Advance in metabolism and target therapy in breast cancer stem cells

Breast cancer,like many other cancers,is believed to be driven by a population of cells that display stem cell properties.Recent studies suggest that cancer stem cells(CSCs)are essential for tumor progression,and tumor relapse is thought to be caused by the presence of these cells.CSC-targeted therapies have also been proposed to overcome therapeutic resistance in breast cancer after the traditional therapies.Additionally,the metabolic properties of cancer cells differ markedly from those of normal cells.The efficacy of metabolic targeted therapy has been shown to enhance anti-cancer treatment or overcome therapeutic resistance of breast cancer cells.Metabolic targeting of breast CSCs(BCSCs)may be a very effective strategy for anti-cancer treatment of breast cancer cells.Thus,in this review,we focus on discussing the studies involving metabolism and targeted therapy in BCSCs.

Progress in target therapy of advanced non-small cell lung cancer

Lung cancer is one of the most common malignant tumors,and its morbidity and mortality are relatively high.Especially for small cell lung cancer(SCLC),the mortality rate is between 80-90%.Unfortunately,more than 50%of lung cancer patients are diagnosed at an advanced stage.The traditional treatment for advanced non-small cell lung cancer(NSCLC)is chemotherapy.In recent years,with the rapid development of molecular pathology,we have a deeper understanding of the underlying pathological mechanism and heterogeneity of lung cancer,especially NSCLC.Molecular targeted therapy is more accurate because of its anti-tumor effect,and the incidence of adverse drug reactions is low.Compared with chemotherapy in the traditional sense,the degree of damage to normal tissues is also significantly reduced.Therefore,it has become a research hotspot in recent years.This article reviews the research progress of various molecular targeted drugs for the treatment of lung cancer based on domestic and foreign research literature and related data.

Chemotherapy and target therapy for hepatocellular carcinoma:New advances and challenges

Primary liver cancer is one of the commonest causes of death.Hepatocellular carcinoma(HCC) accounts for 90% of primary liver cancers.For patients with unresectable or metastatic HCC,conventional chemotherapy is of limited or no benefit.Sorafenib is the only systemic treatment to demonstrate a statistically significant but modest overall survival benefit,leading to an era of targeted agents.Many clinical trials of targeted drugs have been carried out with many more in progress.Some drugs like PTK787 showed potential benefits in the treatment of HCC.Despite these promising breakthroughs,patients with HCC still have a dismal prognosis.Recently,both a phase Ⅲ trial of everolimus and a phase Ⅱ clinical trial of trebananib failed to demonstrate effective antitumor activity in advanced HCC.Sorafenib still plays a pivotal role in advanced HCC,leading to further explorations to exert its maximum efficacy.Combinations targeted with chemotherapy or transarterial chemoembolization is now being tested and might bring about advances.New targeted agents such as mammalian target of rapamycin inhibitors are under investigation,as well as further exploration of the mechanism of hepatocarcinogenesis.

Efficacy and safety of targeted therapy plus immunotherapy combined with hepatic artery infusion chemotherapy (FOLFOX) for unresectable hepatocarcinoma

BACKGROUND The advent of cutting-edge systemic therapies has driven advances in the treatment of hepatocellular carcinoma(HCC),and therapeutic strategies with multiple modes of delivery have been shown to be more efficacious than mono-therapy.However,the mechanisms underlying this innovative treatment modality have not been elucidated.AIM To evaluate the clinical efficacy of targeted therapy plus immunotherapy combined with hepatic arterial infusion chemotherapy(HAIC)of FOLFOX in patients with unresectable HCC.METHODS We enrolled 53 patients with unresectable HCC who received a combination of targeted therapy,immunotherapy,and HAIC of FOLFOX between December 2020 and June 2021 and assessed the efficacy and safety of the treatment regimen.RESULTS The objective response rate was 60.4%(32/53),complete response was 24.5%(13/53),partial response was 35.9%(19/53),and stable disease was 39.6%(21/53).The median duration of response and median progression-free survival were 9.1 and 13.9 months,respectively.The surgical conversion rate was 34.0%(18/53),and 1-year overall survival was 83.0%without critical complicating diseases or adverse events(AEs).CONCLUSION The regimen of HAIC of FOLFOX,targeted therapy,and immunotherapy was curative for patients with unresectable HCC,with no serious AEs and a high rate of surgical conversion.

Advances in targeted therapy for human epidermal growth factor receptor 2 positive in advanced gastric cancer

Emerging therapeutic methods represented by targeted therapy are effective supplements to traditional first-line chemoradiotherapy resistance.Human epidermal growth factor receptor 2(HER2)is one of the most important targets in targeted therapy for gastric cancer.Trastuzumab combined with chemotherapy has been used as the first-line treatment for advanced gastric cancer.The safety and efficacy of pertuzumab and margetuximab in the treatment of gastric cancer have been verified.However,monoclonal antibodies,due to their large molecular weight,inability to penetrate the blood-brain barrier,and drug resistance,lead to decreased therapeutic efficacy,so it is necessary to explore the efficacy of other HER2-targeting therapies in gastric cancer.Small-molecule tyrosine kinase inhibitors,such as lapatinib and pyrrotinib,have the advantages of small molecular weight,penetrating the blood-brain barrier and high oral bioavailability,and are expected to become the drugs of choice for perioperative treatment and neoadjuvant therapy of gastric cancer after validation by large-scale clinical trials in the future.Antibo-drug conjugate,such as T-DM1 and T-DXd,can overcome the resistance of monoclonal antibodies despite their different mechanisms of tumor killing,and are a supplement for the treatment of patients who have failed the treatment of monoclonal antibodies such as trastuzumab.Therefore,after more detailed stratification of gastric cancer patients,various gastric cancer drugs targeting HER2 are expected to play a more significant role.

Research Progress in Targeted Therapy for Esophageal Cancer

Esophageal cancer (EC) is a prevalent malignant tumor that affects the digestive system and is often linked to a poor prognosis. The absence of effective early screening methods results in the diagnosis of esophageal cancer (EC) patients at advanced or metastatic stages. While historically considered incurable, ongoing advancements in medical research have led to the integration of various treatment modalities as primary approaches for managing advanced endometrial cancer. These modalities include surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy. Notably, the introduction of targeted therapy and immunotherapy has significantly enhanced the survival rates of individuals with EC. Immunotherapy has appeared as the predominant treatment for advanced esophageal cancer, while targeted therapy faces certain obstacles. Consequently, this review primarily focuses on the advancements in targeted therapy for esophageal cancer (EC), evaluating the effectiveness and safety of relevant medications, and aiming to provide guidance for the comprehensive management of EC based on current research findings.

c-Met targeted therapy of cholangiocarcinoma

Cholangiocarcinoma continues to be a challenging disease to treat. Systemic therapy is used in unresectable disease, disease progression after surgery, and in the palliative setting. Unfortunately, results of multiple phase Ⅱ trials have rarely yielded positive results. As data on the molecular carcinogenesis of cholangiocarcinoma is developing, we are more able to understand the disease process and can use this understanding to create unique targeted therapies. We reviewed the role of c-Met/ hepatocyte growth factor (HGF) in the development of cholangiocarcinoma. Furthermore, we explored the use of the c-Met guided cascade as a target to treat cholangiocarcinoma. We reviewed the current use and options for future development of c-Met agents to treat this disease.

Efficacy of Wen-Luo-Tong on Peripheral Neuropathy Induced by Chemotherapy or Target Therapy: A Randomized, Double-Blinded, Placebo-Controlled Trial

Objective: To evaluate the efficacy of Wen-Luo-Tong Granules(WLT) local administration in the treatment of patients with peripheral neuropathy(PN) induced by chemotherapy or target therapy. Methods: This study is a randomized, double-blinded, and placebo-controlled trial. Seventy-eight patients with PN induced by chemotherapy or target therapy were enrolled from China-Japan Friendship Hospital between July 2019 and January 2020. They were randomly assigned to WLT(39 cases) and control groups(39 cases) using a block randomization method. The WLT group received WLT(hand and foot bath) plus oral Mecobalamin for 1 week, while the control group received placebo plus oral Mecobalamin. The primary endpoint was PN grade evaluated by the National Cancer Institute-Common Toxicity Criteria for Adverse Events(NCI-CTCAE). The secondary endpoints included quantitative touch-detection threshold, neuropathy symptoms, Quality of Life QuestionnaireChemotherapy Induced Peripheral Neuropathy(QLQ-CIPN20), and Quality of Life Questionnaire-Core30(QLQ-C30). Results: After treatment, the PN grade in the WLT group was significantly lower than that in the control group(1.00±0.29 vs. 1.75±0.68, P<0.01). The total effective rate in the WLT group was significantly higher than that in the control group(82.05% vs. 51.28%, P<0.01). Compared with the control group, the touchdetection thresholds at fingertips, neuropathy symptom score, QLQ-CIPN 20(sensory scale, motor scale, autonomic scale, and sum score), and QLQ-C30(physical functioning, role functioning, emotional functioning, and global health) in the WLT group significantly improved after treatment(P<0.01 or P<0.05). Conclusion: WLT local administration was significantly effective in the treatment of patients with PN induced by chemotherapy or target therapy.(Trial registration No. ChiCTR1900023862)

Survivin:Potential role in diagnosis,prognosis and targeted therapy of gastric cancer

Survivin is a protein that is highly expressed in a vast number of malignancies,but is minimally expressed in normal tissues. It plays a role as an inhibitor of cell death in cancer cells,thus facilitating the growth of these cells. In the case of gastric cancer,survivin is over-expressed in tumor cells and plays a role in the carcinogenesis process. Several studies on gastric cancer have indicated that there is a relationship between survivin expression and the ultimate behavior of the carcinoma. Since the expression pattern of survivin is selective to cancer cells,it has been described as an "ideal target" for cancer therapy. Currently,several pre-clinical and clinical trials are on-going to investigate the effects of interfering with survivin function in cancer cells as a biologic therapy. Survivin is a potentially significant protein in the diagnosis,prognosis and treatment of gastric tumors.

Targeting Gene-Virotherapy of Cancer and its prosperity

Gene and viral therapies for cancer have shown some therapeutic effects, but there has been a lack of real breakthrough. To achieve the goal of complete elimination of tumor xenograft in animal models, we have developed a new strategy called Targeting Gene-Virotherapy of Cancer, which aims to combine the advantages of both gene therapy and virotherapy. This new strategy has produced stronger anti-tumor effects than either gene or viral therapy alone. A tumorspecific replicative adenovirus vector, designated as ZD55, was constructed by deletion of the 55kDa E1B region of adenovirus. The resulting viral construct not only retains a similar function to ONYX-015 by specifically targeting p53 negative tumors, but also allows for the insertion of various therapeutic genes to form appropriate ZD55 derivatives due to the newly introduced cloning site, a task not feasible with the original ONYX-015 virus. We showed that the anti-tumor effect of one such derivative, ZD55-IL-24, is at least 100 times more potent than that of either ZD55 virotherapy or Ad-IL-24 gene therapy. Nevertheless, complete elimination of tumor mass by the use of ZD55-1L-24 was only observed in some but not all mice, indicating that one therapeutic gene was not sufficient to ＂cure＂ these mice. When genes with complementary or synergetic effects were separately cloned into the ZD55 vector and used in combination （designated as the Dual Gene Therapy strategy）, much better results were obtained; and it was possible to achieve complete elimination of all the xenograft tumor masses in all mice if two suitable genes were chosen. More comprehensive studies based on this new strategy will likely lead to a protocol for clinical trial. Finally, the concept of Double Controlled Targeting Virus-Dual Gene Therapy for cancer treatment, and the implication of the recent progress in cancer stem cells are also discussed.

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）.

Targeting gene-virotherapy of cancer

Our purpose is to completely elimination of xenograft tumor in animal tumor model in order to work out a protocal for the cure of patient. Gene therapy and viral therapy for cancer have got some therapeutic effects, but both have no great breakthrough. Therefore, we worked out a new strategy called Targeting Gene-Virotherapy of Cancer which is a combination of the advantage of gene therapy and virotherapy. This new strategy has stronger antitumor effect than either of them alone. A tumor specific replicative adenovirus vector ZD55 （E1B 55KD deleted Adv.） which is similar to ONYX-015 in targeting fuction but significant different in construction was produced and various single therapeutic gene was inserted into ZD55. Now such a conception as Targeting Gene-Virotherapy of Cancer was raised and systemically studied before, although there are some works on ONYX-015-tk, -cd or cd/-tk etc. separately. The antitumor effect of ZD55-Gene （for example IL-24 gene） is much better than ZD55 （virotherapy） alone and hundred fold high than that ofAd-IL-24 （gene therapy） alone. ZD55-IL-24 was in preclinal studying in the ZD55-IL-24 therapy, completely elimination of tumor mass was occurred in some mice but not in all mice, that means one gene was not effictive enough to eliminate all the tumor mass in all mice. Therefore two genes with compensative or synergetic effect were inserted into ZD55 sepearately and used in combinction. This strategy was called Targeting Dual Gene-Virotherapy of Cancer （with PCT patent）. Then much better results were obtained and all the xenograft tumor masses were completely eliminated in all mice, if two suitable genes were chosen. On the basis of the initiation of two gene results, it was thought about that using two tumors promoter to control the virus vector will be better for the targeting effect and the safty of the drugs. Then double tumor controlled virus vector harboring two genes for cancer therapy was worked out. Better results have been obtained and another patent has been applied. This antitumor strategy could be used to kill all the tumor cells completely in all mice with minimum damage to normal cells.

Targeted therapy in gastric cancer:Personalizing cancer treatment based on patient genome

Gastric cancer is the second leading cause of cancerrelated deaths worldwide.Conventional cytotoxic chemotherapy has limited efficacy for metastatic gastric cancer,with an overall survival of approximately ten months.Recent advances in high-throughput technologies have enabled the implementation of personalized cancer therapy for high-risk patients.The use of such high-throughput technologies,including microarray and next generation sequencing,have promoted the discovery of novel targets that offer new treatment strategies for patients lacking other therapeutic options.Many molecular pathways are currently under investigation as therapeutic targets in gastric cancer,including those related to the epidermal growth factor receptor family,the mesenchymal-epithelial transition factor axis,and the phosphatidylinositol 3-kinase-AKTmammalian target of rapamycin factors.Advances in molecular diagnostic tools further support the discovery of new molecular targets.Limitations exist,however;not all patients can be tested for biomarkers,and numerous challenges hamper implementation of targeted therapy in clinical settings.Indeed,the scale of tumor genomic profiling is rapidly outpacing our ability to appropriately synthesize all the information in order to optimally refine patient care.Therefore,clinicians must continue to educate themselves regarding new tools and frameworks,and to utilize multidisciplinary team science,comprised of oncologists,geneticists,pathologists,biologists and bioinformaticians,to successfully implement this genomic approach therapeutically.

Advances in locoregional therapy for hepatocellular carcinoma combined with immunotherapy and targeted therapy

Locoregional therapies(LRTs)of hepatocellular carcinoma(HCC)represented by ablation and TACE has become the main means for the clinical treatment of unresectable HCC.Among these,TACE is used throughout the stageⅠb toⅢb of HCC treatment.In recent years,immunotherapy led by immune checkpoint inhibitors has become a hot direction in clinical research.At the same time,targeted drugs such as Sorafenib and Apatinib have played an important role in the treatment and complementary therapy of advanced HCC,and their clinical application has been quite mature.HCC is the sixth most common malignant tumor in the world.When it comes to its treatment,different therapies have different indications,and their individual efficacies are not satisfactory,which makes the exploration of the use of combination therapy in HCC treatment become a new trend.In this paper,the status of the three therapies and the progress of their combined application are briefly reviewed.

Emerging molecular targets and therapy for cholangiocarcinoma

Cholangiocarcinoma(CCA) is a rare cancer arising from the biliary tree with a poor prognosis and limited therapeutic options. Recent large scale molecular characterisation studies have identified recurrent genetic alterations in CCA which may be amenable to therapeutic targeting. In this review we explore the genomic landscape of CCA and examine results from trials of molecularly targeted agents and immunotherapy in this disease. Challenges in CCA diagnosis, treatment and trial design are discussed and we reflect on future directions which may lead to improved outcomes for CCA patients.

Research Progress in the Use of Drugs for Breast Cancer Targeted Therapy

In recent years,many significant advances have been made on molecular target therapy to aim directly at epidermal growth factor receptors and vascular endothelial growth factor in breast cancers.Clinical studies of such agents as trastuzumab,lapatinib,erlotinib and bevacituzumab have been widely conducted.This paper will review the recent research progress related to targeted therapy.

Targeted Antimicrobial Therapy Against Streptococcus mutans Establishes Protective Non-cariogenic Oral Biofilms and Reduces Subsequent Infection

Aim Dental biofilms are complex communities composed largely of harmless bacteria. Certain pathogenic species including Streptococcus mutans （S. mutans） can become predominant when host factors such as dietary sucrose intake imbalance the biofilm ecology. Current approaches to control S. mutans infection are not pathogen-specific and eliminate the entire oral community along with any protective benefits provided. Here, we tested the hypothesis that removal of S. mutans from the oral community through targeted antimicrobial therapy achieves protection against subsequent S. mutans colonization. Methodology Controlled amounts of S. mutans were mixed with S. mutans-free saliva, grown into biofilms and visualized by antibody staining and cfu quantization. Two specifically-targeted antimicrobial peptides （STAMPs） against S. mutans were tested for their ability to reduce S. mutans biofilm incorporation upon treatment of the inocula. The resulting biofilms were also evaluated for their ability to resist subsequent exogenous S. mutans colonization. Results S. mutans colonization was considerably reduced （9 ± 0.4 fold reduction, P=0.01） when the surface was preoccupied with saliva-derived biofilms. Furthermore, treatment with S. mutans-specific STAMPs yielded S. mutans-deficient biofilms with significant protection against further S. mutans colonization （5 minutes treatment： 38 ± 13 fold reduction P=0.01; 16 hours treatment： 96 ± 28 fold reduction P=0.07）. Conclusion S. mutans infection is reduced by the pre- sence of existing biofilms. Thus maintaining a healthy or ＂normal＂ biofilm through targeted antimicrobial therapy （such as the STAMPs） could represent an effective strategy for the treatment and prevention of S. mutans colonization in the oral cavity and caries progression.

The advanced development of molecular targeted therapy for hepatocellular carcinoma

Hepatocellular carcinoma(HCC),one of the most common malignant tumors in China,severely threatens the life and health of patients.In recent years,precision medicine,clinical diagnoses,treatments,and innovative research have led to important breakthroughs in HCC care.The discovery of new biomarkers and the promotion of liquid biopsy technologies have greatly facilitated the early diagnosis and treatment of HCC.Progress in targeted therapy and immunotherapy has provided more choices for precise HCC treatment.Multiomics technologies,such as genomics,transcriptomics,and metabolomics,have enabled deeper understanding of the occurrence and development mechanisms,heterogeneity,and genetic mutation characteristics of HCC.The continued promotion and accurate typing of HCC,accurate guidance of treatment,and accurate prognostication have provided more treatment opportunities and prolonged survival timelines for patients with HCC.Innovative HCC research providing an in-depth understanding of the biological characteristics of HCC will be translated into accurate clinical practices for the diagnosis and treatment of HCC.

Advances in radiotherapy and targeted therapies for rectal cancer

The last decade witnessed a significant progress in understanding the biology and immunology of colorectal cancer alongside with the technical innovations in radiotherapy.The stepwise implementation of intensitymodulated and image-guided radiation therapy by means of megavolt computed tomography and helical tomotherapy enabled us to anatomically sculpt dose delivery,reducing treatment related toxicity.In addition,the administration of a simultaneous integrated boost offers excellent local control rates.The novel challenge is the development of treatment strategies for medically inoperable patient and organ preserving approaches.However,distant control remains unsatisfactory and indicates an urgent need for biomarkers that predict the risk of tumor spread.The expected benefit of target?ed therapies that exploit the tumor genome alone is so far hindered by high cost techniques and pharmaceuticals,hence hardly justifying rather modest improvements in patient outcomes.On the other hand,the immune landscape of colorectal cancer is now better clarified with regard to the immunosuppressive network that promotes immune escape.Both N2 neutrophils and myeloid-derived suppressor cells(MDSC)emerge as useful clinical biomarkers of poor prognosis,while the growing list of anti-MDSC agents shows promising ability to boost antitumor T-cell immunity in preclinical settings.Therefore,integration of genetic and immune biomarkers is the next logical step towards effective targeted therapies in the context of personalized cancer treatment.