Identification of Potential Glucocorticoid Receptor Therapeutic Targets in Multiple Myeloma

Abstract

Glucocorticoids (GC) are a cornerstone of combination therapies for multiple myeloma. However, patients ultimately develop resistance to GCs frequently based on decreased glucocorticoid receptor (GR) expression. An understanding of the direct targets of GC actions, which induce cell death, is expected to culminate in potential therapeutic strategies for inducing cell death by regulating downstream targets in the absence of a functional GR. The specific goal of our research is to identify primary GR targets that contribute to GC-induced cell death, with the ultimate goal of developing novel therapeutics around these targets that can be used to overcome resistance to GCs in the absence of GR. Using the MM.1S glucocorticoid-sensitive human myeloma cell line, we began with the broad platform of gene expression profiling to identify glucocorticoid-regulated genes further refined by combination treatment with phosphatidylinositol-3’-kinase inhibition (PI3Ki). To further refine the search to distinguish direct and indirect targets of GR that respond to the combination GC and PI3Ki treatment of MM.1S cells, we integrated 1) gene expression profiles of combination GC treatment with PI3Ki, which induces synergistic cell death; 2) negative correlation between genes inhibited by combination treatment in MM.1S cells and genes over-expressed in myeloma patients to establish clinical relevance and 3) GR chromatin immunoprecipitation with massively parallel sequencing (ChIP-Seq) in myeloma cells to identify global chromatin binding for the glucocorticoid receptor (GR). Using established bioinformatics platforms, we have integrated these data sets to identify a subset of candidate genes that may form the basis for a comprehensive picture of glucocorticoid actions in multiple myeloma. As a proof of principle, we have verified two targets, namely RRM2 and BCL2L1, as primary functional targets of GR involved in GC-induced cell death.

Incidence and Risk Factors of Osteonecrosis of Femoral Head in Multiple Myeloma Patients Undergoing Dexamethasone-Based Regimens

“…For demographic characteristics, younger age and male are found to be related to ONFH, which is in accordance with previous studies [10,18]. In human cells, there are around 6500 cytoplasmic binding sites per cell for dexamethasone and saturated around 50 nM [19]. However, receptors may decrease with age and result in insensitivity to corticosteroid.…”

Selinexor synergizes with dexamethasone to repress mTORC1 signaling and induce multiple myeloma cell death

“…In fact, several clinical studies have shown that decreased GC sensitivity is associated with lower GR expression [ 48 – 52 ]. Our results suggest that patients still responding to steroid therapy would benefit from selinexor treatment, while patients with reduced GR expression could be re-sensitized to DEX in the presence of selinexor [ 53 ]. Moreover, our results indicate that patients lacking GR activity may be particularly sensitive to selinexor therapy.…”

Advancing Aptamers as Molecular Probes for Cancer Theranostic Applications—The Role of Molecular Dynamics Simulation

“…• Chimeric antigen receptors (CAR) [86] • Proteasome ubiquitin Rpn13 [87] • Glucocorticoid [88] • CAR [86] • CTL019 [89] since 2012. [102] Monoclonal antibody-mediated cancer therapies have been one of the most effective developments in treating solid tumors and hematological cancers.…”

“…Chimeric antigen receptors (CAR) and proteasome ubiquitin Rpn13 receptors are the most common biomarkers used to diagnose both myeloma and leukemia blood cancer types. Anticancer agents that target glucocorticoid, CAR, and CTL019 are also utilized for targeted treatment of multiple myeloma and leukemia, including acute lymphoblastic leukemia.…”