Mechanisms and biomarkers of response and resistance to current targeted therapies in gastric cancer

Acronym: THERRES
Principal investigator: for IVN Mihaela Economescu (Chivu) PhD

(2018-2022; PN-III-P4-ID-PCCF-2016-0158) – Principal investigator: for IVN Mihaela Economescu (Chivu) PhD

Aim: The main objective is to identify and characterize the regulators of immune function activation (immune checkpoints) within a new, updated molecular classification system for gastric cancer, for the implementation of a personalized treatment in order to improve the survival rate of patients.

Partners: Coordinator: Fundeni Clinical Institute – principal investigator Prof. Dr. Irinel Popescu

Partner 1: Craiova University of Medicine and Pharmacy – principal investigator Prof. Dr. Adrian Saftoiu

Partner 2: Institute of Virology Stefan S. Nicolau – principal investigator Dr. Mihaela Economescu;

Funding: 2.000.000 RON

Working team: Mihaela Economescu, Carmen C. Diaconu, Coralia Bleotu, Laura Necula, Denisa Dragu, Lilia Matei, Ana Iulia Neagu.

Project financed by UEFISCDI program PN-III-P4-ID-PCCF2016-0158, contract no. PCCF17/2018

Implementation period: 01.01.2018 – 30.11.2022

Summary: Functional in vitro studies were carried out on primary cultures generated from gastric cancer tissue fragments to create study models on the identified immune targets. Such models are useful to validate both immune targets and specific inhibitors or therapeutic combinations consisting of immunotherapy + chemotherapy or targeted therapy.

The analysis mainly focused on the changes induced at the level of signalling pathways following the co-culture of gastric cancer cells with increased expression of PD-L1 with human T lymphocytes with PD1 expression in the presence of inhibitors of the PD1/PD-L1 interaction +/ VEGFR2 inhibitor.

Combining the targeted strategy with immunotherapy represents the most interesting and active field of research today due to the durable responses observed in other malignant types such as melanoma and lung cancer. This strategy could represent a quantum leap in gastric cancer therapy.

Results:

Articles:

  1. Chivu-Economescu M., Herlea V., Dima S., Sorop A., Pechianu C., Procop A., Kitahara S., Necula L., Matei L., Dragu D., Neagu A.I., Bleotu C., Diaconu C.C., Popescu I., Duda D.G. Soluble PD-L1 as a diagnostic and prognostic biomarker in resectable gastric cancer patients. Gastric Cancer 2023 Sep 2023, doi:10.1007/s10120-023-01429-7. IF=7.7
  2. Chivu-Economescu M, Necula LG, Matei L, Dragu D, Bleotu C, Sorop A, Herlea V, Dima S, Popescu I, Diaconu CC. Collagen Family and Other Matrix Remodeling Proteins Identified by Bioinformatics Analysis as Hub Genes Involved in Gastric Cancer Progression and Prognosis. International Journal of Molecular Sciences 2022; 23(6):3214. https://doi.org/10.3390/ijms23063214 IF=6.208
  3. Necula L,  Matei L, Dragu D, Pitica I, Neagu A,  Bleotu C, Diaconu CC,  Chivu-Economescu M. Collagen Family as Promising Biomarkers and Therapeutic Targets in Cancer. Int. J. Mol. Sci. 2022, 23, 12415. https://doi.org/10.3390/ijms232012415 IF=6.208/2021
  4. Chivu-Economescu M, Necula L, Matei L, Dragu D, Bleotu C, Diaconu CC. Clinical Applications of Liquid Biopsy in Gastric Cancer. Front Med (Lausanne). 2021;8:749250. doi: 10.3389/fmed.2021.749250. IF=3.9
  5. Necula L, Matei L, Dragu D, Pitica I, Neagu AI, Bleotu C, Dima S, Popescu I, Diaconu CC, Chivu-Economescu M. High plasma levels of COL10A1 are associated with advanced tumor stage in gastric cancer patients. World J Gastroenterol. 2020 Jun 14;26(22):3024-3033. doi: 10.3748/wjg.v26.i22.3024. PMID: 32587446; IF=3.665.
  6. Chivu-Economescu M, Necula LG, Matei L, Dragu DL, Neagu AI, Alexiu I, Bleotu C, Diaconu CC. Gastrointestinal cancer stem cells as targets for innovative immunotherapy. World J Gastroenterol. 2020 Apr 14;26(14):1580-1593. doi: 10.3748/wjg.v26.i14.1580. PMID: 32327907; IF=3.665.
  7. Necula L, Matei L, Dragu D, Neagu AI, Mambet C, Nedeianu S, Bleotu C, Diaconu CC, Chivu-Economescu M. Recent advances in gastric cancer early diagnosis. World J Gastroenterol. 2019 May 7;25(17):2029-2044. doi: 10.3748/wjg.v25.i17.2029. PMID: 31114131; IF= 3.411.

Communications at national/international congresses

  1. Chivu-Economescu M, Necula L, Matei L, Dragu D, Neagu A , Bleotu C, Sorop S, Herlea V, Dima S, Popescu I, Diaconu C. PD-L1 solubil ca biomarker pentru progresia și prognosticul în cancerul gastric. Zilele Științifice ale Institutului Clinic Fundeni, 7-9 decembrie 2022.
  2. Chivu-Economescu M, Necula L, Matei L, Dragu D, Neagu AI, Bleotu C, Sorop A, Herlea V, Dima S, Popescu I and Diaconu C. Soluble PD-L1 Level is Correlated with its Expression in Tissue and is Associated with Poor Overall Survival in Gastric Cancer. The 3rd Immuno-Oncology World Congress, 2-3 noiembrie 2022, Copenhaga, Denemarca.
  3. Chivu-Economescu M,Matei L, Necula L, Dragu D, Neagu AI, Sorop A, Bleotu C, Dima S, Irinel P. Evaluation of tumor immune microenvironment to predict and guide immunotherapeutic response, prezentare în cadrul Congresului Național de Citometrie a XIIIa Ediție, sesiunea de Imunologie, 16-18 decembrie 2020
  4. Chivu-Economescu M. High PD-L1 expression in Epstein-Barr virus positive and microsatellite unstable cancers, prezentare în cadrul Conferinței Webinar „Tratamente Inovative în Oncologie” – ediția a VII-a, 27 noiembrie 2020
  5. Chivu-Economescu M, Necula LG, Dragu D, Matei L, Neagu AI, Bleotu C, Sarbu M, Dima SO, Diaconu CC, Popescu I. New molecular classification of gastric cancer opens new avenues to novel therapeutic strategies, prezentare orală în cadrul “The 12th National Pathology Symposium, sesiunea Omics in pathology, 21-23 noiembrie 2019, București, România.
  6. Necula LG, Matei L, Dragu D, Neagu AI, Pitica I, Nedeianu S, Mambet C, Bleotu C, Dima S, Popescu I, Diaconu CC, Chivu-Economescu M. Plasma level of COL10A1 is associated with tumor stage and survival in patients with Gastric Cancer, prezentare în cadrul “Advances in Cancer Research and Therapy”, 11-12 noiembrie 2019, Madrid, Spania.
  7. Matei L, Dragu D, Necula LG, Neagu AI, Pitica I, Nedeianu S, Mambet C, Bleotu C, Dima S, Popescu I, Diaconu CC, Chivu-Economescu M. Classification of Gastric Cancer samples according to protein expression and MSI status based algorithm, prezentare în cadrul “Advances in Cancer Research and Therapy”, 11-12 noiembrie 2019, Madrid, Spania.
  8. Sîrbu M, Șorop A, Chivu-Economescu M, Dima L, Chiosa A, Dima S, Popescu I.  Molecular classification of gastric cancer opens new opportunities into personalized treatment, poster în cadrul ediției a XIVa a Simpozionului Academician Nicolae Cajal, 17-19 octombrie 2019, București, România.
  9. Necula LG, Matei L, Dragu D, Neagu AI, Pitica I, Mambet C, Bleotu C, Dima S, Popescu I, Diaconu CC, Chivu-Economescu M.  Diagnostic role of circulating COL10A1 in gastric cancer, prezentare în cadrul ediției a XIVa a Simpozionului Academician Nicolae Cajal, 17-19 octombrie 2019, București, România.