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Project
Overcoming drug resistance in multiple myeloma: a study of intrinsic and extrinsic mechanisms. (FWOTM619)
Multiple myeloma (MM) is a hematological cancer affecting around 25000 new patients in the EU. The introduction of new therapies including novel agents such as proteasome inhibitors and immunomodulatory drugs has led to a significantly improved survival rate.
However, relapse of the disease, as the result of the emergence of drug-resistant myeloma subclones remains the main obstacle on the road to cure. Bortezomib is part of the standard regimens in newly diagnosed as well as more advanced myeloma patients. Hence, mechanisms of resistance to bortezomib are very relevant to the field. Resistance can either be explained by the presence of a drug resistant population or by the acquisition of additional genetic lesions during its progression to more aggressive states. Alternatively, or additionally, the microenvironment might govern protection.
This project aims to study mechanisms of resistance to bortezomib. In a first part (work package 1), gene expression analysis will be performed using established MM cell lines with variable levels of bortezomib sensitivity after exposure to a large panel of known myeloma-active drugs. Studies on cross-resistance as well as synergy between drugs will be included. Relevant findings will also be tested in the defined CD138 negative MM subpopulation that has been proposed to have stem cell like properties and is known to be more resistant to therapy. In addition, in vivo assays will be performed with the combination therapy in an established in vivo model. The effects of cell adhesion in the induction of bortezomib resistance will be studied using in-vitro and in-vivo experiments in the 5T33MM mouse model (work package 2). Several new inhibitors of cell-cell adhesion will be assessed through their effect on several apoptosis and cell cycle pathways. The studies
in this project may offer clues to new targets to overcome bortezomib resistance.
However, relapse of the disease, as the result of the emergence of drug-resistant myeloma subclones remains the main obstacle on the road to cure. Bortezomib is part of the standard regimens in newly diagnosed as well as more advanced myeloma patients. Hence, mechanisms of resistance to bortezomib are very relevant to the field. Resistance can either be explained by the presence of a drug resistant population or by the acquisition of additional genetic lesions during its progression to more aggressive states. Alternatively, or additionally, the microenvironment might govern protection.
This project aims to study mechanisms of resistance to bortezomib. In a first part (work package 1), gene expression analysis will be performed using established MM cell lines with variable levels of bortezomib sensitivity after exposure to a large panel of known myeloma-active drugs. Studies on cross-resistance as well as synergy between drugs will be included. Relevant findings will also be tested in the defined CD138 negative MM subpopulation that has been proposed to have stem cell like properties and is known to be more resistant to therapy. In addition, in vivo assays will be performed with the combination therapy in an established in vivo model. The effects of cell adhesion in the induction of bortezomib resistance will be studied using in-vitro and in-vivo experiments in the 5T33MM mouse model (work package 2). Several new inhibitors of cell-cell adhesion will be assessed through their effect on several apoptosis and cell cycle pathways. The studies
in this project may offer clues to new targets to overcome bortezomib resistance.
Date:1 Oct 2012 → 30 Sep 2016
Keywords:Blood, Stem Cell, Coagulation, Myeloma, Immunology, Microbiology, HLA, Hematology, Lymphoma, cancer, Bone Marrow Transplantation
Disciplines:Immunology, Oncology, Hematology, Microbiology