Potential New Drugs in Lymphoma

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Potential New Drugs in Lymphoma

Delforoush, Maryam, 1980- (author): Uppsala universitet,Institutionen för immunologi, genetik och patologi,Gunilla Enblad

Enblad, Gunilla, Professor (thesis advisor): Uppsala universitet,Institutionen för immunologi, genetik och patologi

Berglund, Mattias (thesis advisor): Uppsala universitet,Institutionen för immunologi, genetik och patologi

Drott, Christina, Docent (opponent): Division of Hematology and Transfusion Medicine, Faculty of Medicine, Department of Laboratory Medicine, Lund

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ISBN 9789155495244
Uppsala : Acta Universitatis Upsaliensis, 2016
English 60 s.
Series: Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 1651-6206 ; 1200

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Doctoral thesis (other academic/artistic)

Abstract Subject headings

Lymphomas are malignant tumours arising from cells in the lymphatic system. They are classified as B-cell lymphomas, T-cell lymphomas and Hodgkin lymphoma (HL). Of the B-cell lymphomas, one of the most common is diffuse large B-cell lymphoma (DLBCL). Many patients with lymphomas can be successfully treated however patients who relapse or are refractory have a poor prognosis, warranting further investigations to identify potential targets and develop novel drugs.Picropodophyllin (PPP), a potent and selective inhibitor of IGF-1R, inhibits malignant cell growth with low or no toxicity on normal cells in preclinical models. In paper I, we investigated the potential benefits of using PPP against DLBCL and found that the anti-tumor effects of PPP might possibly be explained by IGF-1R-unrelated mechanism(s). However, the inhibitory effects of PPP on lymphoma cells together with its low toxicity in vivo makes it a promising drug candidate for treatment. Melflufen, a derivative of melphalan, is currently being evaluated in a clinical phase I/II trial in relapsed or refractory multiple myeloma. In paper II, we confirmed previous reports of superior potency of melflufen over melphalan. Being active in cell lines and primary cultures of lymphoma cells as well as in a xenograft model in mice, melflufen considered being a candidate for further evaluation in treatment. bAP-15, a novel inhibitor of proteasome activity, inhibits ubiquitin specific peptidase 14 (USP14) and ubiquitin carboxyl-terminal hydrolase L5 (UCHL5). In paper III, we investigated the activity of b-AP15 in DLBCL and HL cell lines and compared the results to standard drugs used in treatment. Results showed inhibition of the proteasome and growth inhibition/cytotoxicity with IC50-values in the micromolar range. Treatment failure and lack of clinical benefit of proteasome inhibitors like bortezomib in DLBCL patients inspired us investigating for possible new targets, with major focus on proteasome inhibitors in DLBCL. In paper IV, we suggested that UCHL5 and/or USP14, as new targets for proteasome inhibitors in DLBCL, be further evaluated.The findings in this thesis suggest that PPP, Melflufen and b-AP15 are potential candidates for clinical drug development and UCHL5 and/or USP14 are new potential targets for proteasome inhibitors in DLBCL.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

Keyword

lymphoma
diffuse large B-cell lymphoma
DLBCL
picropodophyllin
PPP
J1
melflufen
prodrug
cancer therapeutics
alkylating agents
b-AP15
proteasome inhibitors
DUB inhibition
UCHL5
USP14

Publication and Content Type

vet (subject category)
dok (subject category)

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