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.

Transcriptome changes in stages of non-alcoholic fatty liver disease

BACKGROUND Non-alcoholic fatty liver disease(NAFLD)is the most common chronic liver disease in the United States and globally.The currently understood model of pathogenesis consists of a‘multiple hit’hypothesis in which environmental and genetic factors contribute to hepatic inflammation and injury.AIM To examine the genetic expression of NAFLD and non-alcoholic steatohepatitis(NASH)tissue samples to identify common pathways that contribute to NAFLD and NASH pathogenesis.METHODS We employed the Search Tag Analyze Resource for Gene Expression Omnibus platform to search the The National Center for Biotechnology Information Gene Expression Omnibus to elucidate NAFLD and NASH pathology.For NAFLD,we conducted meta-analysis of data from 58 NAFLD liver biopsies and 60 healthy liver biopsies;for NASH,we analyzed 187 NASH liver biopsies and 154 healthy liver biopsies.RESULTS Our results from the NAFLD analysis reinforce the role of altered metabolism,inflammation,and cell survival in pathogenesis and support recently described contributors to disease activity,such as altered androgen and long non-coding RNA activity.The top upstream regulator was found to be sterol regulatory element binding transcription factor 1(SREBF1),a transcription factor involved in lipid homeostasis.Downstream of SREBF1,we observed upregulation in CXCL10,HMGCR,HMGCS1,fatty acid binding protein 5,paternally expressed imprinted gene 10,and downregulation of sex hormone-binding globulin and insulin-like growth factor 1.These molecular changes reflect low-grade inflammation secondary to accumulation of fatty acids in the liver.Our results from the NASH analysis emphasized the role of cholesterol in pathogenesis.Top canonical pathways,disease networks,and disease functions were related to cholesterol synthesis,lipid metabolism,adipogenesis,and metabolic disease.Top upstream regulators included proinflammatory cytokines tumor necrosis factor and IL1B,PDGF BB,and beta-estradiol.Inhibition of beta-estradiol was shown to be related to derangement of several cellular downstream processes including metabolism,extracellular matrix deposition,and tumor suppression.Lastly,we found riciribine(an AKT inhibitor)and ZSTK-474(a PI3K inhibitor)as potential drugs that targeted the differential gene expression in our dataset.CONCLUSION In this study we describe several molecular processes that may correlate with NAFLD disease and progression.We also identified ricirbine and ZSTK-474 as potential therapy.

Expert consensus on the clinical application of PI3K/AKT/mTOR inhibitors in the treatment of advanced breast cancer

Phosphoinositide 3‐kinase(PI3K)/protein kinase B(PKB or AKT)/mammalian target of rapamycin(mTOR)signaling pathway(PAM pathway)plays an important role in the development of breast cancer and are closely associated with the resistance to endocrine therapy in advanced breast cancer.Therefore,anticancer treatment targeting key molecules in this signaling pathway has become a research hotspot in recent years.Randomized clinical trials have demonstrated that PI3K/AKT/mTOR inhibitors bring significant clinical benefit to patients with advanced breast cancer,especially to those with hormone receptor(HR)‐positive,human epidermal growth factor receptor(HER)2‐negative advanced breast cancer.Alpelisib,a PI3K inhibitor,and everolimus,an mTOR inhibitor,have been approved by FDA.Based on their high efficacy and relatively good safety profile,an expanded indication of everolimus in breast cancer has been approved by National Medical Products Administration(NMPA).Alpelisib is expected to be approved in China in the near future.The members of the consensus expert panel reached this consensus to comprehensively define the role of PI3K/AKT/mTOR signaling pathway in breast cancer,efficacy and clinical applications of PI3K/AKT/mTOR inhibitors,management of adverse reactions,and PIK3CA mutation detection,to promote the understanding of PI3K/AKT/mTOR inhibitors for Chinese oncologists,improve clinical decision‐making,and prolong the survival of target patient population.

AKT inhibitor Hu7691 induces differentiation of neuroblastoma cells

While neuroblastoma accounts for 15%of childhood tumor-related deaths,treatments against neuroblastoma remain scarce and mainly consist of cytotoxic chemotherapeutic drugs.Currently,maintenance therapy of differentiation induction is the standard of care for neuroblastoma patients in clinical,especially high-risk patients.However,differentiation therapy is not used as a first-line treatment for neuroblastoma due to low efficacy,unclear mechanism,and few drug options.Through compound library screening,we accidently found the potential differentiation-inducing effect of AKT inhibitor Hu7691.The protein kinase B(AKT)pathway is an important signaling pathway for regulating tumorigenesis and neural differentiation,yet the relation between the AKT pathway and neuroblastoma differentiation remains unclear.Here,we reveal the anti-proliferation and neurogenesis effect of Hu7691 on multiple neuroblastoma cell lines.Further evidence including neurites outgrowth,cell cycle arrest,and differentiation mRNA marker clarified the differentiation-inducing effect of Hu7691.Meanwhile,with the introduction of other AKT inhibitors,it is now clear that multiple AKT inhibitors can induce neuroblastoma differentiation.Furthermore,silencing AKT was found to have the effect of inducing neuroblastoma differentiation.Finally,confirmation of the therapeutic effects of Hu7691 is dependent on inducing differentiation in vivo,suggesting that Hu7691 is a potential molecule against neuroblastoma.Through this study,we not only define the key role of AKT in the progression of neuroblastoma differentiation but also provide potential drugs and key targets for the application of differentiation therapies for neuroblastoma clinically.

Efficacy and safety of first-line treatment for metastatic triple-negative breast cancer:A network meta-analysis

Background:Metastatic triple-negative breast cancer(mTNBC)is an aggressive histological subtype with poor prognosis.Several first-line treatments are currently available for mTNBC.This study conducted a network meta-analysis to compare these first-line regimens and to determine the regimen with the best efficacy.Methods:A systematic search of PubMed,EMBASE,the Cochrane Central Register of Controlled Bases,and mi-nutes of major conferences was performed.Progression-free survival(PFS),overall survival(OS),and objective response rate(ORR)were analyzed via network meta-analysis using the R software(R Core Team,Vienna,Austria).The efficacy of the treatment regimens was compared using hazard ratios and 95%confidence intervals.Results:A total of 29 randomized controlled trials involving 4607 patients were analyzed.The ranking was based on the surface under the cumulative ranking curve.Network meta-analysis results showed that cisplatin combined with nab-paclitaxel or paclitaxel was superior to docetaxel plus capecitabine in terms of PFS and ORR.For programmed death-ligand 1(PD-L1)and breast cancer susceptibility gene(BRCA)mutation-positive tumors,atezolizumab/pembrolizumab combined with nab-paclitaxel and talazoparib was superior to docetaxel plus capecitabine.No significant difference was observed among the treatments in Os.Neutropenia,diarrhea,and fatigue were common serious adverse events.Conclusion:Cisplatin combined with nab-paclitaxel or paclitaxel is the preferred first-line treatment for mTNBC.For PD-L1 and BRCA mutation-positive tumors,atezolizumab/pembrolizumab combined with nab-paclitaxel and talazoparib is an effective treatment option,Neutropenia,diarrhea,and fatigue are frequently occurring serious adverseevents.