2024-03-29T05:05:45Zhttps://www.tdx.cat/oai/requestoai:www.tdx.cat:10803/5659372018-06-20T01:00:29Zcom_10803_1col_10803_31832
nam a 5i 4500
Oncologia
Oncología
Oncology
Hematologia
Hematología
Hematology
Limfomes
Linfomas
Lymphomas
Resistència als medicaments
Resistencia a los medicamentos
Drug resistance
Apoptosi
Apoptosis
Innovative targeted therapies for chemorefractory B-cell non-Hodgkin lymphomas
[Barcelona] :
Universitat de Barcelona,
2018
Accés lliure
http://hdl.handle.net/10803/565937
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Esteve Arenys, Anna,
autor
1 recurs en línia (223 pàgines)
Tesi
Doctorat
Universitat de Barcelona. Facultat de Medicina
2017
Universitat de Barcelona. Facultat de Medicina
Tesis i dissertacions electròniques
Roué, Gaël,
supervisor acadèmic
Campo Güerri, Elias,
supervisor acadèmic
TDX
Lymphomas are a heterogeneous group of tumors characterized by the proliferation of lymphocytes predominantly in lymphoid structures but also in extranodal tissues. More than 90% of patients are afflicted by lymphomas of B-cell origin.
The current World Health Organization (WHO) classification of hematopoietic and lymphoid tumors categorizes B-cell neoplasms in more than 40 distinct disease entities, according to a combination of the morphology, immunophenotype, genetic, molecular and clinical features. Each entity has its own clinical course and requires specific treatments.
The characterization of activated signaling pathways involved in survival and proliferation, together with the development of a wide pharmacological armamentarium against cancer, have facilitated the bench-to-bedside translation of new targeted therapies in B-cell non-Hodgkin lymphomas (B-NHL). These novel therapies include two of the most relevant drugs lately approved: the anti-apoptotic agent venetoclax and the BTK inhibitor ibrutinib.
One major hurdle to their successful application is the rise of drug resistance. Resistance to therapy is observed in many cases of B-cell malignancies. This phenomenon significantly limits the utility of the current therapeutic strategies, and remains a substantial challenge for the clinical management of patients with advanced cancers. Resistance comes in two flavors: intrinsic resistance (also known as innate or de novo resistance) and acquired resistance, resulting from the clonal evolution of resistant variants.
With this concept in mind, in this thesis we have explored new approaches to overcome the development of drug resistance.
Venetoclax (ABT-199) is a first-in-class BH3 mimetic, FDA-approved for use in patients with R/R del17p chronic lymphocytic leukemia. In the clinical setting, it has demonstrated high response rates and good toxicity profiles in other subtypes of relapsed/refractory non-Hodgkin lymphoma.
We proposed a model of double hit lymphoma (DHL) resistance to ABT-199 in which the capacity of CPI203 to regulate the transcriptome of the cells could help to circumvent this problem. In ABT-199 sensitive cells, the BH3 mimetic acts by displacing BIM from BCL-2 complexes, allowing the de-repression and/or direct activation of BAX and leading to an activation of mitochondrial outer membrane permeabilization. In DHL cells, a compensatory upregulation of BFL-1 would bind and inactivate the pool of BIM proteins released from BCL-2 by ABT-199, avoiding MOMP and preserving cell survival. CPI203 primes cells to death by decreasing BFL-1 and
increasing BIM protein levels, and its combination with ABT-199 allows to tip the balance between pro- and anti-apoptotic signaling toward induction of cell death. This concept provides a new insight in the proposed mechanisms of resistance to BH3- mimetics in NHL cell lines, where MCL-1 and BCL-XL have been proposed as the major determinants of drug sensitivity and acquired resistance.
On the other hand, ibrutinib is a BTK inhibitor approved for first-line therapy in patients with chronic lymphocytic leukemia, as well as for the treatment of some relapsed/refractory B-NHL. Despite its high level of clinical activity, acquiring of mutations or re-wiring of the BCR pathway to retain the downstream signaling appears to be a common mechanism of resistance.
The inhibition of more than one BCR kinase might be useful in B-NHL cases that are resistant to the sole inhibition of BTK. We describe the compound IQS019 as a new BCR kinase inhibitor able to counteract both constitutive and ligand-dependent activation of the BCR pathway. Its capacity to inhibit the three upstream BCR kinases, BTK, SYK and LYN, confer an advantage over the inhibition of BTK alone by ibrutinib, in in vitro and in vivo models of B-NHL, being of special importance for the treatment of those patients with non-canonical NF-κB activation, who are low responders to ibrutinib.
Therefore, the development of innovative therapeutic approaches that permit to overcome drug resistance opens a window to important therapeutic advances in the treatment of B-NHL.
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