The growth of brain tumors can be suppressed by multiple transplantation of mesenchymal stem cells expressing cytosine deaminase

Suicide genes have recently emerged as an attractive alternative therapy for the treatment of various types of intractable cancers. The efficacy of suicide gene therapy relies on efficient gene delivery to target tissues and the localized concentration of final gene products. Here, we showed a potential ex vivo therapy that used mesenchymal stem cells (MSCs) as cellular vehicles to deliver a bacterial suicide gene, cytosine deaminase (CD) to brain tumors. MSCs were engineered to produce CD enzymes at various levels using different promoters. When co-cultured, CD-expressing MSCs had a bystander, anti-cancer effect on neighboring C6 glioma cells in proportion to the levels of CD enzymes that could convert a nontoxic prodrug, 5-fluorocytosine (5-FC) into cytotoxic 5-fluorouracil (5-FU) in vitro. Consistent with the in vitro results, for early stage brain tumors induced by intracranial inoculation of C6 cells, transplantation of CD-expressing MSCs reduced tumor mass in proportion to 5-FC dosages. However, for later stage, established tumors, a single treatment was insufficient, but only multiple transplantations were able to successfully repress tumor growth. Our findings indicate that the level of total CD enzyme activity is a critical parameter that is likely to affect the clinical efficacy for CD gene therapy. Our results also highlight the potential advantages of autograftable MSCs compared with other types of allogeneic stem cells for the treatment of recurrent glioblastomas through repetitive treatments.Grant sponsor: Korea Health 21 R&D Project; Grant number: A040018-0923-0000400; Grant sponsor: the National Cancer Control Planning Board; Grant number: 0520130; Grant sponsor: the 21st Century Frontier Research Program; Grant number: 2009K001245; Grant sponsor: the National Research Foundation of Korea at Ajou University; Grant number: 2009-0093826Kim SM, 2008, CANCER RES, V68, P9614, DOI 10.1158/0008-5472.CAN-08-0451Kucerova L, 2008, J GENE MED, V10, P1071, DOI 10.1002/jgm.1239Kim SW, 2008, MOL CELLS, V26, P26Lazennec G, 2008, STEM CELLS, V26, P1387, DOI 10.1634/stemcells.2007-1006Kendall SE, 2008, STEM CELLS, V26, P1575, DOI 10.1634/stemcells.2007-0887Jordan JT, 2008, CANCER IMMUNOL IMMUN, V57, P123, DOI 10.1007/s00262-007-0336-xKIM Y, 2008, ROUT ADV INTER MED S, V1, P27Kucerova L, 2007, CANCER RES, V67, P6304, DOI 10.1158/0008-5472.CAN-06-4024Birnbaum T, 2007, J NEURO-ONCOL, V83, P241, DOI 10.1007/s11060-007-9332-4Kaliberov SA, 2007, GENE THER, V14, P1111, DOI 10.1038/sj.gt.3302965Portsmouth D, 2007, MOL ASPECTS MED, V28, P4, DOI 10.1016/j.mam.2006.12.001Ramasamy R, 2007, LEUKEMIA, V21, P304, DOI 10.1038/sj.leu.2404489Malhi H, 2006, ONCOGENE, V25, P7333, DOI 10.1038/sj.onc.1209765Djouad F, 2006, TRANSPLANTATION, V82, P1060, DOI 10.1097/01.tp.0000236098.13804.0bKim SK, 2006, CLIN CANCER RES, V12, P5550, DOI 10.1158/1078-0432.CCR-05-2508Khakoo AY, 2006, J EXP MED, V203, P1235, DOI 10.1084/jem.20051921Kim SS, 2005, NEUROREPORT, V16, P1357Watters JJ, 2005, J NEUROSCI RES, V81, P447, DOI 10.1002/jnr.20485Lucas ML, 2005, BLOOD, V106, P51Schmidt NO, 2005, NEOPLASIA, V7, P623, DOI 10.1593/neo.04781Nakamizo A, 2005, CANCER RES, V65, P3307Imitola J, 2004, P NATL ACAD SCI USA, V101, P18117, DOI 10.1073/pnas.0408258102Nakamura K, 2004, GENE THER, V11, P1155, DOI 10.1038/sj.gt.3302276Lee OK, 2004, BLOOD, V103, P1669KIM SS, 2004, KOREAN J ANATOMY, V37, P509Akbulut H, 2003, CANCER GENE THER, V10, P388, DOI 10.1038/sj.cgt.7700579Ohnishi N, 2002, GENE THER, V9, P303, DOI 10.1038/sj/gt/3301655Kaneko S, 2001, HUM GENE THER, V12, P35Aboody KS, 2000, P NATL ACAD SCI USA, V97, P12846Alvarez RD, 2000, MOL THER, V2, P524, DOI 10.1006/mthe.2000.0194Erbs P, 2000, CANCER RES, V60, P3813Erices A, 2000, BRIT J HAEMATOL, V109, P235Legler JM, 1999, J NATL CANCER I, V91, P1382Pittenger MF, 1999, SCIENCE, V284, P143Surawicz TS, 1998, J NEURO-ONCOL, V40, P151BAUM C, 1995, J VIROL, V69, P7541TRINH QT, 1995, CANCER RES, V55, P4808KURATSU J, 1993, J NATL CANCER I, V85, P1836MULLEN CA, 1992, P NATL ACAD SCI USA, V89, P33GREZ M, 1990, P NATL ACAD SCI USA, V87, P92021

STAT3 Inhibitor ODZ10117 Suppresses Glioblastoma Malignancy and Prolongs Survival in a Glioblastoma Xenograft Model

Constitutively activated STAT3 plays an essential role in the initiation, progression, maintenance, malignancy, and drug resistance of cancer, including glioblastoma, suggesting that STAT3 is a potential therapeutic target for cancer therapy. We recently identified ODZ10117 as a small molecule inhibitor of STAT3 and suggested that it may have an effective therapeutic utility for the STAT3-targeted cancer therapy. Here, we demonstrated the therapeutic efficacy of ODZ10117 in glioblastoma by targeting STAT3. ODZ10117 inhibited migration and invasion and induced apoptotic cell death by targeting STAT3 in glioblastoma cells and patient-derived primary glioblastoma cells. In addition, ODZ10117 suppressed stem cell properties in glioma stem cells (GSCs). Finally, the administration of ODZ10117 showed significant therapeutic efficacy in mouse xenograft models of GSCs and glioblastoma cells. Collectively, ODZ10117 is a promising therapeutic candidate for glioblastoma by targeting STAT3

Proteogenomic Characterization of Human Early-Onset Gastric Cancer

We report proteogenomic analysis of diffuse gastric cancers (GCs) in young populations. Phosphoproteome data elucidated signaling pathways associated with somatic mutations based on mutation-phosphorylation correlations. Moreover, correlations between mRNA and protein abundances provided potential oncogenes and tumor suppressors associated with patient survival. Furthermore, integrated clustering of mRNA, protein, phosphorylation, and N-glycosylation data identified four subtypes of diffuse GCs. Distinguishing these subtypes was possible by proteomic data. Four subtypes were associated with proliferation, immune response, metabolism, and invasion, respectively; and associations of the subtypes with immune- and invasion-related pathways were identified mainly by phosphorylation and N-glycosylation data. Therefore, our proteogenomic analysis provides additional information beyond genomic analyses, which can improve understanding of cancer biology and patient stratification in diffuse GCs. © 2018 Elsevier Inc.Mun et al. perform proteogenomic analysis of diffuse gastric cancers (DGC) in a young population, identifying that correlations of mRNA-protein abundance associate with survival and defining four subtypes of DGC. The associations of some subtypes with related pathways are identified mainly by the proteomic data. © 2018 Elsevier Inc11Nsciescopu