De Angelis, Biagio (2013) SYNERGY BETWEEN JAK INHIBITOR RUXOLITINIB AND TYROSINE KINASE INHIBITORS TO OVERCOME DRUG RESISTANCE RELATED TO BONE MARROW STROMA MICROENVIRONMENT IN CHRONIC MYELOID LEUKEMIA. [Tesi di dottorato]

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Item Type: Tesi di dottorato
Lingua: English
Title: SYNERGY BETWEEN JAK INHIBITOR RUXOLITINIB AND TYROSINE KINASE INHIBITORS TO OVERCOME DRUG RESISTANCE RELATED TO BONE MARROW STROMA MICROENVIRONMENT IN CHRONIC MYELOID LEUKEMIA
Creators:
CreatorsEmail
De Angelis, Biagiodeangelis@ceinge.unina.it
Date: 14 March 2013
Number of Pages: 181
Institution: Università degli Studi di Napoli Federico II
Department: Scienze Chimiche
Scuola di dottorato: Biotecnologie
Dottorato: Scienze biotecnologiche
Ciclo di dottorato: 25
Coordinatore del Corso di dottorato:
nomeemail
Sannia, GiovanniSANNIA@UNINA.IT
Tutor:
nomeemail
Pane, FabrizioFABPANE@UNINA.IT
Date: 14 March 2013
Number of Pages: 181
Uncontrolled Keywords: CML;tyrosine kinase inhibitors;stromal microenvironment;JAK inhibitor;
Settori scientifico-disciplinari del MIUR: Area 05 - Scienze biologiche > BIO/12 - Biochimica clinica e biologia molecolare clinica
Area 06 - Scienze mediche > MED/15 - Malattie del sangue
Aree tematiche (7° programma Quadro): SALUTE e TUTELA DEL CONSUMATORE > Biotecnologie, strumenti e tecnologie generiche per la salute umana
Date Deposited: 03 Apr 2013 14:37
Last Modified: 14 Oct 2014 10:00
URI: http://www.fedoa.unina.it/id/eprint/9164

Abstract

Inhibition of the constitutively active kinase BCR-ABL1 with tyrosine kinase inhibitors(TKIs) contributed to a remarkable progress in the treatment of Chronic myeloid leukemia (CML) and Philadelphia chromosome positive (Ph+) Acute Lymphoblastic Leukemia (ALL) with 87% of complete cytogenetic response at 5 years among CML patients receiving the TKI Imatinib. Nevertheless, although the comprehension of the molecular mechanisms of neoplastic transformation in Ph+ cells has greatly improved in the TKI era, less clear are the mechanisms that underlie the variable degree of response to TKI treatment in patients with chronic phase (CP) CML versus patients with advanced phase CML or Ph+ ALL. The importance of tumor microenvironment for cancer progression and drug resistance is becoming widely recognized in recent years. Interaction of cancer cells with their stromal microenvironment overcoming the physiological barrier function of stromal cells synergizes growth, angiogenesis and initiation of an invasive and metastatic phenotype of the cancer cell. Bone Marrow(BM) is loosely composed of hematopoietic cells set within a milieu surrounded by a mesenchymal landscape. There have been various attempts to define bone microenvironments that nurture and determine stem cell fate. Two such stem cell ‘niches’ are well described: the vascular and the endosteal niche. The BM is a dynamic microenvironment with high concentration of growth factors and cytokines regulating haematopoiesis, enhancing leukemia blast survival and modulating their resistant to treatment. Thus, here I demonstrated that the half maximal inhibitory concentration (IC50) of three clinical relevant TKIs (Imatinib, Nilotinib and Dasatinib) is significantly increased when Ph+ cell lines are treated in the presence of soluble factors produced by BM mesenchymal stroma cells (stroma conditioned media or SCM). In addition, I observed that the higher cell viability, noticed in Ph+ cell lines cells treated with TKI in the presence of SCM respect to control cell culture condition (RM), is not related to cytokine cell cycle regulation but to a significant reduction in apoptosis induction. Moreover, the observed TKI resistance is associated to a BCR-ABL independent STAT-3 activation leading to a significant down-modulation of apoptosis when either Ph+ cell line or primary CD34+ progenitor cells derived from patients with CML are treated with TKIs in the presence of a direct mesenchymal stroma cell interaction or exposition to SCM. Finally, I proved that JAK inhibitor Ruxolitinib, that inhibits STAT3 phosphorylation (a marker of JAK activity), synergizes with TKIs in the induction of apoptosis in CML primary cells. Indeed, compared with single agent treatment, exposure of CML cells to the combination of TKI and JAK inhibitor Ruxolitinib significantly decreased viability of CML cells and increased their apoptosis in vitro. Taken together, our data show that the rational drug combination of TKI and Ruxolitinib may enhance the eradication of primary human Ph+ cells homed in BM stroma niche.

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