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Scattered seeding of car T cells in solid tumors augments anticancer efficacy

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National Science review 2022年第3期9卷 42-51页

作者： Hongjun Li Zejun Wang Edikan A.Ogunnaike Qing Wu Guojun Chen Quanyin Hu Tianyuan Ci Zhaowei Chen Jinqiang Wang Di Wen Hongwei Du Jie Jiang Jie Sun Xingcai Zhang Gianpietro Dotti Zhen Gu College of Pharmaceutical Sciences Zhejiang University Liangzhu Laboratory Zhejiang University Medical Center Department of Bioengineering University of California Jonsson Comprehensive cancer Center University of California california Nano Systems Institute University of California Center for Nanotechnology in Drug Delivery Eshelman School of Pharmacy University of North Carolina Lineberger Comprehensive cancer Center University of North Carolina Joint Department of Biomedical Engineering University of North Carolina at Chapel Hill and North Carolina State University Department of Microbiology and Immunology University of North Carolina Department of Cell Biology and Bone Marrow Transplantation Center of the First Affiliated Hospital Zhejiang University School of Medicine John A. Paulson School of Engineering and Applied Sciences Harvard University Department of General Surgery Sir Run Run Shaw Hospital School of Medicine Zhejiang University

Chimeric antigen receptor T cell(car T) therapy was a milestone in the treatment of relapsed and refractory B cell malignancies. However, beneficial effects of car T cells have not been obtained in solid tumors yet. Herein, we implement a porous microneedle patch that accommodates car T cells and allows in situ penetration-mediated seeding of car T cells when implanted in the tumor bed or in the post-surgical resection cavity. car T cells loaded in the pores of the microneedle tips were readily escorted to the tumor in an evenly scattered manner without losing their activity. Such microneedle-mediated local delivery enhanced infiltration and immunostimulation of car T cells as compared to direct intratumoral injection. This tailorable patch offers a transformative platform for scattered seeding of living cells for treating a variety of tumors.

关键词： drug delivery car T therapy microneedle patch solid tumor treatment cell delivery

An information theoretic method to identify combinations of genomic alterations that promote glioblastoma

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Journal of Molecular Cell Biology 2015年第3期7卷 203-213页

作者： rachel D.Melamed Jiguang Wang Antonio Iavarone raul rabadan Department of Systems Biology Columbia University College of Physicians and SurgeonsNew YorkNYUSA Department of Biomedical Informatics Columbia University College of Physicians and SurgeonsNew YorkNYUSA Institute for cancer Genetics Columbia University College of Physicians and SurgeonsNew YorkNYUSA Department of Pathology and Cell Biology Columbia University College of Physicians and SurgeonsNew YorkNYUSA Department of Neurology Columbia University College of Physicians and SurgeonsNew YorkNYUSA

Tumors are the result of accumulated genomic alterations that cooperate synergistically to produce uncontrollable cell *** identifying recurrent alterations among large collections of tumors provides a way to pinpoint genes that endow a selective advantage in oncogenesis and progression,it fails to address the genetic interactions behind this selection process.A non-random pattern of co-mutated genes is evidence for selective forces acting on tumor cells that harbor combinations of these genetic *** existing methods have successfully identified mutually exclusive gene sets,no current method can systematically discover more general genetic *** develop Genomic Alteration Modules using Total Correlation(GAMToC),an information theoretic frameworkthat integrates copynumberandmutation datato identify genemodules with any non-randompattern of joint ***,wepresent theSeed-GAMToCprocedure,which uncoversthe mutational context of any putative cancer *** software is publicly *** to glioblastoma multiforme samples,GAMToC results show distinct subsets of co-occurring mutations,suggesting distinct mutational routes to cancer and providing new insight into mutations associated with proneural,proneural/G-CIMP,and classical types of the *** results recapitulate known relationships such as mutual exclusive mutations,place these alterations in the context of other mutations,and find more complex relationships such as conditional mutual exclusivity.

关键词： genomics sequencing entropy copy number cancer cancer genetics

Kavalactone yangonin induces autophagy and sensitizes bladder cancer cells to flavokawain A and docetaxel via inhibition of the mTOr pathway

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The Journal of Biomedical research 2017年第5期31卷 408-418页

作者： Zhongbo Liu U-Syn Ha Ke Yu Chunli Wu Noriko Yokoyama Xiaolin Zi Departments of Urology University of CaliforniaIrvine Orange CA 92868 USA. Pharmacology University of CaliforniaIrvine Orange CA 92868 USA. Chao Family Comprehensive cancer Center University of CaliforniaIrvine Orange CA 92868 USA.

Consumption of kava(Piper methysticum Forst) has been linked to reduced cancer risk in the South Pacific *** are major bioactive components in kava root extracts, which have recently demonstrated anti-cancer activities. However, molecular mechanisms of kavalactones' anti-cancer action remain largely unknown. We have identified two kavalactones, yangonin and 5' 6'-dehydrokawain, as potent inducers of autophagic cell death in bladder cancer cells. The effect of yangonin inducing autophagy is associated with increased expression of beclin and *** addition, yangonin increases the expression of LKB1 and decreases the phosphorylation of Akt, PrAS40, rpS6,p70S6 K and 4E-BP1, leading to increased binding of 4E-BP1 to m7 GTP. The growth inhibitory effects of yangonin were attenuated in TSC1 or LKB1 knockout mouse embryonic fibroblasts, suggesting that TSC1 and LKB1 expression may contribute to optimal growth inhibition by yangonin. Furthermore, yangonin reduces the viability of bladder cancer cell lines derived from different stages of human bladder cancer, and acts synergistically with apoptosis-inducing agents such as docetaxel and flavokawain A. Our results support a novel anti-bladder cancer mechanism by yangonin and further studies are needed to assess the potential use of yangonin for bladder cancer prevention and treatment

关键词： yangonin bladder cancer autophagy mTOr

Aerosolized immunotherapeutic nanoparticle inhalation potentiates PD-L1 blockade for locally advanced lung cancer

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Nano research 2023年第4期16卷 5300-5310页

作者： Yang Liu William N.Crowe Lulu Wang W.Jeffrey Petty Amyn A.Habib Dawen Zhao Department of Biomedical Engineering Wake Forest University School of MedicineWinston-SalemNC 27157USA Department of Medicine Section on Hematology and OncologyWake Forest University School of MedicineWinston-SalemNC 27157USA Department of Neurology University of Texas Southwestern Medical Center and VA North Texas Medical CenterDallasTX 75390USA Department of cancer Biology Wake Forest University School of MedicineWinston-SalemNC 27157USA

Despite therapeutic advancements,the prognosis of locally advanced non-small cell lung cancer(LANSCLC),which has invaded multiple lobes or the other lung and intrapulmonary lymph nodes,remains *** emergence of immunotherapy with immune checkpoint blockade(ICB)is transforming cancer ***,only a fraction of lung cancer patients benefit from *** clinical evidence suggests that the proinflammatory tumor microenvironment(TME)and programmed death-ligand 1(PD-L1)expression correlate positively with response to the PD-1/PD-L1 *** report here a liposomal nanoparticle loaded with cyclic dinucleotide and aerosolized(AeroNP-CDN)for inhalation delivery to deep-seated lung tumors and target CDN to activate stimulators of interferon(IFN)genes in macrophages and dendritic cells(DCs).Using a mouse model that recapitulates the clinical LANSCLC,we show that AeroNP-CDN efficiently mitigates the immunosuppressive TME by reprogramming tumor-associated macrophage from the M2 to M1 phenotype,activating DCs for effective tumor antigen presentation and increasing tumor-infiltrating CD8+T cells for adaptive anticancer ***,activation of interferons by AeroNP-CDN also led to increased PD-L1 expression in lung tumors,which,however,set a stage for response to anti-PD-L1 ***,anti-PD-L1 antibody-mediated blockade of IFNs-induced immune inhibitory PD-1/PD-L1 signaling further prolonged the survival of the LANSCLC-bearing ***,AeroNP-CDN alone or combination immunotherapy was safe without local or systemic *** conclusion,this study demonstrates a potential nano-immunotherapy strategy for LANSCLC,and mechanistic insights into the evolution of adaptive immune resistance provide a rational combination immunotherapy to overcome it.

关键词： locally advanced non-small cell lung cancer(LANSCLC) nanoparticle immunotherapeutic aerosol inhalation stimulator of interferon genes programmed death 1/programmed death-ligand 1(PD-1/PD-L1)blockade

Design,synthesis and biological evaluation of selective survivin inhibitors

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The Journal of Biomedical research 2019年第2期33卷 82-100页

作者： Min Xiao Yi Xue Zhongzhi Wu Zi-Ning Lei Jin Wang Zhe-Sheng Chen Wei Li Department of Pharmaceutical Sciences University of Tennessee Health Science Center Department of Pharmaceutical Sciences College of Pharmacy and Health Sciences St.John's University

The differential distribution between cancer cells and normal adult tissues makes survivin a very attractive cancer drug target. We have previously reported a series of novel selective survivin inhibitors with the most potent compound MX 106 reaching nanomolar activity in several cancer cell lines. Further optimization of the MX 106 scaffold leads to the discovery of more potent and more selective survivin inhibitors. Various structural modifications were synthesized and their anticancer activities were evaluated to determine the structure activity relationships for this MX 106 scaffold. In vitro anti-proliferative assays using two human melanoma cell lines showed that several new analogs have improved potency compared to MX 106. Very interestingly, these new analogs generally showed significantly higher potency against P-glycoprotein overexpressed cells compared with the corresponding parental cells, suggesting that these compounds may strongly sensitize tumors that have high expressions of the Pglycoprotein drug efflux pumps. Western blotting analysis confirmed that the new MX 106 analogs maintained their mechanism of actions by selectively suppressing survivin expression level among major inhibitors of apoptotic proteins and induced strong apoptosis in melanoma tumor cells.

关键词： selective survivin inhibitors structure activity relationships melanoma human epidermoid carcinoma colorectal cancer P-glycoprotein drug efflux pumps

Effects of DNA topoisomerase IIα splice variants on acquired drug resistance

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cancer Drug resistance 2020年第2期3卷 161-170页

作者： Terry S.Elton Hatice Gulcin Ozer Jack C.Yalowich Division of Pharmaceutics and Pharmacology College of PharmacyThe Ohio State UniversityColumbusOH 43210USA Department of Biomedical Informatics College of MedicineThe Ohio State UniversityColumbusOH 43210USA

DNA topoisomerase IIα(170 kDa,TOP2α/170)induces transient DNA double-strand breaks in proliferating cells to resolve DNA topological entanglements during chromosome condensation,replication,and ***,TOP2α/170 is a prominent target for anticancer drugs whose clinical efficacy is often compromised due to *** many resistance mechanisms have been defined,acquired resistance of human cancer cell lines to TOP2αinterfacial inhibitors/poisons is frequently associated with a reduction of Top2α/170 expression *** studies by our laboratory,in conjunction with earlier findings by other investigators,support the hypothesis that a major mechanism of acquired resistance to TOP2α-targeted drugs is due to alternative rNA processing/***,several TOP2αmrNA splice variants have been reported which retain introns and are translated into truncated TOP2αisoforms lacking nuclear localization sequences and subsequent dysregulated nuclear-cytoplasmic *** addition,intron retention can lead to truncated isoforms that lack both nuclear localization sequences and the active site tyrosine(Tyr805)necessary for forming enzyme-DNA covalent complexes and inducing DNA damage in the presence of TOP2α-targeted ***,these truncated TOP2αisoforms result in decreased drug activity against TOP2αin the nucleus and manifest drug ***,the complete characterization of the mechanism(s)regulating the alternative rNA processing of TOP2αpre-mrNA may result in new strategies to circumvent acquired drug ***,novel TOP2αsplice variants and truncated TOP2αisoforms may be useful as biomarkers for drug resistance,prognosis,and/or direct future TOP2α-targeted therapies.

关键词： DNA topoisomerase IIα chemoresistance alternative splicing intron retention topoisomerase IIαinterfacial inhibitors/poisons

Epithelial protein lost in neoplasm (EPLIN):Beyond a tumor suppressor

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Genes & Diseases 2017年第2期4卷 100-107页

作者： Daqing Wu Georgia cancer Center and Department of Biochemistry and Molecular Biology Medical College of GeorgiaAugusta UniversityAugustaGAUSA MetCure Therapeutics LLC AtlantaGAUSA

The majority of cancer-related deaths are caused by tumor recurrence,metastasis and therapeutic *** the late stages of tumor progression,multiple factors are involved,including the downregulation and/or loss of function of metastasis *** protein lost in neoplasm(EPLIN),an actin-binding protein,was initially identified as a putative tumor suppressor that is frequently downregulated in epithelial *** evidence indicates that EPLIN may negatively regulate epithelia-to-mesenchymal transition(EMT),a crucial process by which cancer cells acquire invasive capabilities and therapeutic ***,downregulation of EPLIN is associated with clinical metastasis in a variety of solid tumors,suggesting that EPLIN could be a suppressor of *** this review,I will discuss the regulation and function of EPLIN in human cancer cells and explore the clinical significance of EPLIN in metastatic disease.

关键词： Actin cytoskeleton Chemoresistance Epithelial-tomesenchymal transition EPLIN Metastasis suppressor Tumor suppressor

Targeting apoptosis to manage acquired resistance to third generation EGFr inhibitors

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Frontiers of Medicine 2022年第5期16卷 701-713页

作者： Shi-Yong Sun Department of Hematology and Medical Oncology Emory University School of Medicine and Winship Cancer Institute of Emory UniversityAtlantaGA 30322USA

A significant clinical challenge in lung cancer treatment is management of the inevitable acquired resistance to third-generation epidermal growth factor receptor(EGFr)tyrosine kinase inhibitors(EGFr-TKIs),such as osimertinib,which have shown remarkable success in the treatment of advanced NSCLC with EGFr activating mutations,in order to achieve maximal response duration or treatment *** is a major type of programmed cell death tightly associated with cancer development and *** of apoptosis is considered a key hallmark of cancer and acquisition of apoptosis resistance is accordingly a key mechanism of drug acquired resistance in cancer *** has been clearly shown that effective induction of apoptosis is a key mechanism for third generation EGFr-TKIs,particularly osimertinib,to exert their therapeutic efficacies and the development of resistance to apoptosis is tightly associated with the emergence of acquired ***,restoration of cell sensitivity to undergo apoptosis using various means promises an effective strategy for the management of acquired resistance to third generation EGFr-TKIs.

关键词： acquired resistance EGFr inhibitor apoptosis lung cancer

Tumor-and osteoclast-derived NrP2 in prostate cancer bone metastases

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Bone research 2021年第2期9卷 233-247页

作者： Navatha Shree Polavaram Samikshan Dutta ridwan Islam Arup K.Bag Sohini roy David Poitz Jeffrey Karnes Lorenz C.Hofbauer Manish Kohli Brian A.Costello raffael Jimenez Surinder K.Batra Benjamin A.Teply Michael H.Muders Kaustubh Datta Department of Microbiology and Pathology University of Nebraska Medical CenterOmahaNEUSA Department of Biochemistry and Molecular Biology University of Nebraska Medical CenterOmahaNEUSA Institute for Clinical Chemistry University Hospital DresdenDresdenGermany Department of Urology Mayo ClinicRochesterMNUSA Center for Healthy Aging and Bone Lab Dresden Department of Medicine IIITechnische Universität DresdenDresdenGermany School of Medicine Division of OncologyHuntsman Cancer InstituteSalt Lake CityUTUSA Division of Anatomic Pathology Department of Pathology and Laboratory MedicineMayo ClinicRochesterMNUSA Internal Medicine Division of Oncology&HematologyUniversity of Nebraska Medical CenterOmahaNEUSA rudolf-Becker Laboratory for Prostate cancer research Institute of PathologyUniversity of Bonn Medical CenterBonnGermany

Understanding the role of neuropilin 2(NrP2)in prostate cancer cells as well as in the bone microenvironment is pivotal in the development of an effective targeted therapy for the treatment of prostate cancer bone *** observed a significant upregulation of NrP2 in prostate cancer cells metastasized to ***,we report that targeting NrP2 in cancer cells can enhance taxane-based chemotherapy with a better therapeutic outcome in bone metastasis,implicating NrP2 as a promising therapeutic ***,osteoclasts present in the tumor microenvironment express NrP2,we have investigated the potential effect of targeting NrP2 in *** results revealed NrP2 negatively regulates osteoclast differentiation and function in the presence of prostate cancer cells that promotes mixed bone *** study further delineated the molecular mechanisms by which NrP2 regulates osteoclast ***,depletion of NrP2 in osteoclasts in vivo showed a decrease in the overall prostate tumor burden in the *** results therefore indicate that targeting NrP2 in prostate cancer cells as well as in the osteoclastic compartment can be beneficial in the treatment of prostate cancer bone metastasis.

关键词： metastasis chemotherapy treatment