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Title: Effect of immunomodulatory agents on critical pathways in chronic lymphocytic leukaemia
Author: Mondru, Anil Kumar
ISNI:       0000 0004 7428 638X
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2018
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Despite recent advances in the therapy of Chronic lymphocytic leukaemia (CLL) the disease remains incurable and relapse remains the norm. There remains a clear need to develop novel therapeutic drugs and regimens to improve responses to frontline treatments. In recent years, immunomodulatory agents (IMiDs) have shown promising therapeutic activity in CLL. Here we investigated and compared the effects of Lenalidomide and a structurally related novel analogue, CC-122, on the proliferation of B-CLL cell lines and primary CLL cells. Both drugs promote down regulation of critical transcriptional factors, and direct targets, Ikaros and Aiolos but do not induce apoptosis of either B-CLL cell lines or primary CLL cells. In the present study, we show, both drugs differentially inhibit proliferation and the induction of p21 in B-CLL cell lines and primary CLL cells. Unlike Multiple myeloma (MM) and Diffuse large B-cell lymphoma (DLBCL), both drugs did not induce apoptosis, however ratios of both anti and pro-apoptotic proteins may predict different drugs combinations with IMiDs. Furthermore, we confirm that the expression of proteins involved in the B cell receptor (BCR) signalling pathway, which is critical to CLL cell survival, are inhibited by Lenalidomide and CC-122 treatment. Interestingly, the expression of the p-ERK and its downstream target c-Myc was suppressed. This, in conjunction with an upregulation of p21 likely contributes to the inhibition of proliferation in primary CLL cells. To enhance the activity of these compounds, pre-treatment with epigenetic priming drugs was investigated. We show that sensitisation with 5-Azacytidine or Romidepsin followed by either Lenalidomide or CC-122 treatment leads to greater inhibition of proliferation than the single agent IMiD in all examined BCLL cell lines and primary CLL cells. Importantly, CC-122 has superior efficacy when compared to Lenalidomide in all aspects of its activity in CLL. Taken together, our results provide a new mechanistic understanding of the antiproliferative effects of Lenalidomide and CC-122 and suggest that combination with epigenetic drugs, may potentiate the therapeutic efficacy of IMiDs in the treatment of CLL.
Supervisor: Kalakonda, Nagesh ; Slupsky, Joseph ; Glenn, Mark Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral