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Projects / Programmes source: ARIS

Molecular biomarkers and biomarker-driven therapy in lung cancer

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
Lung cancer, molecular biomarkers, oncogenic drivers, immune biomarkers, targeted therapies, treatment outcomes
Evaluation (rules)
source: COBISS
Researchers (16)
no. Code Name and surname Research area Role Period No. of publicationsNo. of publications
1.  02275  PhD Ivan Bratko  Computer science and informatics  Researcher  2016 - 2018  743 
2.  12179  PhD Tanja Čufer  Oncology  Head  2016 - 2018  774 
3.  33187  PhD Vida Groznik  Computer science and informatics  Researcher  2016 - 2018  63 
4.  52179  Ana Herzog    Technical associate  2018 
5.  15781  Izidor Kern  Oncology  Researcher  2016 - 2018  586 
6.  29281  PhD Lea Knez  Pharmacy  Researcher  2016 - 2018  201 
7.  34101  PhD Ana Koren  Microbiology and immunology  Researcher  2016 - 2018  87 
8.  22807  PhD Peter Korošec  Microbiology and immunology  Researcher  2016 - 2018  716 
9.  10921  PhD Mitja Košnik  Microbiology and immunology  Researcher  2016 - 2018  1,566 
10.  16229  PhD Viljem Kovač  Medical sciences  Researcher  2016 - 2018  297 
11.  30985  Katja Mohorčič  Microbiology and immunology  Researcher  2016 - 2018  130 
12.  29021  PhD Martin Možina  Computer science and informatics  Researcher  2016 - 2018  77 
13.  20389  PhD Aleksander Sadikov  Computer science and informatics  Researcher  2016 - 2018  191 
14.  12024  PhD Karmen Stanič  Medical sciences  Researcher  2016 - 2018  94 
15.  32452  PhD Danijela Štrbac  Medical sciences  Researcher  2016 - 2018  42 
16.  29020  PhD Jure Žabkar  Computer science and informatics  Researcher  2016 - 2018  129 
Organisations (3)
no. Code Research organisation City Registration number No. of publicationsNo. of publications
1.  0302  Institute of Oncology Ljubljana  Ljubljana  5055733000  15,495 
2.  1539  University of Ljubljana, Faculty of Computer and Information Science  Ljubljana  1627023  16,285 
3.  1613  University Clinic of Respiratory and Allergic Diseases  Golnik  1190997  7,159 
Abstract
Lung cancer is the most common cause of cancer related death and since 2012 also the most frequent cancer worldwide. Traditionally poor survival rates start improving over the last decade, mainly due to better understanding of lung cancer biology; the characterization of molecular subtypes, such as EGFR and ALK subtypes led to the introduction of highly effective targeted therapies in routine clinical practice. Until now, over ten additional druggable oncogenic drivers have been recognized in non-small-cell lung cancer (NSCLC). Most of these markers can already be determined with available methods, however their standardization and validation is still needed. In addition, primary tumour and metastases heterogeneity and genetic changes over systemic therapy require further research. Harnessing the immune system with check point inhibitors is yet another promising treatment strategy. Treatment proved to be effective in patients with PD-L1 protein expression; however, responses were noted also in PD-L1 negative patients, thus leading to multiple unresolved issues on PD-L1 predictive value and used methodology. The recent identification of numerous NSCLC subtypes with small number of patients make the evaluation of biomarkers and treatment outcomes in large prospective clinical trials unfeasible. Thus a thoughtful pre-selection of biomarkers for prospective clinical studies and continuous evaluation of treatment outcomes based on hospital data registries and institutional tumour banks is extremely important. However biases, inherited in observational trials should be avoided using proper methodology, such as computerized balancing of patient cohorts. The overreaching aim of our project is to produce a platform for NSCLC molecular and immune biomarkers assessment in order to link biomarkers with targeted and immune therapies and evaluate treatment outcomes, using hospital lung cancer registry. Besides studying the expression of selected biomarkers (EGFR, ALK, KRAS, ROS1, HER2, BRAF, MET, RET, PIK3CA, FGFR1, DDR2, SOX, PD-L1 and others) in the primary tumour, metastases and peripheral blood (ctDNA), before and during treatment, associations between biomarkers, treatment allocations and outcomes will be evaluated in biomarker selected collectives of patient and in well-balanced groups of patients, selected with artificial intelligence technology. During the three-year period approximately 600 NSCLC patients diagnosed and treated at the University Clinic Golnik will be included, if consented. Tumour tissue will be obtained within routine diagnostic procedures and no additional tumour sampling, with the exception of blood collection for ctDNA at regular check-up visits, will be required. Selected molecular and immune biomarkers will be determined before and during any systemic therapy, according to a pre-defined schedule, in all available tissue and blood samples. Biomarkers will be determined according to the current best methodology, mainly by immunohistochemistry, in situ hybridisation and real time polymerase chain reaction, after careful standardization of protocols and regular quality control check-ups. Patients will receive systemic therapy in the frame of routine clinical practice or within clinical trials, if available. All demographic and clinicopathologic data will be collected prospectively from the well-established hospital-based lung cancer registry using standardized and prospective data collection. Distribution of biomarkers and survival analyses will be performed using standard statistical methodology. In addition, a computer based programme, using heuristic search techniques, will be developed to enable unbiased comparison of treatment outcomes in well- balanced groups of patients. Ultimately, the accomplishments of this project and the translation of findings into routine clinical practice will contribute to a better use of available resources and, most importantly, to improved survival of NSCLC patients.
Significance for science
Over the past years, exploring cancer molecular biology and translating these findings into the treatment of various cancers has become one of the main focuses of cancer research. The identification of new molecular biomarkers that represent clinically important genomic alterations in the last decade has led to a better understanding of the pathogenesis of lung cancer, as well as the mechanisms of proliferation and survival of tumour cells. As a result, nowadays, over half of NSCLC tumours are characterised by a distinct oncogenic driver that guide clinicians in the assessment of disease prognosis and in treatment selection, based on molecular biomarkers predicting for sensitivity or resistance to a particular treatment. Targeted therapies, when applied in patients expressing the allied oncogenic-driver, offers indisputably better treatment results and overall survival, compared to the one-fits-all approach, where treatment is not tailored according to tumour biology. Similar or even bigger expectations are laid in immunotherapy, where recent developments and first results with immune checkpoint inhibitors promise further improvements in overall survival. There are yet no validated immune biomarkers that would predict immunotherapy outcomes and aid in the selection of patients that would benefit most, this being one of the most intensively researched questions at time being. To use these novel therapies at the best, a constant search of predictive biomarkers and a thorough assessment of treatment outcomes are needed at present and in the future. The knowledge and skills gained through this project will provide a new insight in NSCLC tumour biology with a special focus on the prognostic and predictive value of molecular biomarkers for disease outcomes and outcomes of the targeted therapies, respectively. Further on, the project will deliver new and most needed information on the predictive markers in immunotherapy. These findings are the prerequisites to implement precision medicine into everyday clinical practice, tailoring the treatment to the characteristics of each individual patient and the molecular biology of their tumour, monitoring the tumour evolution and adjusting treatment accordingly. In addition, this project will bring into our academic arena standardised procedures for the collection and storage of biologic samples (tumour tissue and blood), with important capacity for improving the methodology of molecular biomarkers detection in our research space. Concurrently, procedures for a high-quality collection of patient clinical data and their regular update will be reinforced. The establishment large clinical database, including data ranging from demographic characteristics to information on molecular biomarkers, will enable further comparative studies on the efficacy and toxicity of various diagnostic and therapeutic approaches on a large collective of routinely treated NSCLC patients, thus serving as a tool for further research and improvement in lung cancer control.
Significance for the country
Cancer presents one of the most burning public-health problems in the developed world. Based on the ageing of the world population, a significant raise in cancer incidence may be expected over the coming years. Research in molecular oncology and the efficient translation of new findings into clinical practice is of outmost importance for the improvement of cancer control globally. Unfortunately, as oppose to breast and colon cancer, our current knowledge on the molecular biology of lung cancer is still limited. The developments in the field of NSCLC molecular biology have indeed led to the introduction of targeted therapies also in lung cancer, however these can be offered only to a minority of approximately 15 % NSCLC patients with nearly no possibilities available in squamous cell lung cancer. The introduction of targeted therapies revealed new problems as the development of resistance to the agents used in first-line: an issue for which we do not have yet a definitive answer, but will need to be tackled to prolong survival in these patients. The launch of the novel and very expensive cancer immunotherapy urges the recognition of immune biomarkers that will predict response to immunotherapy drugs: to safeguard patients from unnecessary toxicity and for the best utilisation of available financial resources. Our project is designed to transfer methodology for multiple biomarker determination in our space, research the association of known biomarkers with outcomes of targeted treatments and to investigate new prognostic and predictive biomarkers on a large group of patients, ensuring a rapid translation of our findings into the routine clinical in Slovenia and abroad, thus tackling all the above stated issues. Moreover, the large number of patients included in the database will enable subgroup analysis to address questions that are unfeasible to be addressed in clinical trials, for example how different subgroups of patients, harbouring different genetic alterations of the same oncogenic-driver, will at different time points od systemic therapy respond to different treatment strategies, e.g. novel targeted agents. The importance and relevance of the project for Slovenian society is reinforced by the fact that each year over 1200 new lung cancer cases are diagnosed in Slovenia, with the absolute numbers of patients dying from the disease still rising, the situation similar to the rest of the world. The optimisation of currently available treatments trough the practicing of precision medicine based on lung cancer molecular biology, will certainly improve lung cancer survival and quality of life of lung cancer patients, and is of upmost importance for improved cost-efficacy of currently available as well as upcoming treatments.
Most important scientific results Interim report, final report
Most important socioeconomically and culturally relevant results Interim report, final report
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