Biologia del Càncer i Medicina de Precisió

Rafael Rosell

Ho sentim, però aquesta pàgina està en construcció

Líneas de investigación

We are using a combination of in vitro models ranging from cell proliferation, migration, apoptosis and cell cycle, to flow cytometry, immunofluorescence, western blotting and quantitative real time polymerase chain reaction (PCR). We are using established cancer cell lines and drug-resistance cell lines developed in our laboratory. We explore circulating and tumor tissue molecular biomarkers of cancer patients. In our models we are also including new technologies that are more sensitive like Next Generation Sequencing (NGS) and nanostring.

Ongoing projects in the lab focus on the following issues:

  1. Co-activation of receptor tyrosine kinases in EGFR mutant NSCLC cells and patients
  2. Proviral integration site for Moloney murine leukemia virus-1 (PIM1) kinase in EGFR mutant NSCLC
  3. Heat shock protein 90 (HSP90) inhibitors to overcome innate resistance to EGFR mutant NSCLC
  4. Co-targeting PIM1 or Src to beat the limitations of single MET inhibition
  5. Defeating the signaling that mediates streaming and metastasis in early stage tumors treated with adjuvant chemotherapy
  6. Combinations with cyclin D-dependent kinase (CDK) 4/6 inhibitors in KRAS mutant NSCLC and not only
  7. Landscape in KRAS mutant lung cancers and therapeutic principles
  8. PAK [p21 (RAC1) activated kinase] inhibitors and combinatorial approaches in lung cancer cell lines
  9. Novel approaches for the treatment of head and neck squamous cell carcinoma
  10. Towards widespread clinical application of blood-based diagnostic tools. The European Liquid Biopsies Academy
  11. Implementation of liquid biopsy as a tool for cancer diagnosis and follow up in our patients.

These are two examples of ongoing research:

  • Common co-activation of AXL and CDCP1 in EGFR mutant NSCLC associated with poor prognosis

The significance of the study is the common presence of elevated expression of receptor tyrosine kinases, frequently AXL and CUB domain-containing protein-1 (CDCP1), a type 1 transmembrane protein, in EGFR mutant NSCLC patients at the time of diagnosis. AXL and CDCP1 mRNA levels are indicative of the clinical outcomes to EGFR tyrosine kinase inhibitors, negatively influencing the progression free survival and overall survival. In addition, the study highlights that non-receptor tyrosine kinases, mainly SRC family kinases, such as, SRC, YES and LYN, as well as focal adhesion kinase (FAK), are also often overexpressed in EGFR mutant lung cancer cells. Single therapy of EGFR mutant cell lines, either with gefitinib, or the third generation osimertinib, induces the activation or expression of STAT3, SRC, FAK and YES-associated protein 1 (YAP1), as well as AXL, CDCP1 and MET. The genetic or pharmacological inhibition of SRC, YES and LYN leads to downregulation of FAK, YAP1, AXL, CDCP1 and MET. The combination of gefitinib or osimertinib with dasatinib or TPX-0005 (a Src/FAK/Janus kinase 2 (JAK2) inhibitor) leads to a strong growth inhibitory effect in EGFR mutant cell lines. We explore the role of TPX-0005 as a unique compound that inhibits SRC, FAK and STAT3. An important aspect of the research is that both gefitinib and osimertinib have nefarious effects in EGFR mutant lung cancer cells through the activation of the above mentioned signaling elements and pathways and they do not aid in the ablation of cell migration.

  • Targeting MET and enrolment biomarkers in several subclasses of NSCLC

In this project, we are exploring the prevalence of MET exon 14 and MET exon 7-8 splicing mutations by testing advanced and early stage NSCLC tissue samples with reverse transcriptase-PCR, immunohistochemistry, fluorescence in situ hybridization and gene copy number. In addition we try to reproduce in lung cancer the data reporting that chemotherapy induces invasion and metastasis in breast cancer that overexpress the invasive form of the actin-regulatory protein Mammalian-enabled (MENAinv) and toll-like receptor 4 (TLR4). In our project we will screen our panel of lung cancer cell lines for the expression of MENAinv and TLR4. Cell culture wound closure assay and transwell cell migration and invasion assay will be applied after the treatment of representative lung cancer cell lines with chemotherapy (mainly paclitaxel, but other drugs commonly used in the adjuvant setting will be tested, like cisplatin, vinorelbine and pemetrexed). Then we will explore whether the addition of a MET tyrosine kinase inhibitor (TKI) can increase the efficacy of chemotherapy alone and reverse the chemotherapy-induced cell migration and invasion. In early stage NSCLC tumor specimens, MENAinv and TLR4 expression will be reported. In our MET-addicted cell lines (MET amplified and MET mutated), we will evaluate already described mechanisms of resistance before any treatment: PIM1 activation, RTKs expression, the role of SFKs and STAT3, CDCP1 and SHP2 (tyrosine phosphatase) expression, and the cells will be classified accordingly. The combination of MET TKIs with PIM inhibitors, Src inhibitors (dasatinib, pterostilbene) as well as the Src/FAK/JAK2 inhibitor TPX0005, will be tested in vitro. In order to understand mechanisms of acquired resistance to MET TKIs (class I and II) we will develop MET TKI resistant cell lines (from one MET amplified, one with MET exon 14 and the MET exon 7-8). Next generation sequencing will be subsequently applied for a comprehensive genomic profiling of the resistance. Based on the results, treatment strategies will be designed and tested in vitro.

Selected publications

  • Chaib I, Karachaliou N, Pilotto S, Codony Servat J, Cai X, Li X, Drozdowskyj A, Servat CC, Yang J, Hu C, Cardona AF, Vivanco GL, Vergnenegre A, Sanchez JM, Provencio M, Reguart N, Zhou C, Cao P, Ma PC, Bivona TG, Rosell R. Co-activation of STAT3 and YES-Associated Protein 1 (YAP1) Pathway in EGFR-Mutant NSCLC. J Natl Cancer Inst 2017 Sep 1;109(9)
  • Codony-Servat C, Codony-Servat J, Karachaliou N, Molina MA, Chaib I, Ramirez JL, de Los Llanos Gil M, Solca F, Bivona TG, Rosell R. Activation of signal transducer and activator of transcription 3 (STAT3) signaling in EGFR mutant non-small-cell lung cancer (NSCLC). Oncotarget 2017; 8:47305-47316
  • Best MG, Sol N, In 't Veld S, Vancura A, Muller M, Niemeijer AN, Fejes AV, Tjon Kon Fat LA, Huis In 't Veld AE, Leurs C, Le Large TY, Meijer LL, Kooi IE, Rustenburg F, Schellen P, Verschueren H, Post E, Wedekind LE, Bracht J, Esenkbrink M, Wils L, Favaro F, Schoonhoven JD, Tannous J, Meijers-Heijboer H, Kazemier G, Giovannetti E, Reijneveld JC, Idema S, Killestein J, Heger M, de Jager SC, Urbanus RT, Hoefer IE, Pasterkamp G, Mannhalter C, Gomez-Arroyo J, Bogaard HJ, Noske DP, Vandertop WP, van den Broek D, Ylstra B, Nilsson RJA, Wesseling P, Karachaliou N, Rosell R, Lee-Lewandrowski E, Lewandrowski KB, Tannous BA, de Langen AJ, Smit EF, van den Heuvel MM, Wurdinger T. Swarm Intelligence-Enhanced Detection of Non-Small-Cell Lung Cancer Using Tumor- Educated Platelets. Cancer Cell 2017; 32(2): 238-52 e9.
  • Karachaliou N, Gonzalez Cao M, Crespo G, Drozdowskyj A, Aldeguer E, Gimenez-Capitan A, Teixido C, Molina-Vila MA, Viteri S, De Los Llanos Gil M, Martin Algarra S, Perez-Ruiz E, Marquez-Rodas I, Rodriguez-Abreu D, Blanco R, T Puertolas T, Angeles Royo M and Rosell R. Interferon gamma, an important marker of response to immune checkpoint blockade in non-small cell lung cancer and melanoma patients. Ther Adv Med Oncol, in press.
  • ​Rosell R, Dafni U, Felip E, Curioni-Fontecedro A, Gautschi O, Peters S, Massuti B, Palmero R, Aix SP, Carcereny E, Fruh M, Pless M, Popat S, Kotsakis A, Cuffe S, Bidoli P, Favaretto A, Froesch P, Reguart N, Puente J, Coate L, Barlesi F, Rauch D, Thomas M, Camps C, Gomez-Codina J, Majem M, Porta R, Shah R, Hanrahan E, Kammler R, Ruepp B, Rabaglio M, Kassapian M, Karachaliou N, Tam R, Shames DS, Molina-Vila MA, Stahel RA. Erlotinib and bevacizumab in patients with advanced non-small-cell lung cancer and activating EGFR mutations (BELIEF): an international, multicentre, single-arm, phase 2 trial. Lancet Respir Med 2017 May; 5(5):435-444.
  • Wu YL, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S, Tsuji F, Linke R, Rosell R, Corral J, Migliorino MR, Pluzanski A, Sbar EI, Wang T, White JL, Nadanaciva S, Sandin R, Mok TS. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation- positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol. 2017 Nov;18(11):1454-1466.
  • Peters S, Camidge DR, Shaw AT, Gadgeel S, Ahn JS, Kim DW, Ou SI, Perol M, Dziadziuszko R, Rosell R, Zeaiter A, Mitry E, Golding S, Balas B, Noe J, Morcos PN, Mok T. Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2017; 377(9): 829-38.

Research projects

ONGOING PROJECTS

European Liquid Biopsies Academy - Towards widespread clinical application of blood- based diagnostic tools (ELBA)
Project Leader: Rafael Rosell
Code: H2020-MSCA-ITN-2017 Proposal Number 765492 Start Date: 01/01/2018
End Date: 31/12/2020

Exploring the potential oncogenic role of the p21-activated kinase 1 (PAK1): A novel approach for personalized therapy in non-small cell lung cancer
Project Leader: Rafael Rosell, Young Investigator: Masaoki Ito Code: IASLC Fellowship and Young Investigator Awards
Start Date: 01/07/2017
End Date: 30/06/2018

Biomarkers and combinatorial drug targets for a personalised therapy for three major cancers (RESPONSE)
Group Leader for Lung Cancer: Rafael Rosell Code: PIE16/00011
Start Date: 01/01/2017
End Date: 31/12/2019

PREVIOUS PROJECTS

Targeting STAT3 to overcome early or intrinsic resistance to EGFR TKIs; multidisciplinary research project in clinical tumor samples, in vitro and in vivo models
Project Leader: Rafael Rosell
Code: La Caixa Foundation" Obra Social La Caixa
Start Date: 01/01/2015 End Date: 31/12/2017

Nuevas oportunidades terapéuticas para el Cáncer de pulmón escamoso
Project Leader: Rafael Rosell Code: Fis 14/1678
Start Date: 01/01/2014
End Date: 31/12/2017

Targeting STAT3 to overcome early or intrinsic resistance to EGFR TKIs; multidisciplinary research project in clinical tumor samples, in vitro and in vivo models
Project Leader: Rafael Rosell
Code: VAT-ID-No.: DE 811138149, Boehringer Ingelheim International GmbH Start Date: 01/01/2015
End Date: 01/01/2017

Estudio de mutaciones de EGFR en pacientes con cáncer de Pulmón
Project Leader: Rafael Rosell
Code: La Caixa Foundation" Obra Social La Caixa Start Date: 01/01/2011
End Date: 31/12/2014