Chemotherapy and molecular targeting therapy for recurrent cervical cancer

For patients with primary stage IVB, persistent, or recurrent cervical cancer, chemotherapy remains the standard treatment, although it is neither curative nor associated with long-term disease control. In this review, we summarized the history of treatment of recurrent cervical cancer, and the current recommendation for chemotherapy and molecular targeted therapy. Eligible articles were identified by a search of the MEDLINE bibliographical database for the period up to November 30, 2014. The search strategy included the following any or all of the keywords： ＂uterine cervical cancer＂, ＂chemotherapy＂, and ＂targeted therapies＂. Since cisplatin every 21 days was considered as the historical standard treatment for recurrent cervical cancer, subsequent trials have evaluated and demonstrated activity for other agents including paclitaxel, gemcitabine, topotecan and vinorelbine among others. Accordingly, promising agents were incorporated into phase III trials. To examine the best agent to combine with cisplatin, several landmark phase III clinical trials were conducted by Gynecologic Oncology Group （GOG） and Japan Clinical Oncology Group （JCOG）. Through, GOG204 and JCOG0505, paclitaxel/cisplatin （TP） and paclitaxel/carboplatin （TC） are now considered to be the recommended therapies for recurrent cervical cancer patients. However, the prognosis of patients who are already resistant to chemotherapy, are very poor. Therefore new therapeutic strategies are urgently required. Molecular targeted therapy will be the most hopeful candidate of these strategies. From the results of GOG240, bevacizumab combined with TP reached its primary endpoint of improving overall survival （OS）. Although, the prognosis for recurrent cervical cancer patients is still poor, the results of GOG240 shed light on the usefulness of molecular target agents to chemotherapy in cancer patients. Recurrent cervical cancer is generally considered incurable and current chemotherapy regiments offer only modest gains in OS, particularly for patients with multiple poor prognostic factors. Therefore, it is crucial to consider not only the survival benefit, but also the minimization of treatment toxicity, and maximization of quality of life （QOL）.

Improving cancer therapy by combining cell biological, physical, and molecular targeting strategies

Successful cancer therapy depends on selective killing of tumor cells while sparing normal cells. Selectivity can be achieved through treatment strategies that target tumor cells. A recent report from the Li laboratory （1） describes an elegant strategy to selectively kill tumor cells by combining several targeting strategies based on cell biological, physical, and molecular （genetic） properties of tumor and normal cells that enhances tumor cell killing in vitro and in an in vivo tumor xenograft model. The idea of using a multiplex targeting approach is reminiscent of strategies in which several antibiotics are used to treat bacterial infections while minimizing the chance that rare antibiotic-resistant mutants will arise within a population.

Quantitative examination of the inhibitory activation of molecular targeting agents in hepatocellular carcinoma patient-derived cell invasion via a novel in vivo tumor model

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.

Distinct molecular targets of ProEGCG from EGCG and superior inhibition of angiogenesis signaling pathways for treatment of endometriosis

Endometriosis is a common chronic gynecological disease with endometrial cell implantation outside the uterus.Angiogenesis is a major pathophysiology in endometriosis.Our previous studies have demonstrated that the prodrug of epigallocatechin gallate(ProEGCG)exhibits superior anti-endometriotic and anti-angiogenic effects compared to epigallocatechin gallate(EGCG).However,their direct binding targets and underlying mechanisms for the differential effects remain unknown.In this study,we demonstrated that oral ProEGCG can be effective in preventing and treating endometriosis.Additionally,1D and 2D Proteome Integral Solubility Alteration assay-based chemical proteomics identified metadherin(MTDH)and PX domain containing serine/threonine kinase-like(PXK)as novel binding targets of EGCG and ProEGCG,respectively.Computational simulation and BioLayer interferometry were used to confirm their binding affinity.Our results showed that MTDH-EGCG inhibited protein kinase B(Akt)-mediated angiogenesis,while PXK-ProEGCG inhibited epidermal growth factor(EGF)-mediated angiogenesis via the EGF/hypoxia-inducible factor(HIF-1a)/vascular endothelial growth factor(VEGF)pathway.In vitro and in vivo knockdown assays and microvascular network imaging further confirmed the involvement of these signaling pathways.Moreover,our study demonstrated that ProEGCG has superior therapeutic effects than EGCG by targeting distinct signal transduction pathways and may act as a novel antiangiogenic therapy for endometriosis.

Predicting bioactive compounds and cancer-related molecular targets of lotus seedpod (Receptaculum Nelumbinis) based on network pharmacology and molecular docking

Background:Lotus seedpod(Receptaculum Nelumbinis)is the abundant by-products produced during lotus seed processing,and the sources are usually considered to be wastes and are abandoned outdoors or incinerated.This study aims at predicting its bioactive compounds and cancer-related molecular targets against six cancers,including lung cancer,gastric cancer,liver cancer,breast cancer,ovarian cancer and cervical cancer.Methods:Network pharmacology and molecular docking methods were performed.Results:Network pharmacology results indicated that 14 core compounds(liensinine,tetrandrine,lysicamine,tricin,sanleng acid,cireneol G,ricinoleic acid,linolenic acid,5,7-dihydroxycoumarin,apigenin,luteolin,morin,quercetin and isorhamnetin)and 10 core targets(AKT1,ESR1,HSP90AA1,JUN,MAPK1,MAPK3,PIK3CA,PIK3R1,SRC and STAT3)were screened for lotus seedpod against the six cancers.Molecular docking analysis suggested that the binding abilities between the core compounds and the core targets were mostly strong.GO analysis revealed that the intersected targets between the bioactive compounds of lotus seedpod and the six cancers were significantly related to biological processes,cell compositions and molecular functions.KEGG analysis showed that PI3K-Akt,TNF,Ras,MAPK,HIF-1 and C-type lectin receptor signaling pathways were notably involved in the anti-cancer activities of lotus seedpod against the six cancers.Conclusions:14 core compounds and 10 core targets were screened for lotus seedpod against lung cancer,gastric cancer,liver cancer,breast cancer,ovarian cancer and cervical cancer.This study supports the application of lotus seedpod in treating cancers,and promotes the recycling and the high-value utilization.

Hyaluronic acid-based dual-responsive nanomicelles mediated mutually synergistic photothermal and molecular targeting therapies

Precise clinical treatment of triple-negative breast cancer(TNBC)is an obstacle in clinic.Nanotechnology-assisted photothermal therapy(PTT)is a superior treatment modality for TNBC in terms of precision.However,thermoresistance arising from PTT and insufficient drug release from nanocarriers decrease the efficacy of PTT.AT13387 is a novel HSP90 inhibitor that can weaken thermoresistance and undergoing clinic II phase study,showing satisfactory antitumour activity through molecularly targeted therapy(MTT).Whereas,it has poor solubility.Hence hyaluronic acid and stearic acid were connected by hydrazone bonds and disulfide bonds,forming an amphipathic copolymer that could self-assembled into nanomicelles,followed by encapsulating Cypate and AT13387.These nanomicelles exhibited great features,including achieving mutually synergistic PTT/MTT for overcoming thermoresistance and promoting translocation of drugs,increasing the solubility of Cypate and AT13387,showing a pH/redox dual response that contributes to drug release,and having the ability of active targeting.Thus,the nanomicelles developed in this study may be a promising strategy for the precise treatment of TNBC.

Novel molecular targets in hepatocellular carcinoma

Globally,hepatocellular carcinoma(HCC)is a leading cause of cancer and cancerrelated deaths.The therapeutic efficacy of locoregional and systemic treatment in patients with advanced HCC remains low,which results in a poor prognosis.The development of sorafenib for the treatment of HCC has resulted in a new era of molecular targeted therapy for this disease.However,the median overall survival was reported to be barely higher in the sorafenib treatment group than in the control group.Hence,in this review we describe the importance of developing more effective targeted therapies for the management of advanced HCC.Recent investigations of molecular signaling pathways in several cancers have provided some insights into developing molecular therapies that target critical members of these signaling pathways.Proteins involved in the Hedgehog and Notch signaling pathways,Polo-like kinase 1,arginine,histone deacetylases and Glypican-3 can be potential targets in the treatment of HCC.Monotherapy has limited therapeutic efficacy due to the development of inhibitory feedback mechanisms and induction of chemoresistance.Thus,emphasis is now on the development of personalized and combination molecular targeted therapies that can serve as ideal therapeutic strategies for improved management of HCC.

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.

Allosteric Mechanism of Calmodulin Revealed by Targeted Molecular Dynamics Simulation

Calmodulin （CAM） is involved in the regulation of a variety of cellular signaling pathways. To accomplish its physiological functions, CaM binds with Ca2＋ at its EF-hand Ca2＋ binding sites which induce the conformational switching of CaM. However, the molecular mechanism by which Ca2＋ binds with CaM and induces conformational switching is still obscure. Here we combine molecular dynamics with targeted molecular dynamics simulation and achieve the state-transition pathway of CaM. Our data show that Ca2＋ binding speeds up the conformational transition of CaM by weakening the interactions which stabilize the closed state. It spends about 6.5 ns and 5.25 ns for transition from closed state to open state for apo and holo CaM, respectively. Regarding the contribution of two EF-hands, our data indicate that the first EF-hand triggers the conformational transition and is followed by the second one. We determine that there are two interaction networks which contribute to stabilize the closed and open states, respectively.

Molecular targeted therapy causes hepatic encephalopathy in patients after Transjugular intrahepatic portosystemic shunt(TIPS):A case report and literature review

We report two cases of hepatic encephalopathy caused by molecular targeted drugs after the Transjugular intrahepatic portosystemic shunt(TIPS)procedure in our center.The liver toxicities and anti-angiogenic effects induced by targeted drugs may generate an imbalance in ammonia metabolism,elevating blood ammonia levels.TIPS diverts partial blood supply from the liver,aggravates liver impairment,and shunts ammonia-rich blood from the intestine into the systemic circulation.These may be the mechanisms leading to hepatic encephalopathy caused by molecular targeted drugs following TIPS.When clinicians choose molecular targeted therapy as the second or third targeted therapy for patients who have undergone TIPS,the consequence of drug-induced hepatic encephalopathy should also be considered.

Molecular neuro-oncology and development of targeted therapeutic strategies for brain tumors

Brain tumors are a diverse group of malignancies that remain refractory to conventional treatment approaches.Molecular neuro-oncologyhas now begun to clarify the transformed phenotype of brain tumors and identify oncogenic pathways that might be amenable to targetedtherapy.Activity of the phosphoinositide 3;kinase(PI3K)/Akt pathway is often upregulated in brain tumors due to excessive stimu-lation by growth factor receptors and Ras.Loss of function of the tumor suppressor gene PTEN also frequently contributesto

Tra2βEnhances Cell Proliferation by Inducing the Expression of Transcription Factor SP1 in Cervical Cancer

Objective In this study,the role and potential mechanism of transformer 2β(Tra2β)in cervical cancer were explored.Methods The transcriptional data of Tra2βin patients with cervical cancer from Gene Expression Profiling Interactive Analysis(GEPIA)and cBioPortal databases were investigated.The functions of Tra2βwere evaluated by using Western blot,MTT,colony formation,Transwell assays,and nude mouse tumor formation experiments.Target genes regulated by Tra2βwere studied by RNA-seq.Subsequently,representative genes were selected for RT-qPCR,confocal immunofluorescence,Western blot,and rescue experiments to verify their regulatory relationship.Results The dysregulation of Tra2βin cervical cancer samples was observed.Tra2βoverexpression in Siha and Hela cells enhanced cell viability and proliferation,whereas Tra2βknockdown showed the opposite effect.Alteration of Tra2βexpression did not affect cell migration and invasion.Furthermore,tumor xenograft models verified that Tra2βpromoted cervical cancer growth.Mechanically,Tra2βpositively regulated the mRNA and protein level of SP1,which was critical for the proliferative capability of Tra2β.Conclusion This study demonstrated the important role of the Tra2β/SP1 axis in the progression of cervical cancer in vitro and in vivo,which provides a comprehensive understanding of the pathogenesis of cervical cancer.

Anti-psoriasis molecular targets and active components discovery of Optimized Yinxieling Formula via affinity-purified strategy

Psoriasis,a prevalent inherited skin condition,involves an inflammatory response as a key pathogenic mechanism.The Optimized Yinxieling Formula(OYF),rooted in traditional Chinese medicine,is extensively utilized in clinical settings to treat psoriasis.Although previous studies have demonstrated OYF’s significant anti-inflammatory effects in psoriasis,its potential molecular targets and active components remain unexplored.This study aimed to unveil the anti-psoriasis molecular targets and active components of OYF.Our findings indicated that OYF extract markedly reduced the production of several inflammatory mediators,including IL-23,nitric oxide,TNF-α,and IL-1β,in LPS-induced RAW264.7 cells.We synthesized OYF extract-crosslinked beads to isolate pharmacological targets from RAW264.7 lysates using an affinity purification strategy,known as Target Fishing.The enriched target proteins were subsequently identified via LC-MS/MS,followed by bioinformatics analysis to map the psoriasis-associated pathway-gene network.We identified a total of 76 potential target proteins,which were highly associated with mRNA transcription mechanisms.In particular,pathway-gene network analysis revealed that the IL-23 inflammatory pathway was involved in the anti-psoriasis effect of OYF extract.We further utilized a target protein-based affinity capture strategy,combined with LC-MS and SPR analysis,to globally screen OYF’s active components,focusing on the mRNA transcription regulator,fused in sarcoma(FUS).This process led to the identification of umbelliferone,vanillic acid,protocatechuic acid,gentisic acid,and echinacoside as key compounds targeting FUS to inhibit IL-23 expression.Additionally,we formulated a compound cocktail(CpdC),which significantly reduced psoriasis area and severity index(PASI)scores and the expressions of IL-23 and Ki67 in an imiquimod(IMQ)-induced psoriasis mouse model.Collectively,our study elucidates the primary molecular targets and active components of OYF,offering novel insights for psoriasis treatment.

Cancer stem cells in glioblastoma—molecular signaling and therapeutic targeting

Glioblastomas(GBMs)are highly lethal primary brain tumors.Despite current therapeutic advances in other solid cancers,the treatment of these malignant gliomas remains essentially palliative.GBMs are extremely resistant to conventional radiation and chemotherapies.We and others have demonstrated that a highly tumorigenic subpopulation of cancer cells called GBM stem cells(GSCs)promotes therapeutic resistance.We also found that GSCs stimulate tumor angiogenesis by expressing elevated levels of VEGF and contribute to tumor growth,which has been translated into a useful therapeutic strategy in the treatment of recurrent or progressive GBMs.Furthermore,stem cell-like cancer cells(cancer stem cells)have been shown to promote metastasis.Although GBMs rarely metastasize beyond the central nervous system,these highly infiltrative cancers often invade into normal brain tissues preventing surgical resection,and GSCs display an aggressive invasive phenotype.These studies suggest that targeting GSCs may effectively reduce tumor recurrence and significantly improve GBM treatment.Recent studies indicate that cancer stem cells share core signaling pathways with normal somatic or embryonic stem cells,but also display critical distinctions that provide important clues into useful therapeutic targets.In this review,we summarize the current understanding and advances in glioma stem cell research,and discuss potential targeting strategies for future development of anti-GSC therapies.

Progress in surgical and nonsurgical approaches for hepatocellular carcinoma treatment

BACKGROUND： Hepatocellular carcinoma （HCC） is a com- plex and heterogeneous malignancy, frequently occurs in the setting of a chronically diseased organ, with multiple con- founding factors making its management challenging. HCC represents one of the leading causes of cancer-related mortal- ity globally with a rising trend of incidence in some of the de- veloped countries, which indicates the need for better surgical and nonsurgical management strategies.

Chemotherapy for hepatocellular carcinoma:The present and the future

Hepatocellular carcinoma(HCC) is the most common primary tumor of the liver. Its relationship to chronic liver diseases, in particular cirrhosis, develops on a background of viral hepatitis, excessive alcohol intake or metabolic steatohepatitis, leads to a high incidence and prevalence of this neoplasia worldwide. Despite the spread of HCC, its treatment it's still a hard challenge, due to high rate of late diagnosis and to lack of therapeutic options for advanced disease. In fact radical surgery and liver transplantation, the most radical therapeutic approaches, are indicated only in case of early diagnosis. Even local therapies, such as transarterial chemoembolization, find limited indications, leading to an important problem regarding treatment of advanced disease. In this situation, until terminal HCC occurs, systemic therapy is the only possible approach, with sorafenib as the only standard treatment available. Anyway, the efficacy of this drug is limited and many efforts are necessary to understand who could benefit more with this treatment. Therefore, other molecules for a targeted therapy were evaluated, but only regorafenib showed promising results. Beside molecular target therapy, also cytotoxic drugs, in particular oxaliplatinand gemcitabine-based regimens, and immune-checkpoint inhibitors were tested with interesting results. The future of the treatment of this neoplasia is linked to our ability to understand its mechanisms of resistance and to find novel therapeutic targets, with the objective to purpose individualized approaches to patients affected by advanced HCC.

Anticancer Properties of Lobetyolin,an Essential Component of Radix Codonopsis(Dangshen)

Lobetyolin(LBT)is a polyacetylene glycoside found in diverse medicinal plants but mainly isolated from the roots of Codo-nopsis pilosula,known as Radix Codonopsis or Dangshen.Twelve traditional Chinese medicinal preparations containing Radix Codonopsis were identified;they are generally used to tonify spleen and lung Qi and occasionally to treat cancer.Here we have reviewed the anticancer properties of Codonopsis extracts,LBT and structural analogs.Lobetyolin and lobetyolinin are the mono-and bis-glucosylated forms of the polyacetylenic compound lobetyol.Lobetyol and LBT have shown activi-ties against several types of cancer(notably gastric cancer)and we examined the molecular basis of their activity.A down-regulation of glutamine metabolism by LBT has been evidenced,contributing to drug-induced apoptosis and tumor growth inhibition.LBT markedly reduces both mRNA and protein expression of the amino acid transporter Alanine-Serine-Cysteine Transporter 2(ASCT2).Other potential targets are proposed here,based on the structural analogy with other anticancer compounds.LBT and related polyacetylene glycosides should be further considered as potential anticancer agents,but more work is needed to evaluate their efficacy,toxicity,and risk-benefit ratio.

Evolving landscape and novel treatments in, metastatic castrate-resistant prostate cancer

Treatment options for castrate-resistant prostate cancer （CRPC） have advanced in recent years and significantly improved the Outlook for patients with this aggressive and lethal disease. Further understanding of the biology＇of CRPC has led to several new targeted therapies and continues to emphasize the importance of androgen receptor （AR） directed therapy. The treatment landscape is rapidly changing and further biologically rationale, biomarker-based ongoing clinical trials are needed. We review the recent results of major clinical trials in CRPC. New and investigational agents now in clinical evaluation are reviewed including inhibitors of angiogenesis, microtubules, chaperones, AR and intracellular kinases, as well as immunotherapy, radiopharmaceuticals and bone-targeted agents. The recent improvement in prognosis for CRPC brings continued optimism for further improvements. Thoughtful planning of clinical trials and further understanding of the mechanisms of resistance to therapies will allow for continued progress in patient care.

Progression of targeted therapy in advanced cholangiocarcinoma

It is necessary to establish an effective therapy to improve the survival of patients with advanced eholangiocarcinoma （CCM. Recently, with the development of pathology research in CCA, a lot of special bio-markers such as EGFR, VEGF, HER2, and MEK et al. could be over expression or mutations in CCA patients. According to their changes, combinations of targeted therapy plus chemotherapy are now recognized as effective therapies for advanced CCA. The aim of this paper is to analyze recent promising studies about targeted therapy alone or combination with each other or with chemotherapies.