objective response rate(ORR)and major complications were also assessed.RESULTS After PSM,82 patients were included both the T-A group and the T-M group.The ORR(85.4%)in the T-M group was significantly higher than that(65.9%)in the T-A group(P<0.001).The cumulative 1-,2-,and 3-year OS rates were 98.7%,93.4%,and 82.0%in the T-M group and 85.1%,63.1%,and 55.0%in the T-A group(hazard ratio=0.22;95%confidence interval:0.10-0.49;P<0.001).The incidence of major complications was 4.9%(6/122)in the T-A group and 5.3%(5/95)in the T-M group,which were not significantly different(P=1.000).CONCLUSION T-M can provide better survival outcomes and comparable safety for Ad-HCC than T-A.展开更多
Gastroenteropancreatic neuroendocrine neoplasms(GEP-NENs)are a rare group of tumors originating from neuroendocrine cells of the digestive system.Their incidence has increased over the last decades.The specific pathog...Gastroenteropancreatic neuroendocrine neoplasms(GEP-NENs)are a rare group of tumors originating from neuroendocrine cells of the digestive system.Their incidence has increased over the last decades.The specific pathogenetic mechanisms underlying GEP-NEN development have not been completely revealed.Unfunctional GEP-NENs are usually asymptomatic;some grow slowly and thus impede early diagnosis,which ultimately results in a high rate of misdiagnosis.Therefore,many GEP-NEN patients present with later staged tumors.Motivated hereby,research attention for diagnosis and treatment for GEP-NENs increased in recent years.The result of which is great progress in clinical diagnosis and treatment.According to the most recent clinical guidelines,improved grading standards can accurately define poorly differentiated grade 3 neuroendocrine tumors and neuroendocrine carcinomas(NECs),which are subclassified into large and small cell NECs.Combining different functional imaging methods facilitates precise diagnosis.The expression of somatostatin receptors helps to predict prognosis.Genetic analyses of mutations affecting death domain associated protein(DAXX),multiple endocrine neoplasia type 1(MEN 1),alpha thalassemia/intellectual disability syndrome X-linked(ATRX),retinoblastoma transcriptional corepressor 1(RB 1),and mothers against decapentaplegic homolog 4(SMAD 4)help distinguishing grade 3 NENs from poorly differentiated NECs.The aim of this review is to summarize the latest research progress on diagnosis and treatment of GEP-NENs.展开更多
Lung cancer,of which non-small lung cancer is the most common subtype,represents the leading cause of cancer related-death worldwide.It is now recognized that a significant proportion of these patients present alterat...Lung cancer,of which non-small lung cancer is the most common subtype,represents the leading cause of cancer related-death worldwide.It is now recognized that a significant proportion of these patients present alterations in certain genes that drive oncogenesis.In recent years,more of these so-called oncogenic drivers have been identified,and a better understanding of their biology has allowed the development new targeted agents.This review aims to provide an update about the current landscape of driver mutation in non-smallcell lung cancer.Alterations in Kirsten rat sarcoma,epidermal growth factor receptor,MET,anaplastic lymphoma kinase,c-ROS oncogene 1,v-raf murine sarcoma viral oncogene homolog B,neurotrophic receptor tyrosine kinase,human epidermal growth factor 2,neuregulin-1 and rearranged during transfection are discussed,as well as agents targeting these alterations.Current standards of treatment as well as promising future strategies are presented.Currently,more than fifteen targeted agents are food and Drug administration-approved for seven oncogenic drivers in non-small-cell lung cancer,highlighting the importance of actively searching for these mutations.Continuous and future efforts made in defining the biology of each of these alterations will help to elucidate their respective resistance mechanisms,and to define the best treatment strategy and therapeutic sequence.展开更多
Anticancer drug nephrotoxicity is an important and increasing adverse drug event that limits the efficacy of cancer treatment.The kidney is an important elimination pathway for many antineoplastic drugs and their meta...Anticancer drug nephrotoxicity is an important and increasing adverse drug event that limits the efficacy of cancer treatment.The kidney is an important elimination pathway for many antineoplastic drugs and their metabolites,which occurs by glomerular filtration and tubular secretion.Chemotherapeutic agents,both conventional cytotoxic agents and molecularly targeted agents,can affect any segment of the nephron including its microvasculature,leading to many clinical manifestations such as proteinuria,hypertension,electrolyte disturbances,glomerulopathy,acute and chronic interstitial nephritis,acute kidney injury and at times chronic kidney disease.The clinician should be alert to recognize several factors that may maximize renal dysfunction and contribute to the increased incidence of nephrotoxicity associated with these drugs,such as intravascular volume depletion,the associated use of nonchemotherapeutic nephrotoxic drugs(analgesics,antibiotics,proton pump inhibitors,and bonetargeted therapies),radiographic ionic contrast media or radiation therapy,urinary tract obstruction,and intrinsic renal disease.Identification of patients at higher risk for nephrotoxicity may allow the prevention or at least reduction in the development and severity of this adverse effect.Therefore,the aim of this brief review is to provide currently available evidences on oncologic drug-related nephrotoxicity.展开更多
Chemoimmunotherapy(CIT)is defined as standard first line treatment for chronic lymphocytic leukemia(CLL)patients while patients with unfavorable biological characteristics such as unmutated immunoglobulin heavy chain(...Chemoimmunotherapy(CIT)is defined as standard first line treatment for chronic lymphocytic leukemia(CLL)patients while patients with unfavorable biological characteristics such as unmutated immunoglobulin heavy chain(UM-IGHV)and TP53 aberration failed to benefit from it.The emergency of the small molecular targeted agents including Bruton’s tyrosine kinase(BTK)inhibitor(BTKi)leads to a brand-new era,from a CIT to a chemo-free era in CLL.However,the treatment of target agents is not enough to attain a deep remission and high rate of complete remission(CR),especially in patients with high risks.The long duration brought about problems,such as cost,drug resistance and toxicity.To benefit CLL in progression free survival(PFS)and long-term remission,exploration of time-limited therapies,mainly with BTKi plus CIT and BCL2i based combination therapy has become a mainstream in clinical trials.The time-limited combination therapy shed light on the promising potentiality to attain sustainable deep remission and partly overcame the risk factors,although long term follow-up is required to consolidate the conclusion.In this review,we intend to introduce key results of clinical trials with combination therapy,discuss the achievements and limitations and put forward future direction for clinical trial design in this field.展开更多
The phase III clinical trial of the novel molecular targeted agent(MTA)lenvatinib for patients with advanced hepatocellular carcinoma(HCC)(REFLECT trial)found that lenvatinib was non-inferior to sorafenib in overall s...The phase III clinical trial of the novel molecular targeted agent(MTA)lenvatinib for patients with advanced hepatocellular carcinoma(HCC)(REFLECT trial)found that lenvatinib was non-inferior to sorafenib in overall survival.Recently,the efficacy of multiple MTAs,including lenvatinib,in practice has been reported,and therapeutic strategies for Barcelona Clinic Liver Cancer(BCLC)intermediate stage HCC are undergoing major changes.Based on these results,lenvatinib could be recommended for patients with transcatheter arterial chemoembolization(TACE)-refractory,ALBI grade 1,within the up-to-seven criteria in the BCLC intermediate stage.Lenvatinib provides a more favorable outcome than TACE,even in cases with large or multinodular HCC beyond the up-to-seven criteria with Child-Pugh grade A.When patients meet the definitions of TACE-refractory or TACE-unsuitable,switching to systemic chemotherapy,including lenvatinib,is for favorable for preserving liver function.If initial treatment,including MTA,has a significant therapeutic effect and downstaging of HCC is obtained,additional TACE or surgical resection should be considered.Lenvatinib also has a therapeutic effect for poorly differentiated type and non-simple nodular type HCC thanks to the survival-prolonging effect of this drug.Furthermore,a significant therapeutic effect is expected in tumors with more than 50%liver involvement or main portal vein invasion,which have traditionally been considered to have a poor prognosis in patients.This suggests that at the start of lenvatinib treatment,HCC patients with ALBI grade 1 may be able to maintain liver functional reserve.展开更多
Second-line therapy for advanced colorectal cancer is an integral part of the treatment strategy that needs to be set from the beginning for each patient, bearing in mind the expected toxicities of chosen treatments, ...Second-line therapy for advanced colorectal cancer is an integral part of the treatment strategy that needs to be set from the beginning for each patient, bearing in mind the expected toxicities of chosen treatments, the patient's clinical condition, comorbidities, preferences, the aims of the treatment and the molecular status. Furthermore, the distinction between lines of therapy is no longer absolute. The perspective of "continuum of care" includes switching chemotherapy prior to disease progression, maintenance therapy, drug "holidays" if needed, surgical resection of metastases in selected patients, and seems to allow a tailored treatment, in which patients are more likely to benefit from exposure to all active agents, which is known to correlate with overall survival. The scenario of second-line treatment has changed dramatically over the years and could currently benefit from several options including chemotherapy with a single agent or in combination and the addition of molecular-targeted agents developed in the last decade, such as epidermal growth factor receptor antibodies(cetuximab, panitumumab) and vascular endothelial growth factor-targeting agents(bevacizumab, aflibercept), with the possibility of bevacizumab use even beyond first progression. The purpose of this review is to summarize the most important scientific data supporting the use of chemotherapy and the new biologic agents in the second-line setting in advanced colorectal cancer.展开更多
Glioblastoma(GBM)is the most aggressive malignant brain tumour,with a median survival of 3 months without treatment and 15 months with treatment.Early GBM diagnosis can significantly improve patient survival due to ea...Glioblastoma(GBM)is the most aggressive malignant brain tumour,with a median survival of 3 months without treatment and 15 months with treatment.Early GBM diagnosis can significantly improve patient survival due to early treatment and management procedures.Magnetic resonance imaging(MRI)using contrast agents is the preferred method for the preoperative detection of GBM tumours.However,commercially available clinical contrast agents do not accurately distinguish between GBM,surrounding normal tissue and other cancer types due to their limited ability to cross the blood-brain barrier,their low relaxivity and their potential toxicity.New GBM-specific contrast agents are urgently needed to overcome the limitations of current contrast agents.Recent advances in nanotechnology have produced alternative GBM-targeting contrast agents.The surfaces of nanoparticles(NPs)can be modified with multimodal contrast imaging agents and ligands that can specifically enhance the accumulation of NPs at GBM sites.Using advanced imaging technology,multimodal NP-based contrast agents have been used to obtain accurate GBM diagnoses in addition to an increased amount of clinical diagnostic information.NPs can also serve as drug delivery systems for GBM treatments.This review focuses on the research progress for GBMtargeting MRI contrast agents as well as MRI-guided GBM therapy.展开更多
BACKGROUND The 5-fluorouracil-based chemotherapy combined with oxaliplatin or irinotecan is usually used in colorectal cancer(CRC).The addition of a targeted agent(TA) to this combination chemotherapy is currently the...BACKGROUND The 5-fluorouracil-based chemotherapy combined with oxaliplatin or irinotecan is usually used in colorectal cancer(CRC).The addition of a targeted agent(TA) to this combination chemotherapy is currently the standard treatment for metastatic CRC.However,the efficacy and safety of combination chemotherapy for metastatic CRC in patients aged above 80 years has yet to be established.AIM To assess the clinical outcomes and feasibility of combination chemotherapy using a TA in extremely elderly patients with CRC.METHODS Eligibility criteria were:(1) Age above 80 years;(2) Metastatic colorectal cancer;(3) Palliative chemotherapy na?ve;(4) Eastern Cooperative Oncology Group performance status 0-1;and(5) Adequate organ function.Patients received at least one dose of combination chemotherapy with or without TA.Response was evaluated every 8 wk.RESULTS Of 30 patients,the median age of 15 patients treated with TA was 83.0 years and that of those without TA was 81.3 years.The median progression-free survival(PFS) and overall survival(OS) in patients treated with TA were 7.4 mo and 15.4 mo,respectively,compared with 4.4 mo and 15.6 mo,respectively,in patients treated without TA.There was no significant difference in PFS(P:0.193) and OS(P:0.748) between patients treated with and without TA.Common grade 3/4 hematologic toxicities were anemia(16.7%) and neutropenia(10.0%).After disease progression,the median OS of patients who were treated with and without salvage chemotherapy were 23.5 mo and 7.0 mo,respectively,suggesting significant difference in OS(P = 0.001).CONCLUSION Combination chemotherapy with TA for metastatic CRC may be considered feasible in patients aged above 80 years,when with careful caution.Salvage chemotherapy can help improve OS in some selected of these elderly patients.展开更多
Solid tumors account for more than 60%of all the pediatric malignancies and contribute substantially to the disease burden in China[1].Currently,there are five primary treatment strategies:surgery,radiation therapy,co...Solid tumors account for more than 60%of all the pediatric malignancies and contribute substantially to the disease burden in China[1].Currently,there are five primary treatment strategies:surgery,radiation therapy,conventional chemotherapy,molecular targeted agents and immunotherapy.While the first three methods are nearing their potential limits,the latter two are advancing rapidly,with new approaches continually emerging and resulting in positive clinical outcomes.展开更多
Acute myeloid leukaemia(AML)is a malignant disease of myeloid hematopoietic stem/progenitor cells.Despite improved understanding of the pathogenesis of AML since the 1980s,the standard treatment for AML has remained v...Acute myeloid leukaemia(AML)is a malignant disease of myeloid hematopoietic stem/progenitor cells.Despite improved understanding of the pathogenesis of AML since the 1980s,the standard treatment for AML has remained virtually unchanged.Numerous studies have found poor survival rates and high relapse rates among older patients with AML.Several novel therapies for AML,including cytotoxic drugs,genetically-and epigenetically-targeted drugs,and immunotherapies,have been developed in recent years.Alternative treatments with improved efficacy are required for AML because many patients cannot tolerate the toxic effects of chemotherapy.Non-coding RNAs,including microRNAs(miRNAs),long noncoding RNAs(lncRNAs)and circular RNAs(circRNAs),are attractive treatment targets for cancers and several other diseases.LncRNAs,miRNAs and circRNAs regulate DNA transcription and translation.Over the past decade,significant efforts have been made to develop RNA-based therapies,mainly antisense oligonucleotides and small interfering RNA,some of which have been approved for clinical use.Here we reviewed the mechanisms underlying the in vitro and in vivo effects of promising targets and potential drugs,focusing on the drugs most likely to be used for clinical treatment,to aid in the development of precision therapy for AML.展开更多
To extend overall survival(OS)in patients with hepatocellular carcinoma(HCC)receiving combination therapy with immune checkpoint inhibitors(ICIs),it is critical to identify patient subgroups that can maximize therapeu...To extend overall survival(OS)in patients with hepatocellular carcinoma(HCC)receiving combination therapy with immune checkpoint inhibitors(ICIs),it is critical to identify patient subgroups that can maximize therapeutic benefits or those unlikely to respond effectively.Specifically,the identification of surrogate markers capable of predicting OS early after treatment initiation and biomarkers that can estimate antitumor efficacy prior to treatment initiation is of utmost importance in optimizing pharmacological therapy for HCC.展开更多
While immunotherapy with immune checkpoint inhibitors(ICIs)has revolutionized the clinical management of various malignancies,a large fraction of patients are refractory to ICIs employed as standalone therapeutics,nec...While immunotherapy with immune checkpoint inhibitors(ICIs)has revolutionized the clinical management of various malignancies,a large fraction of patients are refractory to ICIs employed as standalone therapeutics,necessitating the development of combinatorial treatment strategies.Immunogenic cell death(ICD)inducers have attracted considerable interest as combinatorial partners for ICIs,at least in part owing to their ability to initiate a tumor-targeting adaptive immune response.However,compared with either approach alone,combinatorial regimens involving ICD inducers and ICIs have not always shown superior clinical activity.Here,we discuss accumulating evidence on the therapeutic interactions between ICD inducers and immunotherapy with ICIs in oncological settings,identify key factors that may explain discrepancies between preclinical and clinical findings,and propose strategies that address existing challenges to increase the efficacy of these combinations in patients with cancer.展开更多
Accurate assessment and characterization of the progression and therapy response of prostate cancer are essential for precision healthcare of patients diagnosed with the disease.MRI is a clinical imaging modality rout...Accurate assessment and characterization of the progression and therapy response of prostate cancer are essential for precision healthcare of patients diagnosed with the disease.MRI is a clinical imaging modality routinely used for diagnostic imaging and treatment planning of prostate cancer.Extradomain B fibronectin(EDBFN)is an oncofetal subtype of fibronectin highly expressed in the extracellular matrix of aggressive cancers,including prostate cancer.It is a promising molecular target for the detection and risk-stratification of prostate cancer with high-resolution MR molecular imaging(MRMI).In this study,we investigated the effectiveness of MRMI with an EDB-FN specific contrast agent MT218 for assessing the progression and therapy resistance of prostate cancer.Low grade LNCaP prostate cancer cells became an invasive phenotype LNCaP-CXCR2 with elevated EDB-FN expression after acquisition of the C-X-C motif chemokine receptor 2(CXCR2).MT218-MRMI showed brighter signal enhancement in LNCaP-CXCR2 tumor xenografts with a∼2-fold contrast-to-noise(CNR)increase than in LNCaP tumors in mice.Enzalutamide-resistant C4-2-DR prostate cancer cells were more invasive,with higher EDB-FN expression than parental C4-2 cells.Brighter signal enhancement with a∼2-fold CNR increase was observed in the C4-2-DR xenografts compared to that of C4-2 tumors in mice with MT218-MRMI.Interestingly,when invasive PC3 prostate cancer cells developed resistance to paclitaxel,the drug-resistant PC3-DR cells became less invasive with reduced EDB-FN expression than the parental PC3 cells.MT218-MRMI detected reduced brightness in the PC3-DR xenografts with more than 2-fold reduction of CNR compared to PC3 tumors in mice.The signal enhancement in all tumors was supported by the immunohistochemical staining of EDB-FN with the G4 monoclonal antibody.The results indicate that MRMI of EDB-FN with MT218 has promise for detection,risk stratification,and monitoring the progression and therapy response of invasive prostate cancer.展开更多
Antibody-drug conjugates(ADCs),which combine the advantages of monoclonal antibodies with precise targeting and payloads with efficient killing,show great clinical therapeutic value.The ADCs’payloads play a key role ...Antibody-drug conjugates(ADCs),which combine the advantages of monoclonal antibodies with precise targeting and payloads with efficient killing,show great clinical therapeutic value.The ADCs’payloads play a key role in determining the efficacy of ADC drugs and thus have attracted great attention in the field.An ideal ADC payload should possess sufficient toxicity,low immunogenicity,high stability,and modifiable functional groups.Common ADC payloads include tubulin inhibitors and DNA damaging agents,with tubulin inhibitors accounting for more than half of the ADC drugs in clinical development.However,due to clinical limitations of traditional ADC payloads,such as inadequate efficacy and the development of acquired drug resistance,novel highly efficient payloads with diverse targets and reduced side effects are being developed.This perspective summarizes the recent research advances of traditional and novel ADC payloads with main focuses on the structure-activity relationship studies,co-crystal structures,and designing strategies,and further discusses the future research directions of ADC payloads.This review also aims to provide valuable references and future directions for the development of novel ADC payloads that will have high efficacy,low toxicity,adequate stability,and abilities to overcome drug resistance.展开更多
Viral hepatitis C is responsible for a large burden of disease worldwide.Treatment of hepatitis C infection is currently undergoing a revolution with the development of new direct acting antivirals that offer higher c...Viral hepatitis C is responsible for a large burden of disease worldwide.Treatment of hepatitis C infection is currently undergoing a revolution with the development of new direct acting antivirals that offer higher cure rates and fewer side effects than other medications currently available.Treatment options for children,although well-defined and evidencebased,are limited relative to adults as there are few trials regarding the use of these newly developed agents in children.With so much optimism in the development of novel therapeutic options for hepatitis C,it is timely to review and summarize the current standard of care treatment and indications for treatment of chronic hepatitis C in children.We provide here an overview of recent drug developments and their potential for use in children.展开更多
文摘Hepatocellular carcinoma(HCC)is the fifth most common cause of cancer in the world.According to Barcelona Clinic Liver Cancer modified criteria,patients with early stage disease are candidate to radiofrequency ablation(RFA),while patients with intermediate stage HCC are usually treated by transarterial chemoembolization(TACE).TACE and RFA induce a transient devascularisation effect followed by strong neoangiogenic stimulus.In fact,after these procedures,it has been demonstrated an up-regulation of pro-angiogenic and growth factors such as vascular endothelial growth factor-A,which might contribute to accelerated progression in patients with incomplete response.Several studies have demonstrated that MAP-kinase and AKT pathways,in addition to neo-angiogenesis,have an important role in the development of HCC.In advanced HCC,anti-angiogenic therapy and tyrosine kinases inhibitors showed potential clinical benefit.Actually,a number of clinical studies are ongoing testing these agents in combination with TACE or RFA.In this paper,we have reviewed the most recent preclinical and clinical results of such trials.
基金National Natural Science Foundation of China, Grant/Award Number: 81702986Beijing Municipal Natural Science Foundation, Grant/Award Number: 7142131
文摘Background: The outcomes for patients with advanced hepatocellular carcinoma(HCC) receiving sorafenib are far from satisfactory because of treatment resistance to sorafenib. However, the exact mechanism of resistance to sorafenib remains unclear and it is valuable to establish a novel mouse model to quantitatively analyze the inhibition rates of sorafenib on the invasive growth of HCC cells in the liver.Methods: HCC tissue microblocks derived from patients were cultured and mixed with hydrogel drops. Then, hydrogel drops containing microblocks of HCC tissue were attached onto the surface of the livers of nude mice to form lesions or nodules of HCC. The mice received molecular targeting agents through oral administration. Livers with tumor nodules were harvested for H&E staining(hematoxylin-eosin staining) analysis and H&E staining images were quantitatively analyzed using image J software. The invasive growth of HCC cells into the liver was calculated using the depth of the lesions compared with the total thickness of the liver.Results: Microblocks containing cells derived from HCC patients can form lesions in the liver of nude mice. Oral administration of molecular targeting agents inhibited the invasive growth of HCC cells in the liver of nude mice.Conclusions: The model established in this study involves the invasive growth of HCC cells in the liver of nude mice, and the model allows for the quantitative analysis of the inhibitory effect of molecular targeting agents on the invasion of HCC cells in vivo.
文摘BACKGROUND Gemcitabine plus nab-paclitaxel(GA) is a commonly used first-line treatment regimen for metastatic pancreatic cancer,and many studies will add a novel targeted agent to this regimen for improving patient survival rate.However,the clinical effectiveness of GA is the most controversial issue.AIM To compare the efficacy and safety of GA regimen with a targeted agent and GA regimen.METHODS Up to 1 December 2021,the eligible randomized controlled trials(RCTs) relating to GA and GA with a targeted agent were searched on Pub Med,EMBASE and Cochrane Library for eligible data.We screened out appropriate studies for overall survival(OS),progression-free survival(PFS),objective response rate(ORR),and toxicity,which had been pooled and finally analyzed by using Stata version 15.1.In addition,we use Reference Citation Analysis(https://www.referencecitationanalysis.com/) to collect the latest related literature to improve the latest cutting-edge research results.RESULTS Seven RCTs involving 1544 patients(848 men and 696 women) were included.There were no significant differences between GA with a targeted agent and GA in PFS [hazard ratio(HR):1.18 95% confidence interval(CI):0.91-1.53],OS(HR:1.12 95%CI:0.99-1.27),and ORR(HR:0.96 95%CI:0.71-1.29).There was no notable difference in the two groups in grade 3/4 toxicity(fatigue,anemia,vomiting and neutropenia),whereas the incidence of grade 3/4 diarrhea considerably increased in GA with a targeted drug.CONCLUSION Adding a novel targeted agent to the GA regimen did not improve survival rate of patients with metastatic pancreatic cancer.
文摘This review starts with a brief history of drug discovery & development, and the place of Asia in this worldwide effort discussed. The conditions and constraints of a successful translational R&D involving academic basic research and clinical research are discussed and the Singapore model for pursuit of open R&D described. The importance of well-characterized, validated drug targets for the search for novel targeted anti-cancer agents is emphasized, as well as a structured, high quality translational R&D. Furthermore, the characteristics of an attractive preclinical development drug candidate are discussed laying the foundation of a successful preclinical development. The most frequent sources of failures are described and risk management at every stage is highly recommended. Organizational factors are also considered to play an important role. The factors to consider before starting a new drug discovery & development project are described, and an example is given of a successful clinical project that has had its roots in local universities and was carried through preclinical development into phase I clinical trials.
文摘BACKGROUND Hepatic arterial infusion chemotherapy and camrelizumab plus apatinib(TRIPLET protocol)is promising for advanced hepatocellular carcinoma(Ad-HCC).However,the usefulness of microwave ablation(MWA)after TRIPLET is still controversial.AIM To compare the efficacy and safety of TRIPLET alone(T-A)vs TRIPLET-MWA(TM)for Ad-HCC.METHODS From January 2018 to March 2022,217 Ad-HCC patients were retrospectively enrolled.Among them,122 were included in the T-A group,and 95 were included in the T-M group.A propensity score matching(PSM)was applied to balance bias.Overall survival(OS)was compared using the Kaplan-Meier curve with the log-rank test.The overall objective response rate(ORR)and major complications were also assessed.RESULTS After PSM,82 patients were included both the T-A group and the T-M group.The ORR(85.4%)in the T-M group was significantly higher than that(65.9%)in the T-A group(P<0.001).The cumulative 1-,2-,and 3-year OS rates were 98.7%,93.4%,and 82.0%in the T-M group and 85.1%,63.1%,and 55.0%in the T-A group(hazard ratio=0.22;95%confidence interval:0.10-0.49;P<0.001).The incidence of major complications was 4.9%(6/122)in the T-A group and 5.3%(5/95)in the T-M group,which were not significantly different(P=1.000).CONCLUSION T-M can provide better survival outcomes and comparable safety for Ad-HCC than T-A.
基金Supported by China Scholarship Council,No. 202108080085 to (Dai M) and No. 201908080127 to (Lu LL)
文摘Gastroenteropancreatic neuroendocrine neoplasms(GEP-NENs)are a rare group of tumors originating from neuroendocrine cells of the digestive system.Their incidence has increased over the last decades.The specific pathogenetic mechanisms underlying GEP-NEN development have not been completely revealed.Unfunctional GEP-NENs are usually asymptomatic;some grow slowly and thus impede early diagnosis,which ultimately results in a high rate of misdiagnosis.Therefore,many GEP-NEN patients present with later staged tumors.Motivated hereby,research attention for diagnosis and treatment for GEP-NENs increased in recent years.The result of which is great progress in clinical diagnosis and treatment.According to the most recent clinical guidelines,improved grading standards can accurately define poorly differentiated grade 3 neuroendocrine tumors and neuroendocrine carcinomas(NECs),which are subclassified into large and small cell NECs.Combining different functional imaging methods facilitates precise diagnosis.The expression of somatostatin receptors helps to predict prognosis.Genetic analyses of mutations affecting death domain associated protein(DAXX),multiple endocrine neoplasia type 1(MEN 1),alpha thalassemia/intellectual disability syndrome X-linked(ATRX),retinoblastoma transcriptional corepressor 1(RB 1),and mothers against decapentaplegic homolog 4(SMAD 4)help distinguishing grade 3 NENs from poorly differentiated NECs.The aim of this review is to summarize the latest research progress on diagnosis and treatment of GEP-NENs.
文摘Lung cancer,of which non-small lung cancer is the most common subtype,represents the leading cause of cancer related-death worldwide.It is now recognized that a significant proportion of these patients present alterations in certain genes that drive oncogenesis.In recent years,more of these so-called oncogenic drivers have been identified,and a better understanding of their biology has allowed the development new targeted agents.This review aims to provide an update about the current landscape of driver mutation in non-smallcell lung cancer.Alterations in Kirsten rat sarcoma,epidermal growth factor receptor,MET,anaplastic lymphoma kinase,c-ROS oncogene 1,v-raf murine sarcoma viral oncogene homolog B,neurotrophic receptor tyrosine kinase,human epidermal growth factor 2,neuregulin-1 and rearranged during transfection are discussed,as well as agents targeting these alterations.Current standards of treatment as well as promising future strategies are presented.Currently,more than fifteen targeted agents are food and Drug administration-approved for seven oncogenic drivers in non-small-cell lung cancer,highlighting the importance of actively searching for these mutations.Continuous and future efforts made in defining the biology of each of these alterations will help to elucidate their respective resistance mechanisms,and to define the best treatment strategy and therapeutic sequence.
文摘Anticancer drug nephrotoxicity is an important and increasing adverse drug event that limits the efficacy of cancer treatment.The kidney is an important elimination pathway for many antineoplastic drugs and their metabolites,which occurs by glomerular filtration and tubular secretion.Chemotherapeutic agents,both conventional cytotoxic agents and molecularly targeted agents,can affect any segment of the nephron including its microvasculature,leading to many clinical manifestations such as proteinuria,hypertension,electrolyte disturbances,glomerulopathy,acute and chronic interstitial nephritis,acute kidney injury and at times chronic kidney disease.The clinician should be alert to recognize several factors that may maximize renal dysfunction and contribute to the increased incidence of nephrotoxicity associated with these drugs,such as intravascular volume depletion,the associated use of nonchemotherapeutic nephrotoxic drugs(analgesics,antibiotics,proton pump inhibitors,and bonetargeted therapies),radiographic ionic contrast media or radiation therapy,urinary tract obstruction,and intrinsic renal disease.Identification of patients at higher risk for nephrotoxicity may allow the prevention or at least reduction in the development and severity of this adverse effect.Therefore,the aim of this brief review is to provide currently available evidences on oncologic drug-related nephrotoxicity.
基金grants from the National Natural Science Foundation of China(No.81970146)National Science Foundation of China International Cooperation and Exchange Program(No.81720108002)+1 种基金National Science and Technology Major Project(No.2018ZX09734007)Six Talent Peaks Project in Jiangsu Province,2019(No.WSN-001).
文摘Chemoimmunotherapy(CIT)is defined as standard first line treatment for chronic lymphocytic leukemia(CLL)patients while patients with unfavorable biological characteristics such as unmutated immunoglobulin heavy chain(UM-IGHV)and TP53 aberration failed to benefit from it.The emergency of the small molecular targeted agents including Bruton’s tyrosine kinase(BTK)inhibitor(BTKi)leads to a brand-new era,from a CIT to a chemo-free era in CLL.However,the treatment of target agents is not enough to attain a deep remission and high rate of complete remission(CR),especially in patients with high risks.The long duration brought about problems,such as cost,drug resistance and toxicity.To benefit CLL in progression free survival(PFS)and long-term remission,exploration of time-limited therapies,mainly with BTKi plus CIT and BCL2i based combination therapy has become a mainstream in clinical trials.The time-limited combination therapy shed light on the promising potentiality to attain sustainable deep remission and partly overcame the risk factors,although long term follow-up is required to consolidate the conclusion.In this review,we intend to introduce key results of clinical trials with combination therapy,discuss the achievements and limitations and put forward future direction for clinical trial design in this field.
文摘The phase III clinical trial of the novel molecular targeted agent(MTA)lenvatinib for patients with advanced hepatocellular carcinoma(HCC)(REFLECT trial)found that lenvatinib was non-inferior to sorafenib in overall survival.Recently,the efficacy of multiple MTAs,including lenvatinib,in practice has been reported,and therapeutic strategies for Barcelona Clinic Liver Cancer(BCLC)intermediate stage HCC are undergoing major changes.Based on these results,lenvatinib could be recommended for patients with transcatheter arterial chemoembolization(TACE)-refractory,ALBI grade 1,within the up-to-seven criteria in the BCLC intermediate stage.Lenvatinib provides a more favorable outcome than TACE,even in cases with large or multinodular HCC beyond the up-to-seven criteria with Child-Pugh grade A.When patients meet the definitions of TACE-refractory or TACE-unsuitable,switching to systemic chemotherapy,including lenvatinib,is for favorable for preserving liver function.If initial treatment,including MTA,has a significant therapeutic effect and downstaging of HCC is obtained,additional TACE or surgical resection should be considered.Lenvatinib also has a therapeutic effect for poorly differentiated type and non-simple nodular type HCC thanks to the survival-prolonging effect of this drug.Furthermore,a significant therapeutic effect is expected in tumors with more than 50%liver involvement or main portal vein invasion,which have traditionally been considered to have a poor prognosis in patients.This suggests that at the start of lenvatinib treatment,HCC patients with ALBI grade 1 may be able to maintain liver functional reserve.
文摘Second-line therapy for advanced colorectal cancer is an integral part of the treatment strategy that needs to be set from the beginning for each patient, bearing in mind the expected toxicities of chosen treatments, the patient's clinical condition, comorbidities, preferences, the aims of the treatment and the molecular status. Furthermore, the distinction between lines of therapy is no longer absolute. The perspective of "continuum of care" includes switching chemotherapy prior to disease progression, maintenance therapy, drug "holidays" if needed, surgical resection of metastases in selected patients, and seems to allow a tailored treatment, in which patients are more likely to benefit from exposure to all active agents, which is known to correlate with overall survival. The scenario of second-line treatment has changed dramatically over the years and could currently benefit from several options including chemotherapy with a single agent or in combination and the addition of molecular-targeted agents developed in the last decade, such as epidermal growth factor receptor antibodies(cetuximab, panitumumab) and vascular endothelial growth factor-targeting agents(bevacizumab, aflibercept), with the possibility of bevacizumab use even beyond first progression. The purpose of this review is to summarize the most important scientific data supporting the use of chemotherapy and the new biologic agents in the second-line setting in advanced colorectal cancer.
基金supported by the Natural Science Foundation of China(Grant No.81501462,22075281)the Chengdu International Science and Technology Cooperation Funding(Grant No.2019-GH02-00074-HZ)+4 种基金the 135 project for disciplines of Excellence-Clinical Research Incubation Project,West China Hospital,Sichuan Universitythe Scientific and technological Achievements Transformation Fund of West China Hospital,Sichuan University(Grant No.CGZH21002)the Functional and Molecular Imaging Key Laboratory of Sichuan Province(Grant No.2012JO0011)Zhejiang Provincial Natural Science of Foundation of China(LZ21B010001)University of Chinese Academy of Science(WIUCASQD2020008).
文摘Glioblastoma(GBM)is the most aggressive malignant brain tumour,with a median survival of 3 months without treatment and 15 months with treatment.Early GBM diagnosis can significantly improve patient survival due to early treatment and management procedures.Magnetic resonance imaging(MRI)using contrast agents is the preferred method for the preoperative detection of GBM tumours.However,commercially available clinical contrast agents do not accurately distinguish between GBM,surrounding normal tissue and other cancer types due to their limited ability to cross the blood-brain barrier,their low relaxivity and their potential toxicity.New GBM-specific contrast agents are urgently needed to overcome the limitations of current contrast agents.Recent advances in nanotechnology have produced alternative GBM-targeting contrast agents.The surfaces of nanoparticles(NPs)can be modified with multimodal contrast imaging agents and ligands that can specifically enhance the accumulation of NPs at GBM sites.Using advanced imaging technology,multimodal NP-based contrast agents have been used to obtain accurate GBM diagnoses in addition to an increased amount of clinical diagnostic information.NPs can also serve as drug delivery systems for GBM treatments.This review focuses on the research progress for GBMtargeting MRI contrast agents as well as MRI-guided GBM therapy.
文摘BACKGROUND The 5-fluorouracil-based chemotherapy combined with oxaliplatin or irinotecan is usually used in colorectal cancer(CRC).The addition of a targeted agent(TA) to this combination chemotherapy is currently the standard treatment for metastatic CRC.However,the efficacy and safety of combination chemotherapy for metastatic CRC in patients aged above 80 years has yet to be established.AIM To assess the clinical outcomes and feasibility of combination chemotherapy using a TA in extremely elderly patients with CRC.METHODS Eligibility criteria were:(1) Age above 80 years;(2) Metastatic colorectal cancer;(3) Palliative chemotherapy na?ve;(4) Eastern Cooperative Oncology Group performance status 0-1;and(5) Adequate organ function.Patients received at least one dose of combination chemotherapy with or without TA.Response was evaluated every 8 wk.RESULTS Of 30 patients,the median age of 15 patients treated with TA was 83.0 years and that of those without TA was 81.3 years.The median progression-free survival(PFS) and overall survival(OS) in patients treated with TA were 7.4 mo and 15.4 mo,respectively,compared with 4.4 mo and 15.6 mo,respectively,in patients treated without TA.There was no significant difference in PFS(P:0.193) and OS(P:0.748) between patients treated with and without TA.Common grade 3/4 hematologic toxicities were anemia(16.7%) and neutropenia(10.0%).After disease progression,the median OS of patients who were treated with and without salvage chemotherapy were 23.5 mo and 7.0 mo,respectively,suggesting significant difference in OS(P = 0.001).CONCLUSION Combination chemotherapy with TA for metastatic CRC may be considered feasible in patients aged above 80 years,when with careful caution.Salvage chemotherapy can help improve OS in some selected of these elderly patients.
基金support from the Natural Science Foundation of China(No.81470304)the Key Project of Zhejiang Provincial Science and Technology Department(No.2019C03032).
文摘Solid tumors account for more than 60%of all the pediatric malignancies and contribute substantially to the disease burden in China[1].Currently,there are five primary treatment strategies:surgery,radiation therapy,conventional chemotherapy,molecular targeted agents and immunotherapy.While the first three methods are nearing their potential limits,the latter two are advancing rapidly,with new approaches continually emerging and resulting in positive clinical outcomes.
基金supported by grants from Guangdong Basic and Applied Basic Research Foundation(2021A1515111204)the Project of Science and Technology Planning Project of Shenzhen Municipality(JCYJ20220531092609020)+3 种基金the Project of Guangdong Administration of Traditional Chinese Medicine(20221273)the Medical Scientific Research Foundation of Guangdong Province(A2021475)Shenzhen Longhua District Science and Technology Innovation Fund Projects(2022045,2020036,and 2020152)Research Foundation of Shenzhen Longhua District Central Hospital(202203).
文摘Acute myeloid leukaemia(AML)is a malignant disease of myeloid hematopoietic stem/progenitor cells.Despite improved understanding of the pathogenesis of AML since the 1980s,the standard treatment for AML has remained virtually unchanged.Numerous studies have found poor survival rates and high relapse rates among older patients with AML.Several novel therapies for AML,including cytotoxic drugs,genetically-and epigenetically-targeted drugs,and immunotherapies,have been developed in recent years.Alternative treatments with improved efficacy are required for AML because many patients cannot tolerate the toxic effects of chemotherapy.Non-coding RNAs,including microRNAs(miRNAs),long noncoding RNAs(lncRNAs)and circular RNAs(circRNAs),are attractive treatment targets for cancers and several other diseases.LncRNAs,miRNAs and circRNAs regulate DNA transcription and translation.Over the past decade,significant efforts have been made to develop RNA-based therapies,mainly antisense oligonucleotides and small interfering RNA,some of which have been approved for clinical use.Here we reviewed the mechanisms underlying the in vitro and in vivo effects of promising targets and potential drugs,focusing on the drugs most likely to be used for clinical treatment,to aid in the development of precision therapy for AML.
基金supported in part by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science(KAKENHI:24K10393,N.N.).
文摘To extend overall survival(OS)in patients with hepatocellular carcinoma(HCC)receiving combination therapy with immune checkpoint inhibitors(ICIs),it is critical to identify patient subgroups that can maximize therapeutic benefits or those unlikely to respond effectively.Specifically,the identification of surrogate markers capable of predicting OS early after treatment initiation and biomarkers that can estimate antitumor efficacy prior to treatment initiation is of utmost importance in optimizing pharmacological therapy for HCC.
基金supported(as a PI unless otherwise indicated)by one R01 grant from the NIH/NCI(#CA271915)by two Breakthrough Level 2 grants from the US DoD BCRP(#BC180476P1,#BC210945)+11 种基金by a grant from the STARR Cancer Consortium(#I16--0064)by a Transformative Breast Cancer Consortium Grant from the US DoD BCRP(#W81XWH2120034,PI:Formenti)by a U54 grant from NIH/NCI(#CA274291)from the Leukemia and Lymphoma Society(LLS),by the 2019 Laura Ziskin Prize in Translational Research(#ZP--6177,PI:Formenti)from the Stand Up to Cancer(SU2C)by a Mantle Cell Lymphoma Research Initiative(MCL-RI,PI:Chen-Kiang)grant from the Leukemia and Lymphoma Society(LLS)by a Rapid Response Grant from the Functional Genomics Initiative(New York,US)by a pre-SPORE grant(PI:Demaria,Formenti)and a Clinical Trials Innovation Grant from the Sandra and Edward Meyer of Radiation Oncology at Weill Cornell Medicine(New York,US)and Fox Chase Cancer Center(Philadelphia,US)by industrial collaborations with Lytix Biopharma(Oslo,Norway),Promontory(New York,US)and Onxeo(Paris,France)by donations from Promontory(New York,US),the Luke Heller TECPR2 Foundation(Boston,US),Sotio a.s.(Prague,Czech Republic),Lytix Biopharma(Oslo,Norway),Onxeo(Paris,France),Ricerchiamo(Brescia,Italy),and Noxopharm(Chatswood,Australia)supported by the Flanders Research Foundation(FWO)and the Belgian National Fund for Scientific Research(F.R.S.-FNRS)under the Excellence of Science(EOS)program(#40007488),FWO grant(#G016221N)two Special Research Fund(BOF)grants from Ghent University(#BOF/IOP/2022/033,#BOF23/GOA/029)IOF“PULSE”grant(#F2023/IOF-ConcepTT/033)and IOF“IMMUNO-FER-GUARD”grant(#F2023/IOF-ConcepTT/106)from Ghent UniversityEC holds a Marie Sklodowska Curie(MSCA)postdoctoral fellowship(HORIZON-MSCA-2022 PF-01).
文摘While immunotherapy with immune checkpoint inhibitors(ICIs)has revolutionized the clinical management of various malignancies,a large fraction of patients are refractory to ICIs employed as standalone therapeutics,necessitating the development of combinatorial treatment strategies.Immunogenic cell death(ICD)inducers have attracted considerable interest as combinatorial partners for ICIs,at least in part owing to their ability to initiate a tumor-targeting adaptive immune response.However,compared with either approach alone,combinatorial regimens involving ICD inducers and ICIs have not always shown superior clinical activity.Here,we discuss accumulating evidence on the therapeutic interactions between ICD inducers and immunotherapy with ICIs in oncological settings,identify key factors that may explain discrepancies between preclinical and clinical findings,and propose strategies that address existing challenges to increase the efficacy of these combinations in patients with cancer.
基金supported by the Tissue Resources Shared Resource of the Case Comprehensive Cancer Center(P30CA043703).
文摘Accurate assessment and characterization of the progression and therapy response of prostate cancer are essential for precision healthcare of patients diagnosed with the disease.MRI is a clinical imaging modality routinely used for diagnostic imaging and treatment planning of prostate cancer.Extradomain B fibronectin(EDBFN)is an oncofetal subtype of fibronectin highly expressed in the extracellular matrix of aggressive cancers,including prostate cancer.It is a promising molecular target for the detection and risk-stratification of prostate cancer with high-resolution MR molecular imaging(MRMI).In this study,we investigated the effectiveness of MRMI with an EDB-FN specific contrast agent MT218 for assessing the progression and therapy resistance of prostate cancer.Low grade LNCaP prostate cancer cells became an invasive phenotype LNCaP-CXCR2 with elevated EDB-FN expression after acquisition of the C-X-C motif chemokine receptor 2(CXCR2).MT218-MRMI showed brighter signal enhancement in LNCaP-CXCR2 tumor xenografts with a∼2-fold contrast-to-noise(CNR)increase than in LNCaP tumors in mice.Enzalutamide-resistant C4-2-DR prostate cancer cells were more invasive,with higher EDB-FN expression than parental C4-2 cells.Brighter signal enhancement with a∼2-fold CNR increase was observed in the C4-2-DR xenografts compared to that of C4-2 tumors in mice with MT218-MRMI.Interestingly,when invasive PC3 prostate cancer cells developed resistance to paclitaxel,the drug-resistant PC3-DR cells became less invasive with reduced EDB-FN expression than the parental PC3 cells.MT218-MRMI detected reduced brightness in the PC3-DR xenografts with more than 2-fold reduction of CNR compared to PC3 tumors in mice.The signal enhancement in all tumors was supported by the immunohistochemical staining of EDB-FN with the G4 monoclonal antibody.The results indicate that MRMI of EDB-FN with MT218 has promise for detection,risk stratification,and monitoring the progression and therapy response of invasive prostate cancer.
基金provided by the National Natural Science Foundation of China(82073318)the Fundamental Research Funds for the Central Universities(SCU2022D025,0082604151345,China)+1 种基金Sichuan Science and Technology Program Projects(2019YFS0003,China)to Yuxi Wangprovided by the University of Tennessee College of Pharmacy Drug Discovery Center to Wei Li。
文摘Antibody-drug conjugates(ADCs),which combine the advantages of monoclonal antibodies with precise targeting and payloads with efficient killing,show great clinical therapeutic value.The ADCs’payloads play a key role in determining the efficacy of ADC drugs and thus have attracted great attention in the field.An ideal ADC payload should possess sufficient toxicity,low immunogenicity,high stability,and modifiable functional groups.Common ADC payloads include tubulin inhibitors and DNA damaging agents,with tubulin inhibitors accounting for more than half of the ADC drugs in clinical development.However,due to clinical limitations of traditional ADC payloads,such as inadequate efficacy and the development of acquired drug resistance,novel highly efficient payloads with diverse targets and reduced side effects are being developed.This perspective summarizes the recent research advances of traditional and novel ADC payloads with main focuses on the structure-activity relationship studies,co-crystal structures,and designing strategies,and further discusses the future research directions of ADC payloads.This review also aims to provide valuable references and future directions for the development of novel ADC payloads that will have high efficacy,low toxicity,adequate stability,and abilities to overcome drug resistance.
文摘Viral hepatitis C is responsible for a large burden of disease worldwide.Treatment of hepatitis C infection is currently undergoing a revolution with the development of new direct acting antivirals that offer higher cure rates and fewer side effects than other medications currently available.Treatment options for children,although well-defined and evidencebased,are limited relative to adults as there are few trials regarding the use of these newly developed agents in children.With so much optimism in the development of novel therapeutic options for hepatitis C,it is timely to review and summarize the current standard of care treatment and indications for treatment of chronic hepatitis C in children.We provide here an overview of recent drug developments and their potential for use in children.
