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  • The role of proteasome, immunoproteasome and autophagy in the therapy of chronic lymphocytic leukemia = Vloga proteasoma, imunoproteasoma in avtofagije v terapiji kronične limfocitne levkemije : doctoral dissertation
    Avsec, Damjan, farmacevt, 1993-
    Chronic lymphocytic leukemia (CLL) is a disease of accumulating malignant mature-appearing monoclonal B-lymphocytes in blood, bone marrow, and lymphatic tissues. The incidence of CLL in Slovenia is ... among the Europe’s highest, and with current demographic changes the burden of the disease is expected to increase in the future. In the last decade, a series of small, targeted molecules made it from bench-to-bedside in CLL. Despite the remarkable clinical success of BCR pathway inhibitors (ibrutinib, acalabrutinib, idelalisib, and duvelisib) and Bcl-2 antagonist (venetoclax), we are now faced with concerning drawbacks of these therapies, including high rates of discontinuation, severe adverse events, and the inevitable emergence of resistance. The primary purpose of our work was to address the unmet clinical need to improve the treatment of patients with CLL by delineating the role of proteasome (cP), immunoproteasome (iP), and autophagy in the therapy of CLL. We discovered that different cP/iP inhibitors suppress the prosurvival NF?B signaling and trigger apoptotic cell death independently of genetic background also in hard-to-treat patient-derived CLL cells carrying prognostically unfavorable del(11q), del(17p) and unmutated IGHV. These inhibitors (n=11) are selectively cytotoxic toward malignant CLL cells in low nanomolar concentrations, with cP inhibitor carfilzomib (EC50, 48h 2 nM) and iP inhibitor ONX-0914 (EC50, 48h 10 nM) being investigated in detail. They synergized with targeted therapies by perturbing the prosurvival BCR and NF?B pathways, thus culminating in a synergistic promotion of apoptosis. Moreover, they demonstrated a remarkable resistance-overcoming activity in both de-novo established resistant CLL clones and ex-vivo identified targeted therapy insensitive patient-derived CLL cells. We identified the molecular background to venetoclax resistance in CLL, including IFN?-mediated cytoprotection and iP formation, along with altered apoptotic pathways (downregulation of Bak and Bax, increased p-Bcl-2). The use of ONX-0914 successfully tackled IFN?-mediated cytoprotection and eradicated resistance in venetoclax resistant CLL clone. Delineating the role of autophagy in CLL, we found that targeted therapies activate autophagy via BTK/Akt, AMPK/ULK1/Beclin-1 and PI3K/Akt pathways. Block on autophagy at AMPK (dorsomorphin, EC50, 48h 4.6 µM), ULK1/2 (MRT68921, EC50, 48h 2.1 µM), VPS34 (VPS34-IN1, EC50, 48h 7.9 µM), and autolysosome formation (chloroquine, EC50, 48h 13.6 µM) induced apoptosis independently of the genetic background in hard-to-treat CLL cells carrying prognostically unfavorable del(11q), del(17p), and unmutated IGHV. Activation of autophagy was not cytotoxic to CLL cells, thus establishing that autophagy has a prosurvival role in CLL. De-novo established targeted therapy resistant CLL clones overexpressed several autophagic proteins. Autophagy inhibitors overcame this resistance and synergized with targeted therapies against hard-to-treat CLL cells. Several autophagy proteins were overexpressed in CLL cells compared to healthy controls, which defined the selective cytotoxicity of autophagy inhibitors against CLL cells. The levels of p62/SQSTM1 were higher in patients with unmutated IGHV, thus linking the p62/SQSTM1 to an adverse prognosis. In conclusion, we elucidated the role of cP, iP, and autophagy in the therapy of CLL and put forth a solid rationale to consider the use of cP, iP, and autophagy inhibitors for the treatment of relapsed/refractory patients with CLL.
    Type of material - dissertation ; adult, serious
    Publication and manufacture - Ljubljana : [D. Avsec], 2023
    Language - english, slovenian
    COBISS.SI-ID - 167069187

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Faculty of Pharmacy, Ljubljana Ljubljana FFALJ reading room 1 cop.
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