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Beyond third-generation TKI in EGFR mutated NSCLC: resistance mechanisms, novel combinations and synthesis of new agents
Universita degli Studi di Parma
Dipartimento di Medicina e Chirurgia Università degli Studi di Parma Azienda Ospedaliero Universitaria di Parma Via Gramsci, 14 43126 Parma, Italy
Type of Research Project
- Clinical Project with Laboratory work
What is the background of the project?
Among Non-Small Cell Lung Cancer (NSCLC) patients, about 15% harbour an Epidermal Growth Factor Receptor (EGFR) activating gene mutations and are treated with first- or second-generation EGFR-Tyrosine Kinase Inhibitors (TKIs). Various mechanisms have been identified as responsible of resistance to these agents and EGFR-T790M secondary mutation is the main, accounting for 50-60% of the cases. Osimertinib represents the new standard of care in the treatment of T790M-positive NSCLC, but unfortunately also for this drug resistance occurs. Osimertinib is the last new option in the field of EGFR-TKIs, where, despite intensive research, some aspects remain not fully explored.
What is the aim of the project?
- The comprehension of mechanisms involved in intrinsic resistance to Osimertinib - The stratification of T790M patients with a deeper genetic analysis together with tumor metabolism evaluation - The optimization in preclinical studies of novel therapeutic strategies for prevention.
What techniques and methods are used?
1. Plasma and tissue samples from patients treated with osimertinib and progressed at first radiological evaluation will be collected and analysed with NGS. Primary cell lines will be established from tumor biopsies and cell clones with specific oncogenic alterations will be generated and characterized for osimertinib resistance. 2. In responsive osimertinib patients, plasma and tissue samples will be collected and analysed by NGS at different time points concomitantly to PET (FDG and MISO) evaluation in order to stratify the different clinical benefit. In parallel, the role of metabolism in osimertinib responsiveness will be studied in vitro. 3. Docking and molecular dynamics simulation will be applied to assist the design of the novel fourth-generation irreversible EGFR inhibitors that will be tested in vitro and in vivo in xenograft models. Different schedules of treatment of osimertinib combined with chemotherapy will be tested in NSCLC cell lines in vitro and in vivo.
What is the role of the student?
- The student will mainly observe
- The student will observe the practical experiments but will be highly involved in the analysis of the results
- If the project is clinical
- the student will be allowed to work with patients
- The tasks will be done under supervision
What are the tasks expected to be accomplished by the student?
To participate in collection of new patients and to perform some experiments in lab. In particular, student will be involved in patient enrollment (how to propose a clinical study and how to collect an informed consent). In laboratory, student will take part in processing biological samples (blood and tissue), in DNA extraction and in preparation of Next Generation Sequencing experiments. Moreover, student will learn the principles technique of pre-clinical laboratory: to perform a cell culture, protein extraction and western blot analysis.
Will there be any theoretical teaching provided (preliminary readings, lectures, courses, seminars etc)
The tutor or his collaborators will take a few (2 or 3) seminars about resistance mechanisms, novel combinations and synthesis of new agents for the treatment of EGFR mutated NSCLC.
What is expected from the student at the end of the research exchange? What will be the general outcome of the student?
- The student will prepare a presentation - The student will prepare a scientific report
What skills are required of the student? Is there any special knowledge or a certain level of studies needed?
Knowledge of lung cancer. Previous experience with: cell cultures and in vitro/in vivo model
Are there any legal limitations in the student’s involvement
Type of students accepted
This project accepts: - Medical students - Graduated students (less than 6 months)
- Third generation EGFR inhibitor osimertinib combined with pemetrexed or cisplatin exerts long-lasting anti-tumor effect in EGFR-mutated pre-clinical models of NSCLC. La Monica S; Minari R; Cretella D; Flammini L; Fumarola C; Bonelli M; Cavazzoni A; Digiacomo G; Galetti M; Madeddu D; Falco A; Lagrasta CA; Squadrilli A; Barocelli E; Romanel A; Quaini F; Petronini PG; Tiseo M; Alfieri R. J Exp Clin Cancer Res. 2019 May 28;38(1):222.
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