Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The emergence of drug resistance continues to be a major hurdle towards improving patient outcomes for the treatment of Multiple Myeloma. MTI-101 is a first-in-class peptidomimetic that binds a CD44/ITGA4 containing complex and triggers necrotic cell death in multiple myeloma cell lines. In this report, we show that acquisition of resistance to MTI-101 correlates with changes in expression of genes predicted to attenuate Ca2+ flux. Consistent with the acquired resistant genotype, MTI-101 treatment induces a rapid and robust increase in intracellular Ca2+ levels in the parental cells; a finding that was attenuated in the acquired drug resistant cell line. Mechanistically, we show that pharmacological inhibition of store operated channels or reduction in the expression of a component of the store operated Ca2+ channel, TRPC1 blocks MTI-101 induced cell death. Importantly, MTI-101 is more potent in specimens obtained from relapsed myeloma patients, suggesting that relapse may occur at a cost for increased sensitivity to Ca2+ overload mediated cell death. Finally, we demonstrate that MTI-101 is synergistic when combined with bortezomib, using both myeloma cell lines and primary myeloma patient specimens. Together, these data continue to support the development of this novel class of compounds for the treatment of relapsed myeloma.
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PMID:MTI-101 treatment inducing activation of Stim1 and TRPC1 expression is a determinant of response in multiple myeloma. 2857 93

Cell adhesion-mediated drug resistance (CAM-DR) by the bone marrow (BM) is fundamental to multiple myeloma (MM) propagation and survival. Targeting BM protection to increase the efficacy of current anti-myeloma treatment has not been extensively pursued. To extend the understanding of CAM-DR, we hypothesized that the cytotoxic effects of novel anti-myeloma agents may be abrogated by the presence of BM stroma cells (BMSCs) and restored by addition of the CXCL12 antagonist NOX-A12 or the CXCR4 inhibitor plerixafor. Following this hypothesis, we evaluated different anti-myeloma agents alone, with BMSCs and when combined with plerixafor or NOX-A12. We verified CXCR4, CD49d (also termed ITGA4) and CD44 as essential mediators of BM adhesion on MM cells. Additionally, we show that CXCR7, the second receptor of stromal-derived-factor-1 (CXCL12), is highly expressed in active MM. Co-culture proved that co-treatment with plerixafor or NOX-A12, the latter inhibiting CXCR4 and CXCR7, functionally interfered with MM chemotaxis to the BM. This led to the resensitization of MM cells to the anti-myeloma agents vorinostat and pomalidomide and both proteasome inhibitors bortezomib and carfilzomib. Within a multicentre phase I/II study, NOX-A12 was tested in combination with bortezomib-dexamethasone, underlining the feasibility of NOX-A12 as an active add-on agent to antagonize myeloma CAM-DR.
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PMID:CXCL12 and CXCR7 are relevant targets to reverse cell adhesion-mediated drug resistance in multiple myeloma. 2867 Jun 93

Bortezomib (Btz) is an active agent used to treat multiple myeloma (MM). Not all patients who receive Btz-containing therapy show a favorable response. Interaction of cellular adhesion molecules with MM and bone marrow stromal cells is crucial for the survival of MM cells. However, little is known about the role of these molecules in the sensitivity of MM to Btz-containing therapy. Thus, we evaluated the correlation between the level of cellular adhesion molecules in MM cells and the efficacy of Btz plus dexamethasone (Bd) therapy. The expression of the neural cell adhesion molecule gene (NCAM, also known as CD56), ITGA4, CXCR4, and other genes were analyzed in 74 samples of primary MM cells collected from patients before they received Bd therapy. Of the eight genes tested, expression of NCAM was lower among patients who responded poorly to Bd therapy. In vitro expression of NCAM induced by transfection of MM cells enhanced their sensitivity to Btz treatment by causing accumulation of polyubiquitinated proteins. Our results indicate that expression of NCAM is associated with better response to Btz treatment and is a promising candidate biomarker for predicting response to therapies involving Btz.
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PMID:Low expression of neural cell adhesion molecule, CD56, is associated with low efficacy of bortezomib plus dexamethasone therapy in multiple myeloma. 2973 34