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Translational Oncology

Pedro Cabrales
RRx-001 is a pleiotropic anticancer agent in phase III clinical trials, which polarizes tumor-associated macrophages from a low phagocytic M2 phenotype to a high phagocytic M1 phenotype. One of the ways in which tumors promote M2 polarization and evade macrophage-mediated destruction is through upregulation of CD47 expression. As a myeloid-specific immune checkpoint, CD47 interacts with signal-regulatory protein alpha (SIRPα) on macrophages and monocytes to prevent phagocytosis. Herein, the effect of RRx-001 on CD47 and SIRPα expression was evaluated as well as its activity in vivo in macrophage-depleted tumors...
February 6, 2019: Translational Oncology
Pedro L Azevedo, Nathalia C A Oliveira, Stephany Corrêa, Morgana T L Castelo-Branco, Eliana Abdelhay, Renata Binato
Mesenchymal stromal cells (hMSCs) are key components of the bone marrow microenvironment (BMM). A molecular signature in hMSCs from Acute myeloid leukemia patients (hMSC-AML) has been proposed where BMP4 is decreased and could be regulated by WNT signaling pathway. Therefore, the aim of this work was to verify whether the WNT signaling pathway can regulate the BMP4 gene in hMSCs. The results showed differentially expressed genes in the WNT canonical pathway between hMSC-AML and hMSCs from healthy donors and a real-time quantitative assay corroborated with these findings...
January 28, 2019: Translational Oncology
Naxin Guo, Mitra Azadniv, Myra Coppage, Mary Nemer, Jason Mendler, Michael Becker, Jane Liesveld
Acute myelogenous leukemia (AML) is a heterogeneous disease and often relapses after standard chemotherapy. Recently, the neddylation (NEDD8) and the mammalian target of rapamycin (mTOR) signaling pathways have emerged as promising pharmaceutical targets for AML therapy. However, the interaction of these two pathways remains unclear. Here we evaluated the effects of pevonedistat, an inhibitor of the NEDD8 activating enzyme (NAE), and sapanisertib (TAK-228), an inhibitor of mTORC1 and mTORC2 as single agents or in combination on AML cell lines...
January 27, 2019: Translational Oncology
Seung Tae Kim, Sujin Lee, Minhwa Park, Se Hoon Park, Joon Oh Park, Ho Yeong Lim, Young Suk Park, Won Ki Kang, Esha A Gangolli, Hyeongchan Shin, Kyoung-Mee Kim, Simon J Hollingsworth, Peter G S Mortimer, Jeeyun Lee
MET amplification is a frequently observed genomic aberration in solid tumors. We conducted a phase I trial to evaluate dose-limiting toxicity (DLT) and recommended phase II dose (RP2D) for the combination therapy. The following dose levels were tested in this single-arm phase I study: docetaxel as an intravenous infusion over 1 hour at 60 mg/m2 once every 3 weeks of a 21-day schedule plus savolitinib (level 1, 200 mg qd; level 2, 400 mg qd; level 3, 600 mg qd; level 4800 mg qd). In total, there were 17 patients enrolled on to this study [7 gastric cancer (GC) patients, 5 melanoma patients, 3 sarcoma patients, and 2 rectal cancer patients]...
January 26, 2019: Translational Oncology
Ivana Catacchio, Nicola Silvestris, Emanuela Scarpi, Laura Schirosi, Anna Scattone, Anita Mangia
BACKGROUND: Tumor infiltrating lymphocytes (TILs) are widely considered a key sign of the immune interaction between host and tumor, and potentially prognostic biomarkers of good or bad outcome in many cancers, included invasive breast cancer (BC). However, results about the association between TIL typology, location and BC prognosis, are controversial. The aim of the study was to evaluated the prognostic significance of TIL subtypes (CD4+, CD8+, FOXP3+ T cells) and their location (stromal "s" and intratumoral "i" CD4+ and CD8+) in BC patients, focusing on the association between these markers and immunocheckpoint molecules such as cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed cell death ligand 1 (PD-L1) and its receptor (PD-1)...
January 22, 2019: Translational Oncology
Anja Nilsen, Marte Jonsson, Eva-Katrine Aarnes, Gunnar Balle Kristensen, Heidi Lyng
MicroRNA (miRNA) expressions in tumor biopsies have shown potential as biomarkers in cervical cancer, but suitable reference RNAs for normalization of reverse transcription quantitative polymerase chain reaction (RT-qPCR) assays in patient cohorts with different clinicopathological characteristics are not available. We aimed to identify the optimal reference miRNAs and apply these to investigate the potential of miR-9-5p as human papilloma virus (HPV) 16 biomarker and miR-210-3p as hypoxia biomarker in cervical cancer...
January 17, 2019: Translational Oncology
Anne A Blanchard, Xiuli Ma, Nan Wang, Sabine Hombach, Carla Penner, Arzu Ozturk, Thomas Klonisch, Marshall Pitz, Leigh Murphy, Etienne Leygue, Yvonne Myal
Recent studies provide compelling evidence to suggest that the tight junction protein claudin 1, aberrantly expressed in several cancer types, plays an important role in cancer progression. Dysregulation of claudin 1 has been shown to induce epithelial mesenchymal transition (EMT). Furthermore, activation of the ERK signaling pathway by protein kinase C (PKC) was shown to be necessary for EMT induction. Whether PKC is involved in regulating breast cancer progression has not been addressed. The PKC activator 12-O-tetradecanoylphorbol 13-acetate (TPA) was used to investigate the effect of PKC activity on claudin 1 transcription and protein levels, subcellular distribution, and alterations in EMT markers in human breast cancer (HBC) cell lines...
January 15, 2019: Translational Oncology
David B Donner, Dan T Ruan, Kan Toriguchi, Emily K Bergsland, Eric K Nakakura, Meng Hsun Lin, Ricardo J Antonia, Robert S Warren
PURPOSE: Prognostic schemes that rely on clinical variables to predict outcome after resection of colorectal metastases remain imperfect. We hypothesized that molecular markers can improve the accuracy of prognostic schemes. METHODS: We screened the transcriptome of matched colorectal liver metastases (CRCLM) and primary tumors from 42 patients with unresected CRCLM to identify differentially expressed genes. Among the differentially expressed genes identified, we looked for associations between expression and time to disease progression or overall survival...
January 9, 2019: Translational Oncology
Roberto Tamma, Giuseppe Ingravallo, Francesco Albano, Francesco Gaudio, Tiziana Annese, Simona Ruggieri, Loredana Lorusso, Mariella Errede, Eugenio Maiorano, Giorgina Specchia, Domenico Ribatti
BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin's lymphoma. Signal transducer and activator of transcription 3 (STAT3) is a cytoplasmic transcription with many important functions, including regulation of cell proliferation, differentiation, survival, angiogenesis, and immune response. MATERIALS AND METHODS: In this study, we have compared by means of RNAscope technology STAT3 RNA expression in human DLBCL in a selected group of activated B-cell-like DLBCL (ABC-DLBCL) patients with another group of germinal center B-cell-like DLBCL (GBC-DLBCL) patients...
January 6, 2019: Translational Oncology
Qingqing Cai, Yu Fang, Ken H Young
Primary central nervous system lymphoma (PCNSL) is a group of extranodal non-Hodgkin lymphoma that exhibits specific biological characteristics and clinical behavior, with an aggressive disease course and unsatisfactory patient outcomes. It is of great importance to identify aberrant genetic loci and important molecular pathways that might suggest potential targets for new therapeutics and provide prognostic information. In this review, we listed various genetic and epigenetic alterations that are involved in PCNSL pathogenesis...
January 4, 2019: Translational Oncology
Takaya Shimura, Hiroyasu Iwasaki, Mika Kitagawa, Masahide Ebi, Tamaki Yamada, Tomonori Yamada, Takahito Katano, Hirotada Nisie, Yasuyuki Okamoto, Keiji Ozeki, Tsutomu Mizoshita, Hiromi Kataoka
Since a fecal occult blood test for colorectal cancer (CRC) does not offer sufficient diagnostic power for CRC, novel non-invasive biomarkers are hopeful for CRC screening. We conducted the current study to discover non-invasive urinary biomarkers for diagnosing CRC. Among urine samples from 258 patients (CRC, n = 148; healthy controls, n = 110), a cohort of 176 patients composed of 88 patients with GC and 88 healthy controls was selected after age- and sex-matching using propensity score. This cohort was then randomly divided into 2 groups: 53 pairs (106 patients) in the training cohort, and 35 pairs (70 patients) in the validation cohort...
January 3, 2019: Translational Oncology
Uchini S Kosgodage, Pinar Uysal-Onganer, Amy MacLatchy, Rhys Mould, Alistair V Nunn, Geoffrey W Guy, Igor Kraev, Nicholas P Chatterton, E Louise Thomas, Jameel M Inal, Jimmy D Bell, Sigrun Lange
Glioblastoma multiforme (GBM) is the most common and aggressive form of primary malignant brain tumor in adults, with poor prognosis. Extracellular vesicles (EVs) are key-mediators for cellular communication through transfer of proteins and genetic material. Cancers, such as GBM, use EV release for drug-efflux, pro-oncogenic signaling, invasion and immunosuppression; thus the modulation of EV release and cargo is of considerable clinical relevance. As EV-inhibitors have been shown to increase sensitivity of cancer cells to chemotherapy, and we recently showed that cannabidiol (CBD) is such an EV-modulator, we investigated whether CBD affects EV profile in GBM cells in the presence and absence of temozolomide (TMZ)...
December 28, 2018: Translational Oncology
Cheng-Jen Ma, Ching-Wen Huang, Tsung-Kun Chang, Hsiang-Lin Tsai, Wei-Chih Su, Yung-Sung Yeh, Po-Jung Chen, Jaw-Yuan Wang
BACKGROUND: To evaluate the efficacy and toxicities of regorafenib plus irinotecan, dose-escalated on the basis of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotyping, in previously heavily treated metastatic colorectal cancer (mCRC) and the prognostic values of EGFR expression, KRAS mutations, and tumor sidedness. METHODS: Forty-one patients with mCRC with disease progression after treatment with fluoropyrimidines, oxaliplatin, irinotecan, anti-VEGF, and anti-EGFR MoAbs were subjected to UGT1A1 genotyping and received regorafenib combined with FOLFIRI with dose-escalated irinotecan...
December 26, 2018: Translational Oncology
Anusha Angajala, Essynce Mothershed, Melissa B Davis, Shweta Tripathi, Qinghua He, Deepa Bedi, Windy Dean-Colomb, Clayton Yates
PURPOSE: Despite the availability of current standards of care treatments for triple negative breast cancer (TNBC), many patients still die from this disease. Quadruple negative tumors, which are TNBC tumors that lack androgen receptor (AR), represent a more aggressive subtype of TNBC; however, the molecular features are not well understood. METHODS: Immunohistochemistry of estrogen receptor (ER), progesterone receptor (PR), HER2, and AR was determined in 244 primary and 630 recurrent/metastatic site biopsies...
December 26, 2018: Translational Oncology
Wentao Zhang, Junfeng Zhang, Ziwei Zhang, Yadong Guo, Yuan Wu, Ruiliang Wang, Longsheng Wang, Shiyu Mao, Xudong Yao
Indoleamine 2,3-dioxygenase 1 (IDO1) is a key enzyme in tryptophan metabolism and plays an important role in tumor cell immunosuppression and angiogenesis. The molecular mechanisms of IDO1 and epithelial-mesenchymal transition (EMT) have not been elucidated or studied in bladder cancer. Therefore, the aims of this study were to detect IDO1 expression in bladder cancer tissues and then to investigate the role of IDO1 in bladder cancer cell EMT and malignant phenotypes as well as the underlying molecular mechanisms...
December 26, 2018: Translational Oncology
Jingwen Luo, Xu-Qiao Chen, Ping Li
Early detection of gastrointestinal tumors improves patient survival. However, patients with these tumors are typically diagnosed at an advanced stage and have poor prognosis. The incidence and mortality of gastrointestinal cancers, including esophageal, gastric, liver, colorectal, and pancreatic cancers, are increasing worldwide. Novel diagnostic and therapeutic agents are required to improve patient survival and quality of life. The tumor microenvironment, which contains nontumor cells, signaling molecules such as growth factors and cytokines, and extracellular matrix proteins, plays a critical role in cancer cell proliferation, invasion, and metastasis...
December 23, 2018: Translational Oncology
Kerstin Tiedemann, Gulzhakhan Sadvakassova, Nicholas Mikolajewicz, Michal Juhas, Zarina Sabirova, Sébastien Tabariès, Jan Gettemans, Peter M Siegel, Svetlana V Komarova
Bone metastasis from breast and prostate carcinomas is facilitated by activation of bone-resorbing osteoclasts. Using proteomics approaches, we have identified peroxiredoxin-4 (PRDX4) as a cancer-secreted mediator of osteoclastogenesis. We now report characterization of L-plastin in the conditioned media (CM) of MDA-MB-231 human breast cancer cells using immunoblotting and mass spectrometry. The osteoclastogenic potential of MDA-MB-231 CM with siRNA-silenced L-plastin was significantly reduced. L-plastin was detected in cancer-derived exosomes, and inhibition of exosomal release significantly decreased the osteoclastogenic capacity of MDA-MB-231 CM...
December 20, 2018: Translational Oncology
Jie Yang, Hong Yin, Jie Yang, Yanhong Wei, Lin Fang, Dafei Chai, Qing Zhang, Junnian Zheng
The interleukin-24 (IL-24), a member of the IL-10-related cytokine gene family, is well known for its tumor suppressor activity in a broad spectrum of human tumors without damaging normal cells. However, poor tumor penetration remains a key problem for the efficacy of IL-24 as a treatment. iRGD is a novel tumor-specific peptide with unique tumor-penetrating and cell-internalizing properties. To enhance the tumor-penetrating and antitumor effects of IL-24, we engineered a recombinant protein consisting of the IL-24 fused to iRGD, which was named IL-24-iRGD...
December 20, 2018: Translational Oncology
Kirill Gorshkov, Ni Sima, Wei Sun, Billy Lu, Wei Huang, Jameson Travers, Carleen Klumpp-Thomas, Samuel G Michael, Tuan Xu, Ruili Huang, Emily M Lee, Xiaodong Cheng, Wei Zheng
Heterogeneous response to chemotherapy is a major issue for the treatment of cancer. For most gynecologic cancers including ovarian, cervical, and placental, the list of available small molecule therapies is relatively small compared to options for other cancers. While overall cancer mortality rates have decreased in the United States as early diagnoses and cancer therapies have become more effective, ovarian cancer still has low survival rates due to the lack of effective treatment options, drug resistance, and late diagnosis...
December 18, 2018: Translational Oncology
Kristine Raaby Gammelgaard, Johan Vad-Nielsen, Michelle Simone Clement, Simone Weiss, Tina Fuglsang Daugaard, Frederik Dagnæs-Hansen, Peter Meldgaard, Boe Sandahl Sorensen, Anders Lade Nielsen
Non-small cell lung carcinoma patients with epidermal growth factor receptor (EGFR) mutations are offered EGFR tyrosine kinase inhibitors (TKI) as first line treatment, but 20-40% of these patients do not respond. High expression of alternative receptor tyrosine kinases, such as Fibroblast growth factor receptor 1 (FGFR1), potentially mediates intrinsic EGFR TKI resistance. To study this in molecular detail, we used CRISPR-dCas9 Synergistic Activation Mediator (SAM) for up-regulation of FGFR1 in physiological relevant levels in the EGFR mutated NSCLC cell lines HCC827 and PC9 thereby generating HCC827gFGFR1 and PC9gFGFR1 ...
December 15, 2018: Translational Oncology
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