Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0153690 (bone metastases)
 6,382 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The burden of metastatic disease in prostate cancer is largely distributed to bone in the form of osteoblastic metastases. Interactions between malignant epithelial cells of prostate cancer and the bone microenvironment are implicated in the progression of prostate cancer. Because prostate cancer cells in bone metastases express the platelet-derived growth factor receptor (PDGFR), it is possible that inhibition of PDGFR can be an effective means of altering the clinical course of prostate cancer. Preclinical data suggest that preferential expression of PDGFRs in endothelial cells of tumor vasculature in experimental prostate cancer bone metastases is an important target for combination therapy incorporating the PDGFR inhibitor imatinib mesylate. Clinical trials combining imatinib and docetaxel are under way in the metastatic and neoadjuvant settings. Clinical and translational data from these studies are likely to provide additional insights into the role of imatinib in combination therapy for prostate cancer.
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PMID:Combination docetaxel and platelet-derived growth factor receptor inhibition with imatinib mesylate in prostate cancer. 1517 1

Imatinib mesylate (imatinib) is a potent and selective inhibitor of the tyrosine kinases, Bcr-Abl, c-Kit and platelet-derived growth factor receptors (PDGFRs). Recently, it has been reported that imatinib also targets the macrophage colony-stimulating factor (M-CSF) receptor c-Fms. M-CSF signals are essential for the differentiation of osteoclasts. Bone metastases of breast cancer are frequently associated with osteoclastic bone destruction. Furthermore, several lines of evidence suggest that osteoclasts play central roles in the development and progression of bone metastases. Thus, in the present study, we examined the effects of imatinib on bone metastases of breast cancer. Coimmunoprecipitation assays showed that imatinib inhibited the M-CSF-induced phosphorylation of c-Fms in osteoclast precursor cells as well as the PDGF-induced PDGFR phosphorylation in MDA-MB-231 human breast cancer cells. Imatinib also markedly reduced osteoclast formation in vitro. In contrast, those concentrations of imatinib did not affect osteoblast differentiation. We then examined the effects of imatinib on bone metastases of MDA-MB-231 cells in a nude mouse model. Radiographic and histomorphometric analyses demonstrated that imatinib significantly decreased bone metastases associated with the reduced number of osteoclasts. In support of the notion that the inhibition of c-Fms acts to suppress the development of bone metastases, we found that a specific inhibitor of c-Fms Ki20227 also decreased bone metastases. In conclusion, these results collectively suggest that imatinib reduced bone metastases, at least in part, by inhibiting osteoclastic bone destruction through the blockade of c-Fms signals. Our results also suggest that imatinib may have a protective effect against cancer treatment-induced bone loss.
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PMID:Imatinib mesylate suppresses bone metastases of breast cancer by inhibiting osteoclasts through the blockade of c-Fms signals. 1881 79

The antivascular function of the platelet-derived growth factor receptor (PDGFR) inhibitor imatinib combined with paclitaxel has been demonstrated by invasive immunohistochemistry. The purpose of this study was to 1) noninvasively monitor the response to anti-PDGFR treatment, and 2) understand the underlying mechanism of this response. Thus, response to treatment was studied in a prostate cancer bone metastasis model using macromolecular (biotin-bovine serum albumin [BSA]-Gd-diethylene triamine pentaacetic acid [GdDTPA]) dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Human prostate cancer (PC-3MM2) bone metastases that caused osteolysis and grew in neighboring muscle showed a high blood-volume fraction (fBV) and vascular permeability (PS) at the tumor periphery compared to muscle tissue and intraosseous tumor. Imatinib alone or with paclitaxel significantly reduced PS by 35% (one-tailed paired t-test, P = 0.045) and 40% (P = 0.0003), respectively, whereas paclitaxel alone or no treatment had no effect. Based on changes in PS, we hypothesized that imatinib interferes with the signaling pathway of vascular endothelial growth factor (VEGF). This mechanism was verified by immunohistochemistry. It demonstrated reduced activation of both PDGFR-beta and VEGF receptor 2 (VEGFR2) in imatinib-treated mice. Our study therefore demonstrates that macromolecular DCE-MRI can be used to detect early vascular effects associated with response to therapy targeted to PDGFR, and provides insight into the role played by VEGF in anti-PDGFR therapy.
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PMID:Macromolecular dynamic contrast-enhanced (DCE)-MRI detects reduced vascular permeability in a prostate cancer bone metastasis model following anti-platelet-derived growth factor receptor (PDGFR) therapy, indicating a drop in vascular endothelial growth factor receptor (VEGFR) activation. 1881 66

In a placebo-controlled randomised study of the platelet-derived growth factor receptor (PDGFR) inhibitor imatinib mesylate and docetaxel in metastatic prostate cancer with bone metastases (n=116), no significant differences in progression-free and overall survival were observed. To evaluate pharmacodynamic correlates of outcomes, we assessed the association of plasma platelet-derived growth factor (PDGF) isoform kinetics and PDGFR inhibition with progression-free and overall survival by individual treatment arm. We found that in the docetaxel-placebo arm alone, the probability of decrease in PDGFR phosphorylation (Pr-Decr-pPDGFR) above 0.5 (vs </=0.5) was associated with a sharp increase in all measured plasma PDGF isoforms (P=0.006 for AA, 0.002 for BB, 0.045 for AB); a decreased median progression-free survival of 3.3 months vs 6.8 months (hazard ratio (HR) 2.5; P=0.006 in log-rank test) and an inferior median overall survival of 20 months vs >30 months (HR 3.1; P=0.04 in log-rank test). By contrast, in the docetaxel plus imatinib arm, the association of Pr-Decr-pPDGFR >0.5 with a rise in plasma PDGF isoform concentrations and inferior survival was not observed. The data suggest that dynamic changes in PDGFR phosphorylation in peripheral blood leukocytes predict docetaxel efficacy. Rising plasma PDGF concentrations may explain and/or mark docetaxel resistance. Validation and mechanistic studies addressing these unexpected findings should anticipate a confounding influence of concurrent PDGFR inhibitor therapy.
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PMID:Dynamic change in phosphorylated platelet-derived growth factor receptor in peripheral blood leukocytes following docetaxel therapy predicts progression-free and overall survival in prostate cancer. 1884 Nov 58

Advances in understanding the biological underpinnings of many cancers have led increasingly to the use of molecularly targeted anti-cancer therapies. Because the platelet-derived growth factor receptor (PDGFR) has been implicated in the progression of prostate cancer bone metastases, it is of great interest to examine possible relationships between PDGFR inhibition and therapeutic outcomes. Here, we analyze the association between change in activated PDGFR (p-PDGFR) and progression free survival (PFS) time based on large within-patient samples of cell-specific p-PDGFR values taken before and after treatment from each of 88 prostate cancer patients. To utilize these paired samples as covariate data in a regression model for PFS time, and because the p-PDGFR distributions are bimodal, we first employ a Bayesian hierarchical mixture model to obtain a deconvolution of the pre-treatment and post-treatment within-patient p-PDGFR distributions. We evaluate fits of the mixture model and a non-mixture model that ignores the bimodality by using a supnorm metric to compare the empirical distribution of each p-PDGFR data set with the corresponding fitted distribution under each model. Our results show that first using the mixture model to account for the bimodality of the within-patient p-PDGFR distributions, and then using the posterior within-patient component mean changes in p-PDGFR so obtained as covariates in the regression model for PFS time provides an improved estimation.
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PMID:A Bayesian hierarchical mixture model for platelet derived growth factor receptor phosphorylation to improve estimation of progression-free survival in prostate cancer. 2039 57