Therapeutic targets and cell death regulation in lymphoid malignancies
- Principle investigator:
- Dolors Colomer
- Contact details:
Our objective is to unveil new targets for the treatment of B lymphoid malignancies, mediated by new drug development, drug reprofiling (seek new indications for already-known drugs) and optimization of the treatment of each individual patient. The application of systems biology approaches will permit a comprehensive evaluation of underlying predisposition to disease, disease diagnosis and progression. The idea is to find the most effective points and information routes that we need to block in order to interfere with the pathological function of the system, thus allowing both drug-reprofiling and proposal of novel drugs.
Typical cell and molecular biology techniques will be performed using cryopreserved primary cells, human cell lines and mouse models.
The publications that support the research made are:
- 1: López-Guerra M, et al. Sorafenib targets BCR kinases and blocks migratory and microenvironmental survival signals in CLL cells. Leukemia. 2011 Dec 20.
- 2: Xargay-Torrent S, et al. Vorinostat-induced apoptosis in mantle cell lymphoma is mediated by acetylation of proapoptotic BH3-only gene promoters. Clin Cancer Res. 2011;17(12):3956-68.
- 3: Roué G, et al. The Hsp90 inhibitor IPI-504 overcomes bortezomib resistance in mantle cell lymphoma in vitro and in vivo by down-regulation of the prosurvival ER chaperone BiP/Grp78. Blood. 2011;117(4):1270-9.
- 4: Alonso R, et al. Forodesine has high antitumor activity in chronic lymphocytic leukemia and activates p53-independent mitochondrial apoptosis by induction of p73 and BIM. Blood. 2009;114(8):1563-75.
- 5: López-Guerra M, et al. p65 activity and ZAP-70 status predict the sensitivity of chronic lymphocytic leukemia cells to the selective IkappaB kinase inhibitor BMS-345541. Clin Cancer Res. 2009;15(8):2767-76.
- 6: Roué G, et al. Bendamustine is effective in p53-deficient B-cell neoplasms and requires oxidative stress and caspase-independent signaling. Clin Cancer Res.2008;14(21):6907-15.
- 7: López-Guerra M, et al. Identification of TIGAR in the equilibrative nucleoside transporter 2-mediated response to fludarabine in chronic lymphocytic leukemia cells. Haematologica. 2008;93(12):1843-51.
- 8: Pérez-Galán P, et al. BCL-2 phosphorylation modulates sensitivity to the BH3 mimetic GX15-070 (Obatoclax) and reduces its synergistic interaction with bortezomib in chronic lymphocytic leukemia cells. Leukemia. 2008;22(9):1712-20.
- 9: Roué G, et al. Selective inhibition of IkappaB kinase sensitizes mantle cell lymphoma B cells to TRAIL by decreasing cellular FLIP level. J Immunol. 2007;178(3):1923-30.
- 10: Pérez-Galán P, et al. The BH3-mimetic GX15-070 synergizes with bortezomib in mantle cell lymphoma by enhancing Noxa-mediated activation of Bak. Blood. 2007;109(10):4441-9.
- 11: Marcé S, et al. Expression of human equilibrative nucleoside transporter 1 (hENT1) and its correlation with gemcitabine uptake and cytotoxicity in mantle cell lymphoma. Haematologica. ;91(7):895-902.
- 12: Marcé S, et al. Lack of methylthioadenosine phosphorylase expression in mantle cell lymphoma is associated with shorter survival: implications for a potential targeted therapy. Clin Cancer Res. 2006;12(12):3754-61.
- 13. Pérez-Galán P, et al. The proteasome inhibitor bortezomib induces apoptosis in mantle-cell lymphoma through generation of ROS and Noxa activation independent of p53 status. Blood. 2006;107(1):257-64.
The program is a continuation of work published in the last years which has provided the identification of new therapies and their mechanism of action for the treatment of B lymphoid malignancies.
The research group aims the translation bench-to-beside to the clinic and to make personalized therapy a reality in the clinical practice, based on the optimization of treatment for each patient, improving the benefits and avoiding the negative side effects.
Drug targets, leukemia/lymphoma, targeted therapy, personalized medicine
Our project is based on a translational approach including the use of cell lines, primary cells from patients and mouse models. The information obtained with these studies will set the rational basis to develop phase I and II clinical trials. These studies will also facilitate the design of more individualized therapies according to the biological characteristic of the tumor. Our goal is to publish our results in the highest impact journals of hematology and oncology journals.
The candidate should have ability to develop ideas logically and design experiments to test hypotheses, ability to modify and apply new methods to advance a project, and to analyze and write up data for presentations and publications. The candidate should have experience in multi-disciplinary working and clear interest in working as part of the team. All the members of the team will collaborate in this research project, although it is important to have ability to work independently and to use own initiative when required.
Team strategic objective in IDIBAPS
The hematology-oncology area performs basic, experimental and clinical research tasks in the fields of oncology and hematology. One of the objectives of the group “Physiopathology and molecular bases in hematology” is the analysis of the molecular bases of apoptosis regulation induced by drugs in lymphoid neoplasms and the evaluation of new strategies for the treatment of these disorders.
The large number of national and international collaborations produced in this area, together with the many original articles generated, show that oncology and hematology are topics of current interest in the biomedical sector(Read eligibility criteria)