The effect of the dual PI3K and mTOR inhibitor BEZ235 on tumour growth and osteolytic bone disease in multiple myeloma

2014 ◽  
Vol 94 (4) ◽  
pp. 343-354 ◽  
Author(s):  
Zhen Ying Gan ◽  
Stephen Fitter ◽  
Kate Vandyke ◽  
Luen B. To ◽  
Andrew C.W. Zannettino ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Disease ◽  
Tumour Growth ◽  
Mtor Inhibitor ◽  
Osteolytic Bone Disease

The effect of the PI3K inhibitor BKM120 on tumour growth and osteolytic bone disease in multiple myeloma

2015 ◽  
Vol 39 (3) ◽  
pp. 380-387 ◽  
Author(s):  
Sally K. Martin ◽  
Zhen Ying Gan ◽  
Stephen Fitter ◽  
Luen B. To ◽  
Andrew C.W. Zannettino
Keyword(s):  
Multiple Myeloma ◽  
Bone Disease ◽  
Tumour Growth ◽  
Pi3k Inhibitor ◽  
Osteolytic Bone Disease

scholarly journals A Molecular Signature of Circulating MicroRNA Can Predict Osteolytic Bone Disease in Multiple Myeloma

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3877
Author(s):  
Aristea-Maria Papanota ◽  
Panagiotis Tsiakanikas ◽  
Christos K. Kontos ◽  
Panagiotis Malandrakis ◽  
Christine-Ivy Liacos ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Logistic Regression ◽  
Bone Disease ◽  
Characteristic Curve ◽  
Molecular Signature ◽  
Circulating Microrna ◽  
Prognostic Role ◽  
Clinical Value ◽  
Osteolytic Bone Disease ◽  
Circulating Levels

Background: Multiple myeloma bone disease (MMBD) constitutes a common and severe complication of multiple myeloma (MM), impacting the quality of life and survival. We evaluated the clinical value of a panel of 19 miRNAs associated with osteoporosis in MMBD. Methods: miRNAs were isolated from the plasma of 62 newly diagnosed MM patients with or without MMBD. First-strand cDNA was synthesized, and relative quantification was performed using qPCR. Lastly, we carried out extensive biostatistical analysis. Results: Circulating levels of let-7b-5p, miR-143-3p, miR-17-5p, miR-214-3p, and miR-335-5p were significantly higher in the blood plasma of MM patients with MMBD compared to those without. Receiver operating characteristic curve and logistic regression analyses showed that these miRNAs could accurately predict MMBD. Furthermore, a standalone multi-miRNA–based logistic regression model exhibited the best predictive potential regarding MMBD. Two of those miRNAs also have a prognostic role in MM since survival analysis indicated that lower circulating levels of both let-7b-5p and miR-335-5p were associated with significantly worse progression-free survival, independently of the established prognostic factors. Conclusions: Our study proposes a miRNA signature to facilitate MMBD diagnosis, especially in ambiguous cases. Moreover, we provide evidence of the prognostic role of let-7b-5p and miR-335-5p as non-invasive prognostic biomarkers in MM.

scholarly journals Elevated Serum Levels of Stromal-Derived Factor-1α Are Associated with Increased Osteoclast Activity and Osteolytic Bone Disease in Multiple Myeloma Patients

2005 ◽  
Vol 65 (5) ◽  
pp. 1700-1709 ◽  
Author(s):  
Andrew C.W. Zannettino ◽  
Amanda N. Farrugia ◽  
Angela Kortesidis ◽  
Jim Manavis ◽  
L. Bik To ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Disease ◽  
Elevated Serum ◽  
Serum Levels ◽  
Osteoclast Activity ◽  
Osteolytic Bone Disease

Peripheral Blood Cells from Multiple Myeloma Patients Show Increased Osteoclast and Decreased Osteoblast Gene Expression.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5098-5098
Author(s):  
Melinda S. Gordon ◽  
Ariana M. Berenson ◽  
Charles B. Drucker ◽  
Matthew Katz ◽  
Hee Jin Lee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Alkaline Phosphatase ◽  
Bone Disease ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Bisphosphonate Treatment ◽  
Rt Pcr ◽  
Circulating Cells ◽  
Osteolytic Bone Disease

Abstract Bone resorption leading to osteolytic bone disease is characteristic of multiple myeloma (MM). Recent studies show the presence of bone-resorbing osteoclasts and bone-forming osteoclasts in the circulation, and these cells may correlate with bone disease and change with anti-bone resorptive therapies. We have investigated whether there is an imbalance in the expression of osteoblast and osteoclast genes in the peripheral blood mononuclear cells (PBMCs) from MM patients relative to normal age-matched controls and the effect of bisphosphonate treatment on the expression of these genes. We analyzed the expression of a panel of osteoblast-related (bone alkaline phosphatase [bone AP], bone morphogenic protein 2 [BMP2], collagen I and osteocalcin) and osteoclast-related (b3 integrin, calcitonin, receptor for activation of nuclear factor kappa B [RANK] and tartrate-resistant alkaline phosphatase [TRAP]) genes by semi-quantitative RT-PCR on total RNA isolated from PBMCs obtained following density gradient separation. We demonstrated that the expression of the osteoblast-related gene BMP2 was reduced in eight of nine MM patients when compared with normal donors. In marked contrast, three osteoclast-related genes, b3 integrin, RANK and TRAP, were more highly expressed in all nine MM patients compared to the normal donors; only calcitonin expression was similar to the control subjects. Interestingly, patients receiving bisphosphonate treatment appeared to show increased osteoblast gene expression with higher amounts of bone AP, BMP2 and osteocalcin RNA compared to the patients not receiving anti-bone resorptive therapy. However, there was no alteration in the level of the RNA in any of the four osteoclast genes compared to patients not receiving anti-bone resorptive therapy. We are extending our analysis to a larger panel of MM patients in order to determine the relationship between these circulating cells and bone disease, overall clinical status and change in their levels with anti-bone resorptive therapy. In addition, we are also investigating whether there exist larger and smaller numbers of circulating osteoclasts and osteoblasts, respectively, in MM patients, or whether these circulating cells show alteration of their expression of these genes. Our semi-quantitative RT-PCR results are being correlated with immunohistochemical staining results from osteoblast and osteoclast markers obtained on PBMCs from MM and normal subjects. These studies provide evidence that the number of circulating osteoblasts and osteoclasts is altered in patients with MM, and also may suggest that bisphosphonate therapy may also be associated with changes in these cell populations.

scholarly journals Altering Glycosphingolipid Composition to Improve Multiple Myeloma Bone Complication

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1942-1942
Author(s):  
Houfu Leng ◽  
Adel Ersek ◽  
Emma Morris ◽  
Beatriz Gamez Molina ◽  
Claire M. Edwards ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Side Effects ◽  
Bone Disease ◽  
Bone Destruction ◽  
Germinal Centre ◽  
Nuclear Accumulation ◽  
Dependent Manner ◽  
Osteolytic Bone Disease ◽  
Hematological Cancers

Abstract Multiple myeloma (MM) is an incurable cancer of plasma cells (PC), with a median survival of 5-7 years. Osteolytic bone disease and skeletal complications occur in more than 80% of MM patients and significantly contribute to the morbidity and mortality of these patients. Glycosphingolipid (GSL), an essential constituent of the outer leaflet of the cellular membrane, is altered in MM and other hematological cancers. We previously reported that GM3, a subtype of GSL promotes osteoclastogenesis. On the other hand, the GSL synthase inhibitor N-butyl-deoxynojirimycin (NB-DNJ) reduces myeloma bone disease in the 5TGM1 mouse model of MM. Mechanistically, NB-DNJ prevents osteoclast (OC) development and activation by disrupting RANKL-induced localization of TRAF6 and c-SRC into lipid rafts and preventing nuclear accumulation of the transcriptional activator NFATc1. Although NB-DNJ is an FDA-approved drug treating Gaucher's disease, it has many undesired off-target effects, such as inhibiting lysosomal and plasma membrane Beta-glucocerebrosidase and interfering with intestinal glucosidases which leads to gastrointestinal toxicities and severe weight loss. Therefore, more specific GSL inhibitors are required to minimize the side effects. Here we report a novel GSL inhibitor called Genz112638 with comparable effects as NB-DNJ but reduced side effects. Genz112638 inhibits both OC formation (p < 0.01) and MM cell growth (p < 0.0001) in vitro in a dose-dependent manner. Moreover, compared to NB-DNJ, Genz112638 more significantly improved bone condition and potentially reduced MM burden, as evidenced by the amelioration of bone loss in the 5TGM1 model of myeloma, and a reduction in the proportion of MM within bone marrow and spleen without obvious adverse effects (n=6) (p < 0.01). As excessive malignant PC in MM normally arise from germinal centre, we also checked the effects of Genz112638 on germinal centre reactions in wildtype mice. We found that Genz112638 suppresses the formation of germinal centre B cells in mouse spleen induced by sheep red blood cells (n=7). Thus, Genz112638 may affect the pathogenesis of MM disease at the initial stage. Taken together, our data elucidate a novel specific GSL inhibitor as a promising candidate drug relieving two main features of MM: bone destruction and tumour burden with negligible side effects. In vitro, it decreases OC differentiation and proliferation, and meanwhile decreases MM viability and proliferation. In vivo, it may suppress B cell formation in germinal centre, ameliorate bone destruction, and potentially interfere with the vicious cycle between increased OC and susceptibility to MM. In short, we provide a preclinical platform for GSL inhibition as a new tool against MM and its related complications. Figure. Figure. Disclosures Horwood: Genzyme: Research Funding.

scholarly journals The Src Inhibitor AZD0530 Prevents the Development of Osteolytic Bone Disease in Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3018-3018
Author(s):  
Roy Heusschen ◽  
Joséphine Muller ◽  
Marilène Binsfeld ◽  
Erwan Plougonven ◽  
Nadia Mahli ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Disease ◽  
Osteoblast Differentiation ◽  
Osteoclast Differentiation ◽  
Disease Stage ◽  
Bone Lesions ◽  
Mrna Levels ◽  
Osteoblast Function ◽  
Src Inhibitor ◽  
Osteolytic Bone Disease

Abstract Destructive bone lesions due to osteolytic bone disease are a major cause of morbidity and mortality in multiple myeloma patients, occurring in more than 80% of cases. Underlying osteolytic bone disease is an uncoupling of the bone remodeling process, with an increased activity of osteoclasts and a decreased activity of osteoblasts. Current strategies to treat osteolytic bone disease focus on anti-resorptive agents, which do not rebuild bone loss. Src kinase has been implicated in both osteoclast and osteoblast function. In this study, we assessed the effect of Src inhibition with AZD0530 (saracatinib, Astra Zeneca) on the development of multiple myeloma and its associated osteolytic bone disease. We first determined Src family kinase expression in the multiple myeloma microenvironment and found that patient-derived myeloma cells express Src at low levels but disease stage does not correlate with Src expression levels. In accordance with the literature, Src mRNA expression was found to increase during osteoclast differentiation and decrease during osteoblast differentiation in publicly available microarray datasets. Next, we validated an inhibitory role of AZD0530 on osteoclast differentiation and function. At a pharmacological relevant concentration of 1 micromolar, AZD0530 inhibited the differentiation of RAW264.7 osteoclasts (Oc.N/FOV: 15.5+-1.6 treated vs. 53+-1.5 non-treated). AZD0530 treatment appeared to hamper efficient progenitor cell fusion and osteoclast polarization, reflected by a decrease of CTSK and DC-STAMP mRNA levels and a defective actin ring formation in treated cultures, which culminated in a complete inhibition of bone resorption. When assessing the effect of AZD0530 on osteoblast function we found that AZD0530 inhibits osteoblast differentiation, with a decreased expression of OSX and OCN, and alters osteoblast morphology. In vivo, AZD0530 did not alter myeloma cell bone marrow infiltration in both the 5TGM.1 (37+-6.3% AZD0530 treated vs. 25.2+-6.7% non-treated) and 5T2MM (26.1+-7.7% vs. 29.1+-6.4%) murine multiple myeloma models. However, bone health was significantly improved in both models following treatment with AZD0530. In the 5TGM.1 model multiple trabecular bone parameters were restored to levels observed in healthy control mice following AZD0530 treatment, including BV/TV (11.7+-0.3% treated vs. 6.4+-0.3% non-treated), Tb.N. (2.5+-6x10^-2/mm vs. 1.7+-9x10^-2/mm) and Tb.Th (46.2+-1micron vs. 37+-0.8micron). These results were confirmed in the 5T2MM model, which displays a more severe osteolytic bone disease. In addition, AZD0530 treatment resulted in an increase in cortical thickness (157.8+-0.8micron treated vs. 151.4+-0.7micron non-treated) and a decrease in the number and size of cortical lesions in 5TGM.1 mice. Finally, our findings were corroborated by histomorphometric analyses. In conclusion, we report a potent inhibitory effect of the Src inhibitor AZD0530 on the development of osteolytic bone disease in multiple myeloma. Our results indicate that AZD0530 exerts this effect via the modulation of both osteoclast and osteoblast function. These findings warrant further study of the feasibility and efficacy of AZD0530 to treat osteolytic bone disease in multiple myeloma patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Monoclonal immunoglobulins promote bone loss in multiple myeloma

Blood ◽  
2020 ◽  
Vol 136 (23) ◽  
pp. 2656-2666
Author(s):  
Marita Westhrin ◽  
Vlado Kovcic ◽  
Zejian Zhang ◽  
Siv H. Moen ◽  
Tonje Marie Vikene Nedal ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Sialic Acid ◽  
Bone Loss ◽  
Bone Disease ◽  
Osteoclast Differentiation ◽  
Osteolytic Bone Disease ◽  
Monoclonal Immunoglobulins ◽  
Diagnostic Criterion ◽  
Acid Precursor

Abstract Most patients with multiple myeloma develop a severe osteolytic bone disease. The myeloma cells secrete immunoglobulins, and the presence of monoclonal immunoglobulins in the patient’s sera is an important diagnostic criterion. Here, we show that immunoglobulins isolated from myeloma patients with bone disease promote osteoclast differentiation when added to human preosteoclasts in vitro, whereas immunoglobulins from patients without bone disease do not. This effect was primarily mediated by immune complexes or aggregates. The function and aggregation behavior of immunoglobulins are partly determined by differential glycosylation of the immunoglobulin-Fc part. Glycosylation analyses revealed that patients with bone disease had significantly less galactose on immunoglobulin G (IgG) compared with patients without bone disease and also less sialic acid on IgG compared with healthy persons. Importantly, we also observed a significant reduction of IgG sialylation in serum of patients upon onset of bone disease. In the 5TGM1 mouse myeloma model, we found decreased numbers of lesions and decreased CTX-1 levels, a marker for osteoclast activity, in mice treated with a sialic acid precursor, N-acetylmannosamine (ManNAc). ManNAc treatment increased IgG-Fc sialylation in the mice. Our data support that deglycosylated immunoglobulins promote bone loss in multiple myeloma and that altering IgG glycosylation may be a therapeutic strategy to reduce bone loss.

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