Efficacy and Safety of Chemotherapy with or without Targeted Therapy in Biliary Tract Cancer:A Meta-analysis of 7 Randomized Controlled Trials

The systematic treatment based on gemcitabine plus cisplatin is recommended as the current standard chemotherapy for unresectable or metastatic biliary tract cancers.However,the exact benefits from the recognized regime are still dismal.We thus elicit this study in an attempt to analyze whether targeted therapy coupled with various chemotherapy could produce improvement of survival benefits.The clinical trials were searched electronically from databases till July 2016 published in English and Chinese.Nine hundred and sixty-four patients from 7 trials were identified in our analysis.The overall analysis achieved a significantly higher overall response rate（ORR） among the patients treated with targeted drugs plus chemotherapy than chemotherapy alone（OR=1.87;95% CI：1.37–2.57;P=0.000）,but failed in the overall progression-free survival（PFS） [mean difference（MD）=0.63;95% CI：–0.45–1.72;P=0.26] and overall survival（OS）（MD=–0.67;95% CI：–2.54–1.20;P=0.49）.In the sub analysis,better ORR was obtained with the addition of EGFR（OR=1.75;95% CI：1.20–2.56;P=0.004） and VEGFR（OR=2.5;95% CI：1.28–4.87;P=0.007） targeted therapy.Furthermore,the sub analysis of EGFR target showed an significant improvement on PFS（MD=1.36;95% CI：0.29–2.43;P=0.01）.No significant differences were observed in the incidences of neutropenia（OR=1.37;95% CI：0.89–2.12）,thrombocytopenia（OR=1.40;95% CI：0.83–2.39）,anemia（OR=1.21;95% CI：0.62–2.38）,peripheral neuropathy（OR=1.52;95% CI：0.81–2.88）,increased AST/ALT（OR=1.40;95% CI：0.82–2.39） as well as fatigue（OR=1.65;95% CI：0.96–2.84） in either of the treatment groups.In conclusion,better ORR associated with chemotherapy combined with targeted therapy（both targeting EGFR and VEGF） is found in the present meta-analysis without the cost of increased unacceptable toxicities,but regretfully not for the OS.The sub-analysis of targeting EGFR instead of VEGF obtains a superior PFS.Otherwise,there is no statistically significant difference in the overall PFS between the combination regime and chemotherapy alone.Given the paucity of favorable data,we need further studies to characterize optimal targeted agents to confirm the potential value to biliary tract cancer.

A self-assembled affibody-PROTAC conjugate nanomedicine for targeted cancer therapy

Proteolysis targeting chimeras (PROTACs) have recently emerged as promising therapeutic agents for cancer therapy. However, their clinical application is considerably hindered by the poor membrane permeability and insufficient tumor distribution of PROTACs. Here we proposed a nanoengineered targeting strategy to construct a self-assembled affibody-PROTAC conjugate nanomedicine (APCN) for tumor-specific delivery of PROTACs. As proof of concept, a hydrophobic PROTAC MZ1 (a bromodomain-containing protein 4 degrader) was selected to couple with a hydrophilic affibody ZHER2:342 (an affinity protein of human epidermal growth factor receptor 2, HER2) via a smart linker containing disulfide bond to form an amphiphilic ZHER2:342-MZ1 conjugate. It spontaneously self-assembled into nanoparticles (ZHER2:342-MZ1 APCN) in water. Upon the excellent targeting property of ZHER2:342 and HER2 receptor-mediated endocytosis, ZHER2:342-MZ1 APCN was accumulated in tumor sites and internalized by cancer cells effectively in vitro. Under the intracellular high level of glutathione (GSH), ZHER2:342-MZ1 APCN released MZ1 to specifically degrade bromodomain-containing protein 4 (BRD4) and subsequently induced BRD4 deficiency-mediated apoptosis of cancer cells. By the tail-vein injection, ZHER2:342-MZ1 APCN showed the outstanding tumor-specific targeting ability, drug accumulation capacity, enhanced BRD4 degradation and antitumor efficacy in vivo for an HER2-positive SKOV-3 tumor model. Such an affibody mediated nanoengineered strategy would facilitate the application of PROTACs for targeted cancer therapy.

Biointerface engineering nanoplatforms for cancer-targeted drug delivery

Over the past decade,nanoparticle-based therapeutic modalities have become promising strategies in cancer therapy.Selective delivery of anticancer drugs to the lesion sites is critical for elimination of the tumor and an improved prognosis.Innovative design and advanced biointerface engineering have promoted the development of various nanocarriers for optimized drug delivery.Keeping in mind the biological framework of the tumormicroenvironment,biomembrane-camouflaged nanoplatforms have been a research focus,reflecting their superiority in cancer targeting.In this review,we summarize the development of various biomimetic cell membrane-camouflaged nanoplatforms for cancertargeted drug delivery,which are classified according to the membranes fromdifferent cells.The challenges and opportunities of the advanced biointerface engineering drug delivery nanosystems in cancer therapy are discussed.

Changing the paradigm：the potential for targeted therapy in laryngeal squamous cell carcinoma

Laryngeal squamous cell carcinoma(LSCC) remains a highly morbid and fatal disease. Historically, it has been a model example for organ preservation and treatment stratification paradigms. Unfortunately, survival for LSCC has stagnated over the past few decades. As the era of next-generation sequencing and personalized treatment for cancer approaches, LSCC may be an ideal disease for consideration of further treatment stratification and personalization. Here, we will discuss the important history of LSCC as a model system for organ preservation, unique and potentially targetable genetic signatures of LSCC, and methods for bringing stratified, personalized treatment strategies to the 21^(st) century.

EXPERIMENTAL STUDIES OF TARGETING THERAPY OF GASTRIC CANCER WITH ^(131)-I LABELED McAbs

To investigate the radioimmunotherapeutic efficacy, radio-immunoconjugate 131-I-3G9, 811-I-3H11 and 131-I-NMIgG (irre levant antibody) were i.p. injected into nude mice bearing human gastric cancer xenograftes. Each animal received a single doses of 555MBq. Over 14 days the accumulative absorbed doses in tumors were 13.7 Gy for 131-I-3H11 and 12.17 Gy for 131-I-3G9. Both were significantly higher than that for 131-I-NMIgG (3.23 Gy). Thera peutic efficacy appeared most sharply from 2 to 3 weeks after injection. The inhibition ratio of tumor were 86% and 70% for 131-I-3H11 and 131-I-3G9 respectively. Histopathological evidance indicated that in tumor tissues radioactive damage was showed as karyopyknosis, karyorrhexis and necrosis or partial disappearance of tumor cells, while in the other tissues no radioactive damage was observed. WBC counts of all animals did not show significant difference before and after treatment, which indicated that the haemopoietic function of bone marrow was not affected.

Self-Assembled Nanomicelles of Affibody-Drug Conjugate with Excellent Therapeutic Property to Cure Ovary and Breast Cancers

Affibody molecules are small nonimmunoglobulin affinity proteins,which can precisely target to some cancer cells with specific overexpressed molecular signatures.However,the relatively short in vivo half-life of them seriously limited their application in drug targeted delivery for cancer therapy.Here an amphiphilic affibody-drug conjugate is self-assembled into nanomicelles to prolong circulation time for targeted cancer therapy.As an example of the concept,the nanoagent was prepared through molecular self-assembly of the amphiphilic conjugate of Z_(HHR2:342)-Cys with auristatin E derivate,where the affibody used is capable of binding to the human epidermal growth factor receptor 2(HER2).Such a nanodrug not only increased the blood circulation time,but also enhanced the tumor targeting capacity(abundant affibody arms on the nanoagent surface) and the drug accumulation in tumor.As a result,this affibody-based nanoagent showed excellent antitumor activity in vivo to HER2-positive ovary and breast tumor models,which nearly eradicated both small solid tumors(about 100 mm^(3)) and large established tumors(exceed 500 mm^(3)).The relative tumor proliferation inhibition ratio reaches 99.8% for both models.

Advances in understanding the molecular mechanism of pancreatic cancer metastasis

BACKGROUND： Pancreatic cancer（PC） is usually diagnosed at the late-stage and therefore, has widespread metastasis and a very high mortality rate. The mechanisms underlying PC metastasis are not well understood. Recent advances in genomic sequencing have identified groups of gene mutations that affect PC metastasis, but studies elucidating their roles are lacking. The present review was to investigate the molecular mechanisms of PC metastasis.DATA SOURCES： Relevant articles on PC metastasis were searched in MEDLINE via Pub Med prior to April 2015. The search was limited in English publications.RESULTS： PC metastatic cascades are multi-factorial events including both intrinsic and extrinsic elements. This review highlights the most important genetic alterations and other mechanisms that account for PC invasion and metastasis, with particular regard to epithelial-mesenchymal transition, inflammation, stress response, and circulating tumor cells.CONCLUSIONS： Analyses of relevant gene functions and signaling pathways are needed to establish the gene regulatory network and to define the pivotal modulators. Another promising area of study is the genotyping and phenotyping of circulating tumor cells, which could lead to a new era of personalized therapy by identifying specific markers and targets.

Increased Activity of the Human Telomerase Catalytic Subunit Promoter by the VEGF Enhancer in Human Cancer Cells

We attempted to improve the activity of hTERT promoter by fusing the vascular endothelial growth factor （VEGF） enhancer. To determine the potential as cancer specific promoters, we measured the reporter gene transfection assay driven by the hTERT promoter and the VEGF enhancer in human cancer cells. We found that the hTERT promoter containing VEGF enhancer conferred strong expression of the reporter gene only in different cancer cell lines but not in normal human cells. Retrovirus vector expressing HSV-TK controlled by the hTERT promoter and the VEGF enhancer was constructed. A549 cells infected with LN-enh-hT-TK was significantly suppressed and induced to apoptosis more than those infected with LN-hT-TK. The apoptosis ratio ofA549 cell infected with two kinds of retrovirus cell with GCV in lower concentration is 20.94% and 50.7%. It suggested that there is significant differentiation between the assay groups. Our results demonstrated the possible application of hTERT promoter and the VEGF enhancer in targeted cancer gene therapy.

Searching for Better Outcomes among Patients with Metastatic Triple- Negative Breast Cancer – Do We Have Novel Options on the Treatment Landscape?

Triple-negative breast cancer(TNBC),which accounts for approximately 15%of breast cancers(BCs)is characterized by a lack of expression of the hormone receptors(HRs)(estrogen receptor(ER)and progesterone receptor(PR)),and human epidermal growth factor receptor 2(HER2).TNBC reveals very aggressive behavior and often leads to poor prognosis.Unfortunately,standard chemotherapy(CHT)is related to low response rates and short progression-free survival(PFS)in patients with metastatic TNBC,creating an unmet need.However,recent recognition of different molecular subtypes and mutations within TNBC has allowed exploring some innovative targeted therapies,bringing new hope for women suffering from TNBC.Currently,some promising systemic treatment options in this area have been developed,including targeted therapies,such as poly(ADP-ribose)polymerase(PARP)inhibitors,immune checkpoint inhibitors,antibody-drug conjugates,and AKT inhibitors.The aim of this mini-review is to address these novel treatment modalities and highlight the main directions for further research and clinical practice in the advanced or metastatic forms of TNBC.This article presents poly(ADP-ribose)polymerase(PARP)inhibitors(e.g.,olaparib,talazoparib,and valaparib for treatment of BRCA-mutated,HER2-negative metastatic BC),immune checkpoint inhibitors(atezolizumab and pembrolizumab),an antibody-drug conjugate(ADC)(sacituzumab govitecan),and AKT inhibitors(ipatasertib and capivasertib).A brief outline of the main clinical trials leading to the approval of these new medications has been provided.Moreover,this overview discusses the efficacy and safety of these innovative treatment options,focusing on women with metastatic TNBC.In addition,this paper comments on some recent considerations,regarding avenues of delivering care and conduct clinical trials in patients with BC,during the COVID-19 pandemic.

Nanoformulations targeting immune cells for cancer therapy: mRNA therapeutics

The approved worldwide use of two messenger RNA(mRNA)vaccines(BNT162b2 and mRNA-1273)in late 2020 has proven the remarkable success of mRNA therapeutics together with lipid nanoformulation technology in protecting people against coronaviruses during COVID-19 pandemic.This unprecedented and exciting dual strategy with nanoformulations and mRNA therapeutics in play is believed to be a promising paradigm in targeted cancer immunotherapy in future.Recent advances in nanoformulation technologies play a prominent role in adapting mRNA platform in cancer treatment.In this review,we introduce the biologic principles and advancements of mRNA technology,and chemistry fundamentals of intriguing mRNA delivery nanoformulations.We discuss the latest promising nano-mRNA therapeutics for enhanced cancer immunotherapy by modulation of targeted specific subtypes of immune cells,such as dendritic cells(DCs)at peripheral lymphoid organs for initiating mRNA cancer vaccine-mediated antigen specific immunotherapy,and DCs,natural killer(NK)cells,cytotoxic T cells,or multiple immunosuppressive immune cells at tumor microenvironment(TME)for reversing immune evasion.We highlight the clinical progress of advanced nano-mRNA therapeutics in targeted cancer therapy and provide our perspectives on future directions of this transformative integrated technology toward clinical implementation.

Editorial Preface for Targeted Cancer Therapy

Chemotherapy has been used for treatment of human cancer since early 1900 with purified natural products or synthetic compounds to kill rapidly growing tumor cells or to reduce their growth.However,chemotherapy is also toxic to some rapidly proliferating normal cells such as bone marrow,therefore causing undesirable

Engineered microorganisms-based delivery systems for targeted cancer therapy:a narrative review

Microorganisms with innate and artificial advantages have been regarded as intelligent drug delivery systems for cancer therapy with the help of engineering technology.Although numerous studies have confirmed the promising prospects of microorganisms in cancer,several problems such as immunogenicity and toxicity should be addressed before further clinical applications.This review aims to investigate the developments of engineered microorganisms-based delivery systems for targeted cancer therapy.The main types and characteristics of microorganisms such as bacteria,viruses,fungi,microalgae,and their components are introduced in detail.Moreover,the engineering strategies and biomaterials design of microorganisms are further discussed.Most importantly,we discussed the innovative attempts and therapeutic effects of engineered microorganisms in cancer.Taken together,engineered microorganisms-based delivery systems hold tremendous prospects for biomedical applications in targeted cancer therapy.

Cathepsin B-responsive prodrugs for cancer-targeted therapy:Recent advances and progress for clinical translation

The cathepsin B-responsive prodrugs are promising strategies to reduce the serious adverse effects of anticancer drugs by improving the cancer selectivity that can be specifically activated by overexpressed cathepsin B in targeted cancer cells.However,clinical translation of such therapeutic approaches has been restricted by low antitumor efficacy that is mainly attributable to undesirable pharmacokinetic profiles and inefficient tumor-targeting of cathepsin B-responsive prodrugs,due to their small-molecule structure.In recent decades,many researchers have widely investigated the drug delivery system(DDS)to improve the in vivo pharmacokinetic profiles and tumor-targeting efficiency of cathepsin B-responsive prodrugs via the application of polymers,dendrimers,antibodies,lipids,and inorganic nanoparticles as drug carriers.In addition,the potential therapeutic efficacy of DDS for cathepsin B-responsive prodrugs is demonstrated in multiple studies and combinatorial treatment with typical therapeutic modalities can effectively overcome the challenges of tumor heterogeneity and multidrug resistance.In this review,recent advances and progress of new DDS for cathepsin B-responsive prodrugs are outlined,and their clinical trials are discussed.Besides,potential challenges and the outlooks for clinical translation of cathepsin B-responsive prodrugs are highlighted.

Editor Profiles: Guest Editor of Special Column on Targeted Cancer Therapy

Dr.Guan Chen previously worked in Sun Yat-sen University and German cancer research Center as well in Dana-Farber focused on investigating on biochemical mechanisms involved in cancer drug response by discovering Thaliblastine as a novel and non-toxic

Self-assembled multifunctional DNA nanoflowers for the circumvention of multidrug resistance in targeted anticancer drug delivery

Cancer chemotherapy has been limited by its side effects and multidrug resistance （MDR）, the latter of which is partially caused by drug efflux from cancer cells. Thus, targeted drug delivery systems that can circumvent MDR are needed. Here, we report multifunctional DNA nanoflowers （NFs） for targeted drug delivery to both chemosensitive and MDR cancer cells that circumvented MDR in both leukemia and breast cancer cell models. NFs are self-assembled via potential co-precipitation of DNA and magnesium pyrophosphate generated by rolling circle replication, during which NFs are incorporated using aptamers for specific cancer cell recognition, fluorophores for bioimaging, and doxorubicin （Dox）- binding DNA for drug delivery. NF sizes are tunable （down to N200 nm in diameter）, and the densely packed drug-binding motifs and porous intrastructures endow NFs with a high drug-loading capacity （71.4%, wt/wt）. Although the Dox- loaded NFs （NF-Dox） are stable at physiological pH, drug release is facilitated under acidic or basic conditions. NFs deliver Dox into target chemosensitive and MDR cancer cells, preventing drug efflux and enhancing drug retention in MDR cells. NF-Dox induces potent cytotoxicity in both target chemosensitive cells and MDR cells, but not in nontarget cells, thus concurrently circumventing MDR and reducing side effects. Overall, these NFs are promising tools for circumventing MDR in targeted cancer therapy.

Targeting an oncogenic kinase/phosphatase signaling network for cancer therapy

Protein kinases and phosphatases signal by phosphorylation and dephosphorylation to precisely control the activities of their individual and common substrates for a coordinated cellular outcome. In many situations, a kinase/phosphatase complex signals dynamically in time and space through their reciprocal regulations and their cooperative actions on a substrate. This complex may be essential for malignant transformation and progression and can therefore be considered as a target for therapeutic intervention. p38γ is a unique MAPK family member that contains a PDZ motif at its C-terminus and interacts with a PDZ domain-containing protein tyrosine phosphatase PTPH1. This PDZcoupled binding is required for both PTPH1 dephosphorylation and inactivation of p38γ and for p38γ phosphorylation and activation of PTPH1. Moreover, the p38γ/PTPH1 complex can further regulate their substrates phosphorylation and dephosphorylation, which impacts Ras transformation, malignant growth and progression, and therapeutic response. This review will use the p38γ/PTPH1 signaling network as an example to discuss the potential of targeting the kinase/phosphatase signaling complex for development of novel targeted cancer therapy.

Therapeutic strategies for targeting cancer stem cells

The therapeutic limitations of conventional chemotherapeutic drugs present a challenge for cancer therapy;these shortcomings are largely attributed to the ability of cancer cells to repopulate and metastasize after initial therapies.Compelling evidence suggests that cancer stem cells(CSCs)have a crucial impact in current shortcomings of cancer therapy because they are largely responsible for tumor initiation,relapse,metastasis,and chemo-resistance.Thus,a better understanding of the properties and mechanisms underlying CSC resistance to treatments is necessary to improve patient outcomes and survival rates.In this review,the authors characterize and compare different CSC-specific biomarkers that are present in various types of tumors.We further discuss multiple targeting approaches currently in preclinical or clinical testing that show great potential for targeting CSCs.This review discusses numerous strategies to eliminate CSCs by targeting surface biomarkers,regulating CSC-associated oncogenes and signaling pathways,inhibiting drug-efflux pumps involved in drug resistance,modulating the tumor microenvironment and immune system,and applying drug combination therapy using nanomedicine.

Highly efficient gene silencing and bioimaging based on fluorescent carbon dots in vitro and in vivo

Small interfering RNA （siRNA） is an attractive therapeutic candidate for sequence- specific gene silencing to treat incurable diseases using small molecule drugs. However, its efficient intracellular delivery has remained a challenge. Here, we have developed a highly biocompatible fluorescent carbon dot （CD）, and demonstrate a functional siRNA delivery system that induces efficient gene knockdown in vitro and in vivo. We found that CD nanoparticles （NPs） enhance the cellular uptake of siRNA, via endocytosis in tumor cells, with low cytotoxicity and unexpected immune responses. Real-time study of fluorescence imaging in live cells shows that CD NPs favorably localize in cytoplasm and successfully release siRNA within 12 h. Moreover, we demonstrate that CD NP-mediated siRNA delivery significantly silences green fluorescence protein （GFP） expression and inhibits tumor growth in a breast cancer cell xenograft mouse model of tumor-specific therapy. We have developed a multifunctional siRNA delivery vehicle enabling simultaneous bioimaging and efficient downregulation of gene expression, that shows excellent potential for gene therapy.

Therapeutic approaches and drug-resistance in chronic lymphocytic leukaemia

The treatment of chronic lymphocytic leukaemia has been revolutionised in recent years,first by the introduction of chemoimmunotherapy regimens and subsequently by the development of drugs,including ibrutinib,idelalisib and venetoclax,that target components of the B-cell receptor signalling pathway or B-cell lymphoma 2 family of proteins.Despite high initial response rates in patients treated with chemoimmunotherapy or targeted agents,a significant proportion of patients relapse with progressive and refractory disease.In a subset of these patients,drug resistance has been associated with specific genetic lesions or activation of alternate pro-survival pathways.However,the mechanisms that confer drug resistance in the remainder of the patients with refractory disease have yet to be fully elucidated.In this review,we discuss our current understanding of the mechanics of drug resistance in chronic lymphocytic leukaemia and describe how this knowledge may aid in rationalising future treatment strategies to prevent the development of refractory or aggressive transformation of the disease.