Targeted Therapy in Chronic Lymphocytic Leukemia: Past, Present, and Future

Abstract

Background Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia in the western world. Recent advances in understanding the biology of B-cell malignancies resulted in the development of novel agents targeting key pro-survival pathways in the neoplastic B-cell. Objective The goal of this article was to summarize current literature on the emerging therapeutic approaches in CLL and B-cell malignancies. Methods A literature review was performed, identifying pathways and key clinical trials involving novel therapies in CLL with special emphasis on B-cell receptor targeting agents. Results Understanding the biology of B-cell receptor signaling pathway led to identification of novel molecular targets. Most notably, inhibitors of Bruton tyrosine kinase and phosphatidylinositide 3-kinase-δ have entered clinical trials and demonstrated high response rates in CLL, including high-risk disease. Cyclin-dependent kinase inhibitors may evolve into an alternative therapeutic approach in CLL. New drugs which target molecules within and outside of the B-cell receptor signaling pathway show promise in pre-clinical studies. Conclusions Both pre-clinical and early clinical trial results involving novel targeted therapies suggest that the standard treatment paradigm in CLL and B-cell malignancies will soon change. Particular attention should be paid to the BCR-targeting agents, whose favorable side effect profile may improve lives of the elderly patients with CLL.

Continuous signaling of CD 79b and CD 19 is required for the fitness of Burkitt lymphoma B cells

“…With our Fab‐PLA technique, we found that these receptors not only have an open conformation, but are also in close proximity to the CD19 protein, thus combining PI3K signaling with active ITAM signaling (unpublished observation). In line with this, the growth of B‐CLL cells is blocked by Syk or PI3K inhibitors (Gobessi et al , 2009; Danilov, 2013). The BCR is also stably expressed on all ABC‐DLBCLs, although the growth of these tumors is driven more by active NFkB than by PI3K signaling (Davis et al , 2010).…”

Pro‐survival signal inhibition by CDK inhibitor dinaciclib in Chronic Lymphocytic Leukaemia

“…In order to better understand the sensitivity of CLL cells to CDK inhibitor dinaciclib, we compared its effects on the viability of MEC-1, an EVB-positive B-cell line derived from a patient with CLL that is often used as a model for 8 this disease (Stacchini, et al 1999), to that of different targeted inhibitors of pro-survival pathways often activated in leukaemia. We selected other drugs that have been studied in the context of leukaemia, such as MG-132 (a proteasome inhibitor (Guo and Peng 2013)), ibrutinib (a BTK inhibitor , Danilov 2013), vemurafenib (a V600E BRAF inhibitor (Samuel, et al 2014)), ver155008 (a HSP70 inhibitor (Reikvam, et al 2013)), BX-912 (a PDK1 inhibitor targeting PI3K/Akt pathway (Feldman, et al 2005)) and fedratinib (a Jak/STAT pathway inhibitor (Pardanani, et al 2007)). As shown in Figure 1A, dinaciclib demonstrated more than 100-fold greater inhibitory effects on the metabolic activity of MEC-1 than any of the other drugs tested, confirming its potential as a therapeutic approach for CLL and consistent with recent results that showed the strong cytotoxic effects of CDK inhibitors in CLL (Johnson, et al 2012, Paiva, et al 2015, Sylvan, et al 2016.…”

Synthesis, Characterization and Antimicrobial Activity of New 2-Phenylquinoline-4(3H)-one Derivatives

“…A SHMADZU-FT-IR-8400 spectrometer was used to record the Infrared spectra atyrhe miss KBr disc. All 1 H, 13 C-NMR spectra measurement were made at Al-Albayt University, Jordan and Cairo University, Egypt on a Bruker 300 MHz and Avance III HD spectrometers using DMSO-d 6 a solvent and TMS as internal reference. The progress of the reaction was monitored by TLC using aluminum silica gel plates.…”

“…Quinazolines and its derivatives represent one of the most active classes of compounds. Medically it has been exhibited various activites as antibacterial 1,2 ,cytotoxic 3 , analgesic , anti-inflammatory 4 , anticonvusant 5 ,antitubercular 6,7 , anticancer 8 , and antioxidant 9 , anti-HIV 10 ,antitumour 11 ,and antimicrobial 12 .Quinazolinones derivatives were exhibit substantial in treating of leukemia than the common drugs 13 . Recent studies demonstrated the significant effect of quinazolinones derivatives via breast cancer in vitro study [14][15][16] .…”