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Projects / Programmes source: ARIS

Molecular and other prognosticators of lung cancer and mesothelioma

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Research activity

Code Science Field Subfield
3.04.00  Medical sciences  Oncology   

Code Science Field
B200  Biomedical sciences  Cytology, oncology, cancerology 

Code Science Field
3.02  Medical and Health Sciences  Clinical medicine 
Keywords
NON-SMALL-CELL LUNG CANCER, MOLECULAR BIOMARKERS, PROGNOSTIC AND PREDICTIVE FACTORS, SYSTEMIC THERAPY
Evaluation (rules)
source: COBISS
Evaluation of bibliographic research performance indicators according to ARIS methodology
Citations Citations for bibliographic records in COBIB.SI that are linked to records in citation databases
source: WoS source: Scopus source: COBISS
Researchers (16)
no. Code Name and surname Research area Role Period No. of publications
1.  02275  PhD Ivan Bratko  Computer science and informatics  Researcher  2011 - 2014  743 
2.  12179  PhD Tanja Čufer  Oncology  Head  2011 - 2014  774 
3.  28365  PhD Matej Guid  Computer science and informatics  Researcher  2011 - 2014  88 
4.  31896  Andraž Jakelj  Psychiatry  Researcher  2014  24 
5.  15781  Izidor Kern  Oncology  Researcher  2011 - 2014  585 
6.  10921  PhD Mitja Košnik  Microbiology and immunology  Researcher  2011 - 2014  1,563 
7.  22680  PhD Mitja Lainščak  Cardiovascular system  Researcher  2011 - 2014  710 
8.  06630  PhD Pika Meško Brguljan  Biochemistry and molecular biology  Researcher  2011 - 2014  347 
9.  29021  PhD Martin Možina  Computer science and informatics  Researcher  2011 - 2014  77 
10.  25177  PhD Aleš Rozman  Oncology  Researcher  2011 - 2014  538 
11.  20389  PhD Aleksander Sadikov  Computer science and informatics  Researcher  2011 - 2014  191 
12.  33392  Taja Tijana Šumer  Oncology  Researcher  2011 - 2014  12 
13.  17896  Nadja Triller  Oncology  Researcher  2011 - 2013  292 
14.  11737  Miljana Vegnuti  Public health (occupational safety)  Researcher  2011 - 2013  130 
15.  29020  PhD Jure Žabkar  Computer science and informatics  Researcher  2011 - 2014  129 
16.  07627  PhD Marija Žolnir-Dovč  Microbiology and immunology  Researcher  2011 - 2014  303 
Organisations (2)
no. Code Research organisation City Registration number No. of publications
1.  1539  University of Ljubljana, Faculty of Computer and Information Science  Ljubljana  1627023  16,250 
2.  1613  University Clinic of Respiratory and Allergic Diseases  Golnik  1190997  7,133 
Abstract
Lung cancer is the leading cause of death due to cancer worldwide. Survival rates of patients with lung cancer and mesothelioma continue to be very low, with 5-year survival rates of 12% and 5%, respectively. Systemic treatment with chemotherapy has reached its plateau.  Better survival rates can only be achieved through a better understanding of molecular biology of primary tumors and host characteristics, which will enable us to tailor and individualize therapy for these malignancies in future.  The treatment of non- small-cell lung cancer (NSCL) with tyrosine kinase inhibitors (TKIs), targeted against the epidermal growth factor (EGFR), represent the first individualized treatment approach based on the molecular biology of tumor in lung cancer. Patients with activating EGFR mutations (EGFRmu+) in the primary tumor respond especially well to this type of treatment. However, not all the patients with EGFRmu + tumors respond to therapy and almost all of them eventually develop resistance to the treatment. To overcome resistance, additional biomarkers of sensitivity/resistance to TKIs, such as additional EGFR mutations, KRAS mutations and others need to be researched. Platinum-based chemotherapy represents the standard treatment of lung cancer as well as mesothelioma nowadays. It is predicted that in the near future, by means of a better understanding and detection of certain biomarkers, such as ERCC1 and TOPO2, we will be able to select which patients will respond to a particular cytostatic . In addition, host characteristics were found to influence the efficacy of any particular systemic therapy substantially, with various polymorphisms in genes which code for enzymes from the CYP family playing an important role. All of these factors, alongside with new biomarkers such as tumor stem cells, have not yet been researched thoroughly enough in lung cancer and mesothelioma to allow for individualized treatment approaches.  The main goal of our research project is to study the value of various EGFR mutations, KRAS mutations, cMET amplifications and EML4/ALK translocation for response to TKI therapy in lung adenocarcinoma and mesothelioma and by doing that to form a prognostic model which will predict for resistance/sensitivity to TKI treatment. We will also study the predictive value of the expression of ERCC1 and TOPO2 in primary tumors of lung cancer and mesothelioma for response to different cytostatics, such as cisplatin and etoposide. By determining the plasma drug concentrations and by defining polymorphisms of the CYP3A enzyme, our research will look into the pharmacokinetics of per oral and/or intravenous administered etoposide. Additional research focus will be on determining the presence of cancer stem cells in the blood of lung cancer patients. The trial will include 330 patients with lung cancer and mesothelioma, treated with standard systemic therapy at the University Clinic Golnik (UCG) during the next two years. The efficacy of treatment will be determined by using the RECIST method and on the basis of survival rates. Simultaneously the standards for a tissue and blood sample biobank will be formed and institutionalized. Biological markers in the primary tumor tissue and in the blood will be determined by use of the standard methods at histological and molecular biology laboratory at the UCG. Drug concentrations in the plasma will be determined by liquid chromatography. Prognostic models for response to certain systemic therapy, based on the presence of multiple biomarkers will be formed by using standardized statistical tools and artificial intelligence methods. We strongly believe that our findings will have a significant contribution towards improving the overall understanding of the molecular biology of lung cancer and host characteristics on the outcome of systemic therapy, thus enabling us individualize treatment of patients with these types of cancer in everyday clinical practice.
Significance for science
Cancer is the major public health issue in whole developed world. With the ageing of the population, a sustained increase in cancer incidence can also be foreseen. Research and new findings in the field of molecular oncology as well as transfer of this knowledge into individualized cancer therapies has already improved efficiency of treatments and prolonged survival of patients with certain forms of cancer, per example breast cancer. Lung cancer still remains one of the most frequent types of cancer and is most common reason for cancer-related death worldwide as well in Slovenia. Therefore, additional research on molecular markers, which will individualize lung cancer treatment and improve survival probabilities, is urgently needed. What gives our project special value is that we successfully determined the expression and prognostic value of important molecular markers, such as EGFR mutations, KRAS mutations, cMET amplification and ALK rearrangements for treatment response in a large cohort of lung cancer patients. Importantly, more methods for specific molecular marker determination were tested and sensibility and reliability of each used method was evaluated. In addition, molecular markers and their prognostic value were assessed in different biological tissues (primary tumor, metastases, blood). According to the literature, we were one of the first groups who studied and published prognostic value of ERCC1 in SCLC. Also, influence of ABCB1 and CYP3A polymorphisms on response rate to chemotherapy on Caucasian population has been investigated for the first time in our study. In addition, a special value of the project lies in the fact that in the same population of patients biomarkers defining cancer stem cells and epithelial-mesenchymal transition (EMT), as a critical process required for cancer invasion and metastasis have been researched. Special importance is also in established collaboration with European partners, like is EORTC, especially in the field of rare cancer, such as mesothelioma. Because of the diversity of molecular biomarkers, also so called frequent cancers are becoming rare cancers nowadays. Therefore for new discoveries in these types of cancer and moreover, efficient transfer of new knowledge into individualized treatments of patients such integration and collaboration of research groups across the world is of upmost importance.
Significance for the country
Cancer is one of the most pressing public health issues of the developed world. According to IARC data, over 12. 6 million new cancer patients are diagnosed each year while forecasts predict a doubling of this figure over the next couple decades. Better understanding of cancer biology with a continuous transfer of these new findings into clinical practice is of upmost importance for improved cancer care. The already concluded research program, aimed at studying prognostic and predictive biomarkers in lung cancer was designed in such a way that it allowed for a rapid transfer of obtained findings into routine clinical practice in Slovenia. The importance and actuality of the research program is supported by the fact that over 1000 new cases of lung cancer patients are diagnosed in Slovenia each year, with a majority of these cases still resulting in death. Lung cancer is still a deadly disease with 5 year survival rates of only about 15%, in Slovenia and globally. But, during the last few years major improvements in the understanding of molecular biology and introduction of targeted systemic led to some very encouraging results, for example median survival rates of advanced lung cancer patients with EGFR mutations increased from 10 months at the beginning of this decade to approximately 30 months. Therefore it is of upmost importance for any society to thoroughly research the expression levels of molecular markers in their populations and introduce biomarker-directed, personalized treatment of lung cancer. As shown also by our study, such translational studies ultimately lead to a better cancer care. In Slovenia, median survival rates of patients which were diagnosed during the course of the study with EGFR mutated lung cancer and received targeted therapy, increased to approximately 28 months. This confirms without a doubt that the study provides a significant contribution to better lung cancer control in Slovenia. A higher rate of curability or at least long term disease control in such a common disease as lung cancer at the same time most certainly also provides significant savings for the society.
Most important scientific results Annual report 2011, 2012, 2013, final report, complete report on dLib.si
Most important socioeconomically and culturally relevant results Annual report 2011, 2012, 2013, final report, complete report on dLib.si
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