TY - JOUR AU - Kovács, Szonja Anna AU - Fekete, János Tibor AU - Győrffy, Balázs TI - Predictive biomarkers of immunotherapy response with pharmacological applications in solid tumors JF - ACTA PHARMACOLOGICA SINICA J2 - ACTA PHARMACOL SIN VL - 44 PY - 2023 IS - 9 SP - 1879 EP - 1889 PG - 11 SN - 1671-4083 DO - 10.1038/s41401-023-01079-6 UR - https://m2.mtmt.hu/api/publication/33754849 ID - 33754849 N1 - Department of Bioinformatics, Semmelweis University, Tűzoltó utca 7-9, Budapest, 1094, Hungary Doctoral School of Pathological Sciences, Semmelweis University, Üllői út 26, Budapest, 1085, Hungary National Laboratory for Drug Research and Development, Magyar tudósok körútja 2 1117, Budapest, Hungary Research Centre for Natural Sciences, Oncology Biomarker Research Group, Institute of Enzymology, Eötvös Loránd Research Network, Magyar Tudósok körútja 2, Budapest, 1117, Hungary Department of Pediatrics, Semmelweis University, Tűzoltó utca 7-9, Budapest, 1094, Hungary Cited By :7 Export Date: 7 February 2024 CODEN: APSCG Correspondence Address: Győrffy, B.; Department of Bioinformatics, Tűzoltó utca 7-9, Hungary; email: gyorffy.balazs@med.semmelweis-univ.hu Chemicals/CAS: atezolizumab, 1380723-44-3; durvalumab, 1428935-60-7; fibroblast growth factor receptor 3, 306781-00-0; ipilimumab, 477202-00-9; MutL protein homolog 1, 155577-96-1; nivolumab, 946414-94-4; pembrolizumab, 1374853-91-4; protein bcl 2, 219306-68-0; histone lysine methyltransferase, 9076-80-6; Biomarkers, Tumor; Histone-Lysine N-Methyltransferase; Ipilimumab; SETD7 protein, human Funding details: Nemzeti Kutatási, Fejlesztési és Innovaciós Alap, NKFIA Funding details: National Research, Development and Innovation Office, 2020-1.1.6-JÖVŐ-2021-00013, KDP-14-3/PALY-2021, RRF-2.3.1-21-2022-00015, TKP-2021-NVA-15 Funding text 1: This project was supported by the Hungary National Research, Development and Innovation Office (PharmaLab, RRF-2.3.1-21-2022-00015, TKP-2021-NVA-15, and 2020-1.1.6-JÖVŐ-2021-00013). Project no. KDP-14-3/PALY-2021 has been implemented with the support provided by the Ministry of Culture and Innovation of Hungary from the National Research, Development and Innovation Fund, financed under the KDP-2020 funding scheme. The authors acknowledge the support of ELIXIR-Hungary ( https://www.bioinformatics.hu/ ) and thank Viktoria Lakatos for the careful English editing of the manuscript. Funding text 2: This project was supported by the Hungary National Research, Development and Innovation Office (PharmaLab, RRF-2.3.1-21-2022-00015, TKP-2021-NVA-15, and 2020-1.1.6-JÖVŐ-2021-00013). Project no. KDP-14-3/PALY-2021 has been implemented with the support provided by the Ministry of Culture and Innovation of Hungary from the National Research, Development and Innovation Fund, financed under the KDP-2020 funding scheme. The authors acknowledge the support of ELIXIR-Hungary (https://www.bioinformatics.hu/ ) and thank Viktoria Lakatos for the careful English editing of the manuscript. AB - Immune-checkpoint inhibitors show promising effects in the treatment of multiple tumor types. Biomarkers are biological indicators used to select patients for a systemic anticancer treatment, but there are only a few clinically useful biomarkers such as PD-L1 expression and tumor mutational burden, which can be used to predict immunotherapy response. In this study, we established a database consisting of both gene expression and clinical data to identify biomarkers of response to anti-PD-1, anti-PD-L1, and anti-CTLA-4 immunotherapies. A GEO screening was executed to identify datasets with simultaneously available clinical response and transcriptomic data regardless of cancer type. The screening was restricted to the studies involving administration of anti-PD-1 (nivolumab, pembrolizumab), anti-PD-L1 (atezolizumab, durvalumab) or anti-CTLA-4 (ipilimumab) agents. Receiver operating characteristic (ROC) analysis and Mann-Whitney test were executed across all genes to identify features related to therapy response. The database consisted of 1434 tumor tissue samples from 19 datasets with esophageal, gastric, head and neck, lung, and urothelial cancers, plus melanoma. The strongest druggable gene candidates linked to anti-PD-1 resistance were SPIN1 (AUC = 0.682, P = 9.1E-12), SRC (AUC = 0.667, P = 5.9E-10), SETD7 (AUC = 0.663, P = 1.0E-09), FGFR3 (AUC = 0.657, P = 3.7E-09), YAP1 (AUC = 0.655, P = 6.0E-09), TEAD3 (AUC = 0.649, P = 4.1E-08) and BCL2 (AUC = 0.634, P = 9.7E-08). In the anti-CTLA-4 treatment cohort, BLCAP (AUC = 0.735, P = 2.1E-06) was the most promising gene candidate. No therapeutically relevant target was found to be predictive in the anti-PD-L1 cohort. In the anti-PD-1 group, we were able to confirm the significant correlation with survival for the mismatch-repair genes MLH1 and MSH6 . A web platform for further analysis and validation of new biomarker candidates was set up and available at https://www.rocplot.com/immune . In summary, a database and a web platform were established to investigate biomarkers of immunotherapy response in a large cohort of solid tumor samples. Our results could help to identify new patient cohorts eligible for immunotherapy. LA - English DB - MTMT ER - TY - JOUR AU - Tigyi, Gabor AU - Dacheux, Mélanie A. AU - Lin, Kuan-Hung AU - Yue, Junming AU - Norman, Derek AU - Benyó, Zoltán AU - Lee, Sue Chin TI - Anti-cancer strategies targeting the autotaxin-lysophosphatidic acid receptor axis: is there a path forward? JF - CANCER AND METASTASIS REVIEWS J2 - CANCER METAST REV VL - 40 PY - 2021 IS - 1 SP - 3 EP - 5 PG - 3 SN - 0167-7659 DO - 10.1007/s10555-021-09955-5 UR - https://m2.mtmt.hu/api/publication/31822186 ID - 31822186 N1 - Department of Physiology, University of Tennessee Health Science Center Memphis, 3 N. Dunlap Street, Memphis, TN 38163, United States Department of Pathology, University of Tennessee Health Science Center Memphis, 3 N. Dunlap Street, Memphis, TN 38163, United States Institute of Translational Medicine, Semmelweis University, POB 2, Budapest, H-1428, Hungary Cited By :1 Export Date: 21 February 2022 CODEN: CMRED Correspondence Address: Tigyi, G.; Department of Pathology, 3 N. Dunlap Street, United States; email: gtigyi@uthsc.edu LA - English DB - MTMT ER - TY - JOUR AU - Lee, Dongjun AU - Suh, Dong-Soo AU - Lee, Sue Chin AU - Tigyi, Gabor AU - Kim, Jae Ho TI - Role of autotaxin in cancer stem cells JF - CANCER AND METASTASIS REVIEWS J2 - CANCER METAST REV VL - 37 PY - 2018 IS - 2-3 SP - 509 EP - 518 PG - 10 SN - 0167-7659 DO - 10.1007/s10555-018-9745-x UR - https://m2.mtmt.hu/api/publication/30515673 ID - 30515673 N1 - Department of Medical Science, Pusan National University School of Medicine, Yangsan, 50612, South Korea Department of Obstetrics and Gynecology, Pusan National University School of Medicine, Yangsan, 50612, South Korea Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, United States Department of Physiology, Pusan National University School of Medicine, Yangsan, Gyeongsangnam-do 50612, South Korea Cited By :6 Export Date: 15 March 2020 CODEN: CMRED Correspondence Address: Kim, J.H.; Department of Physiology, Pusan National University School of MedicineSouth Korea; email: jhkimst@pusan.ac.kr AB - Stem cells are a rare subpopulation defined by the potential to self-renew and differentiate into specific cell types. A population of stem-like cells has been reported to possess the ability of self-renewal, invasion, metastasis, and engraftment of distant tissues. This unique cell subpopulation has been designated as cancer stem cells (CSC). CSC were first identified in leukemia, and the contributions of CSC to cancer progression have been reported in many different types of cancers. The cancer stem cell hypothesis attempts to explain tumor cell heterogeneity based on the existence of stem cell-like cells within solid tumors. The elimination of CSC is challenging for most human cancer types due to their heightened genetic instability and increased drug resistance. To combat these inherent abilities of CSC, multi-pronged strategies aimed at multiple aspects of CSC biology are increasingly being recognized as essential for a cure. One of the most challenging aspects of cancer biology is overcoming the chemotherapeutic resistance in CSC. Here, we provide an overview of autotaxin (ATX), lysophosphatidic acid (LPA), and their signaling pathways in CSC. Increasing evidence supports the role of ATX and LPA in cancer progression, metastasis, and therapeutic resistance. Several studies have demonstrated the ATX-LPA axis signaling in different cancers. This lipid mediator regulatory system is a novel potential therapeutic target in CSC. In this review, we summarize the evidence linking ATX-LPA signaling to CSC and its impact on cancer progression and metastasis. We also provide evidence for the efficacy of cancer therapy involving the pharmacological inhibition of this signaling pathway. LA - English DB - MTMT ER - TY - JOUR AU - Gotoh, M AU - Fujiwara, Y AU - Yue, J AU - Liu, J AU - Lee, S AU - Fells, J AU - Uchiyama, A AU - Murakami-Murofushi, K AU - Kennel, S AU - Wall, J AU - Patil, R AU - Gupte, R AU - Balazs, L AU - Miller, DD AU - Tigyi, Gabor TI - Controlling cancer through the autotaxin-lysophosphatidic acid receptor axis. JF - BIOCHEMICAL SOCIETY TRANSACTIONS J2 - BIOCHEM SOC T VL - 40 PY - 2012 IS - 1 SP - 31 EP - 36 PG - 6 SN - 0300-5127 DO - 10.1042/BST20110608 UR - https://m2.mtmt.hu/api/publication/2756703 ID - 2756703 N1 - Megjegyzés-26416565 Megjegyzés-26404469 PN 1 Department of Physiology, College of Medicine, University of Tennessee Health Science Center, 894 Union Avenue, Memphis, TN 38163, United States Department of Biology, Ochanomizu University, 2-1-1 Ohtsuka, Bunkyo-ku, Tokyo 112-8610, Japan Human Immunology and Cancer Program, Preclinical and Diagnostic Molecular Imaging Laboratory, University of Tennessee Graduate School of Medicine, 1924 Alcoa Highway, Knoxville, TN 37920, United States Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, United States Department of Pathology, College of Medicine, University of Tennessee Health Science Center, 894 Union Avenue, Memphis, TN 38163, United States Cited By :50 Export Date: 15 March 2020 CODEN: BCSTB Correspondence Address: Tigyi, G.J.; Department of Physiology, College of Medicine, University of Tennessee Health Science Center, 894 Union Avenue, Memphis, TN 38163, United States; email: gtigyi@uthsc.edu AB - LPA (lysophosphatidic acid, 1-acyl-2-hydroxy-sn-glycero-3-phosphate), is a growth factor-like lipid mediator that regulates many cellular functions, many of which are unique to malignantly transformed cells. The simple chemical structure of LPA and its profound effects in cancer cells has attracted the attention of the cancer therapeutics field and drives the development of therapeutics based on the LPA scaffold. In biological fluids, LPA is generated by ATX (autotaxin), a lysophospholipase D that cleaves the choline/serine headgroup from lysophosphatidylcholine and lysophosphatidylserine to generate LPA. In the present article, we review some of the key findings that make the ATX-LPA signalling axis an emerging target for cancer therapy. LA - English DB - MTMT ER - TY - JOUR AU - Tigyi, Gabor TI - Aiming drug discovery at lysophosphatidic acid targets. JF - BRITISH JOURNAL OF PHARMACOLOGY J2 - BR J PHARMACOL VL - 161 PY - 2010 IS - 2 SP - 241 EP - 270 PG - 30 SN - 0007-1188 DO - 10.1111/j.1476-5381.2010.00815.x UR - https://m2.mtmt.hu/api/publication/2756712 ID - 2756712 N1 - Megjegyzés-23221640 N1 : Chemicals/CASglycerol 3 phosphate acyltransferase, 9029-96-3; sphingosine 1 phosphate, 26993-30-6; Ligands; Lysophospholipids; Receptors, G-Protein-Coupled; lysophosphatidic acid, 22002-87-5 Cited By :114 Export Date: 15 March 2020 CODEN: BJPCB Correspondence Address: Tigyi, G.; Department of Physiology, University of Tennessee Health Science Center, 894 Union Avenue, Memphis, TN 38163, United States; email: gtigyi@uthsc.edu Cited By :115 Export Date: 17 March 2020 CODEN: BJPCB Correspondence Address: Tigyi, G.; Department of Physiology, University of Tennessee Health Science Center, 894 Union Avenue, Memphis, TN 38163, United States; email: gtigyi@uthsc.edu Cited By :115 Export Date: 19 March 2020 CODEN: BJPCB Correspondence Address: Tigyi, G.; Department of Physiology, University of Tennessee Health Science Center, 894 Union Avenue, Memphis, TN 38163, United States; email: gtigyi@uthsc.edu AB - Lysophosphatidic acid (LPA, 1-radyl-2-hydroxy-sn-glycero-3-phosphate) is the prototype member of a family of lipid mediators and second messengers. LPA and its naturally occurring analogues interact with G protein-coupled receptors on the cell surface and a nuclear hormone receptor within the cell. In addition, there are several enzymes that utilize LPA as a substrate or generate it as a product and are under its regulatory control. LPA is present in biological fluids, and attempts have been made to link changes in its concentration and molecular composition to specific disease conditions. Through their many targets, members of the LPA family regulate cell survival, apoptosis, motility, shape, differentiation, gene transcription, malignant transformation and more. The present review depicts arbitrary aspects of the physiological and pathophysiological actions of LPA and attempts to link them with select targets. Many of us are now convinced that therapies targeting LPA biosynthesis and signalling are feasible for the treatment of devastating human diseases such as cancer, fibrosis and degenerative conditions. However, successful targeting of the pathways associated with this pleiotropic lipid will depend on the future development of as yet undeveloped pharmacons. LA - English DB - MTMT ER -