Pharmacological modulation of CXCR4 cooperates with BET bromodomain inhibition in diffuse large B-cell lymphoma

Abstract

Constitutive activation of the chemokine receptor CXCR4 has been associated with tumor progression, invasion, and chemotherapy resistance in different cancer subtypes. Although the CXCR4 pathway has recently been suggested as an adverse prognostic marker in diffuse large B-cell lymphoma, its biological relevance in this disease remains underexplored. In a homogeneous cohort of 52 patient biopsies, an antibody-based cytokine array showed that tissue levels of CXCL12 correlated with high microvessel density and bone marrow involvement at diagnosis, supporting a role for CXCL12-CXCR4 axis in disease progression. We then identified the tetra-amine IQS-01.01RS as a potent inverse agonist of the receptor, preventing CXCL12-mediated chemotaxis and triggering apoptosis in a panel of 18 cell lines and primary cultures, with superior mobilizing properties in vivo than standard agent. IQS-01.01RS activity was associated with downregulation of p-AKT, p-ERK1/2 and destabilization of MYC, allowing to a synergistic interaction with the bromodomain and extra-terminal domain inhibitor, CPI203. In a xenotransplant model of diffuse large B-cell lymphoma, IQS-01.01RS/CPI203 combination decreased tumor burden through MYC and p-AKT downregulation, and enhanced apoptosis induction. Thus, our results point out an emerging role of CXCL12-CXCR4 in the pathogenesis of diffuse large B-cell lymphoma and support the simultaneous targeting of CXCR4 and bromodomain proteins as a promising, rationale-based strategy for this disease.

A CXCR4-targeted nanocarrier achieves highly selective tumor uptake in diffuse large B-cell lymphoma mouse models

“…IQS-01.01RS). 40 Our approach differs from these studies since it is not focused on inhibiting signaling downstream of the CXCR4 receptor, but, instead, in delivering high concentrations of potent therapeutic agents to specifically kill CXCR4 + lymphoma cells. The active delivery of the drugloaded nanocarriers only to CXCR4 + cells should increase the therapeutic index compared to low molecular weight CXCR4 inhibitors, which biodistribute to all tissues independently of their CXCR4 expression.…”

Pharmacological Targeting of BET Bromodomain Proteins in Acute Myeloid Leukemia and Malignant Lymphomas: From Molecular Characterization to Clinical Applications

“…These promising results led to the design and development of other BET inhibitors structurally related to JQ1. Among them, CPI203 showed an improved bioavailability when compared to its precursor [64,65] together with a remarkable antitumoral activity in different preclinical models of B-cell non-Hodgkin lymphomas (B-NHLs), including MCL [66], DLBCL [67,68], MM [69], and MYC+/BCL2+ double hit lymphoma [70]. Originated from the same company, the benzoisoxazoloazepine CPI0610 was assessed in in vivo studies in mice, where its tumor reducing activity appeared to correlate with a BET-driven reduction in MYC gene expression.…”

“…Overactivation of the CXCR4-CXL12 axis leads also to hyperphosphorylation of ERK and AKT, and its inhibition with the CXCR4 antagonist led to a reduction in the phosphorylation levels of these proteins and to the destabilization of MYC protein. Accordingly, IQS-01.01RS and CPI203 combinatorial treatment achieved a synergistic downregulation of MYC an improved tumor growth inhibition in DLBCL cell lines and xenograft model [67]. Thanks to its capacity to modulate BCL-2 and BCL-2-like protein levels, and to block IRF4/MYC signaling, CPI203 also exerted notable activity either as single agent or in combination with the BCL-2 antagonist venetoclax in MYC+/BCL2+ DHL [70], or combined with the proteasome inhibitor bortezomib or lenalidomide in bortezomib-resistant MCL [66].…”

Recent Advances in the Targeting of Epigenetic Regulators in B-Cell Non-Hodgkin Lymphoma

“…These promising results from (+)-JQ1 encouraged the development of BET inhibitors with similar chemical structure, including the BRD4 inhibitor CPI203 characterized by a higher bioavailability profile in mice (Normant et al, 2012; King et al, 2013). This agent displayed remarkable efficacy in different preclinical models of B-NHL, either as single agent or in combination with the BCL-2 antagonist venetoclax in DHLs (Esteve-Arenys et al, 2018), in DLBCL-ABC (Ceribelli et al, 2014) and in both ABC and GCB subtypes of DLBCL in combination with blockade of the CXCR4 chemokine receptor (Recasens-zorzo et al, 2018). In these studies, BRD4i activity was mainly related to the blockade of MYC transcriptional program.…”