Dual-mTOR inhibitor Rapalink-1 reduces prostate cancer patient-derived xenograft growth and alters tumor heterogeneity
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PROVIDER: EGAS00001004431 | EGA |
REPOSITORIES: EGA
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Project description:Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer. Pathologic activation of PI3K/mTOR pathway and elevated expression of c-Myc are frequently detected in MCC. Yet, there is no targeted therapy presently available for this lethal disease. Recently, MLN0128, a second-generation dual TORC1/2 inhibitor is shown to have therapeutic efficacy in preclinical studies. MLN0128 is currently in clinical trials as a potential therapy for advanced cancers. Here we characterize the therapeutic efficacy of MLN0128 in the preclinical setting of MCC and delineate downstream targets of mTORC1/2 in MCC cellular systems. MLN0128 significantly attenuates xenograft MCC tumor growth independent of Merkel cell polyomavirus. Moreover, MLN0128 markedly diminishes MCC cell proliferation and induces apoptosis. Further investigations indicate that senescence does not contribute to MLN0128-mediated repression of xenograft MCC tumor growth. Finally, we also observe robust antitumor effects of MLN0128 when administered as a dual therapy with JQ1, a bromodomain protein BRD4 inhibitor. These results suggest dual blockade of PI3K/mTOR pathway and c-Myc axis is effective in the control of MCC tumor growth. Our results demonstrate that MLN0128 is potent as monotherapy or as a member of combination therapy with JQ1 for advanced MCC.
| S-EPMC4872734 | biostudies-literature
Project description:The principal problem arising from prostate cancer (PCa) is its propensity to metastasize to bone. MicroRNAs (miRNAs) play a crucial role in many tumor metastases.The importance of miRNAs in bone metastasis of PCa has not been elucidated to date. We investigated whether the expression of certain miRNAs was associated with bone metastasis of PCa.
2011-01-31 | GSE26964 | GEO
Project description:The principal problem arising from prostate cancer (PCa) is its propensity to metastasize to bone. MicroRNAs (miRNAs) play a crucial role in many tumor metastases.The importance of miRNAs in bone metastasis of PCa has not been elucidated to date. We investigated whether the expression of certain miRNAs was associated with bone metastasis of PCa. We examined the miRNA expression profiles of 6 primary and 7 bone metastatic PCa samples by miRNA microarray analysis. Total RNA was taken from the specimens, low molecular weight RNA was seperate and labeled , and then hybridized to capitalbio V3.0 biochip representing about 924 microRNA.
2011-01-31 | E-GEOD-26964 | biostudies-arrayexpress
Project description:Bone metastasis is the leading cause of prostate cancer (PCa) mortality, frequently marking the progression to castration-resistant PCa. Dysregulation of the androgen receptor pathway is a common feature of castration-resistant PCa, frequently appearing in association with mTOR pathway deregulations. Advanced PCa is also characterized by increased tumor heterogeneity and cancer stem cell (CSC) frequency. CSC-targeted therapy is currently being explored in advanced PCa, with the aim of reducing cancer clonal divergence and preventing disease progression. In this study, we compared the molecular pathways enriched in a set of bone metastasis from breast and prostate cancer from snap-frozen tissue. To further model PCa drug resistance mechanisms, we used two patient-derived xenografts (PDX) models of bone-metastatic PCa, BM18, and LAPC9. We developed in vitro organoids assay and ex vivo tumor slice drug assays to investigate the effects of mTOR- and CSC-targeting compounds. We found that both PDXs could be effectively targeted by treatment with the bivalent mTORC1/2 inhibitor Rapalink-1. Exposure of LAPC9 to Rapalink-1 but not to the CSC-targeting drug disulfiram blocked mTORC1/2 signaling, diminished expression of metabolic enzymes involved in glutamine and lipid metabolism and reduced the fraction of CD44+ and ALDEFluorhigh cells, in vitro. Mice treated with Rapalink-1 showed a significantly delayed tumor growth compared to control and cells recovered from the tumors of treated animals showed a marked decrease of CD44 expression. Taken together these results highlight the increased dependence of advanced PCa on the mTOR pathway, supporting the development of a targeted approach for advanced, bone metastatic PCa.
| S-EPMC7324765 | biostudies-literature
Project description:Clinically, osteolytic phenotype is rare in prostate cancer. The molecular mechanism of bone metastasis in PCa is not fully understood. We performed RNA-seq to identify osteogenic and tumor associated roles in prostate cancer by a co-culture of osteoblasts (MG63) and prostate cancer cells (C4-2, C4-2B, 22Rv1 and DU145). We compared osteoblastic prostate cancer with osteolytic prostate cancer to evaluate the difference in phenotype of bone metastasis.
2023-09-26 | GSE210729 | GEO
Project description:: Prostate cancer (PCa) is the most commonly diagnosed genital cancer in men worldwide. Among patients who developed advanced PCa, 80% suffered from bone metastasis, with a sharp drop in the survival rate. Using quantitative global succinylome analysis, we characterized a significant increase of lysine 118 succinylation (K118su) of lactate dehydrogenase A (LDHA), which plays a role in increasing LDHA activity. As a substrate of SIRT5, LDHA-K118su significantly increased the migration and invasion of PCa cells and LDHA activity in PCa patients.
2023-06-21 | PXD022005 | Pride
Project description:We found that RANKL, expressed by cancer cells or derived from exogenous sources, consistently induced human prostate, breast, kidney, lung and liver cancer cells to colonize or metastasize to bone in an animal model of cancer bone metastasis. RANK-mediated signaling established a premetastatic niche through a forward feedback loop by inducing RANKL and c-Met expression and downstream signaling via upregulation of master regulator transcription factors regulating EMT (Twist1, Slug, Zeb1, Zeb2), stem cells (Sox2, Myc, Oct3/4 and Nanog), neuroendocrine cells (Sox 9, HIF-1α and FoxA2) and osteomimicry (c-Myc/Max, Sox2, Sox9, HIF1α and Runx2). Abrogating RANK or its downstream signaling network, c-Myc/Max or c-Met, abolished PCa skeletal metastasis in mice. We observed that a small number of RANKL-expressing PCa cells can initiate bone and soft tissue metastases by recruiting non-tumorigenic or bystander PCa or host cells from the circulation or at metastatic sites to co-colonize bone. The recruited bystander PCa cells assume the phenotypes of RANKL-expressing PCa cells by expressing increased c-Met, phosphorylated c-Met and RANKL. RANKL expression at a single cell level in primary PCa tissues predicted disease-specific survival, reflecting the significant role of RANKL-RANK signaling in the development of lethal bone metastasis. Global gene expression analysis perturbed by RANKL in LNRANKL compared to LNNeo cells.
2014-02-06 | E-GEOD-48432 | biostudies-arrayexpress
Project description:The propensity for prostate cancer to metastasize to bone led us and others to propose that bidirectional interaction between prostate cancer cells and bone are critical for the preferential metastasis of PCa to bone. We previous identified a secreted isoform of ErbB3 (p45-sErbB3) from the bone marrow supernatants of patients with prostate cancer and bone metastasis. Immunohistochemical analysis of p45-sErbB3 expression in human specimens showed that p45-sErbB3 was highly expressed in metastatic prostate cancer cells in bone. Here we show that p45-sErbB3 stimulates calvarial bone to secrete factors that increase the invasiveness of prostate cancer cells in Boyden chamber invasion assay. We used gene array analysis to identify p45-sErbB3 regulated osteoblast genes that may enhance the invasiveness of PC-3 cells and found that p45-sErbB3 stimulated the expression of osteonectin, biglycan, and type I collagen in mouse calvaria. We further showed that recombinant osteonectin increases the invasiveness of PC-3 cells and osteonectin neutralizing antibody blocked p45-sErbB3 mediated invasiveness. These results suggest that p45-sErbB3 enhances the invasiveness of PC-3 cells is due, at least in part, to the stimulation of the secretion of osteonectin from bone. Thus, p45-sErbB3 mediates the bi-directional interaction between PCa cells and bone through osteonectin. Keywords: Prostate cancer, bone metastasis, P45-sErbB3, osteonectin
2008-05-01 | GSE8001 | GEO
Project description:The propensity for prostate cancer to metastasize to bone led us and others to propose that bidirectional interaction between prostate cancer cells and bone are critical for the preferential metastasis of PCa to bone. We previous identified a secreted isoform of ErbB3 (p45-sErbB3) from the bone marrow supernatants of patients with prostate cancer and bone metastasis. Immunohistochemical analysis of p45-sErbB3 expression in human specimens showed that p45-sErbB3 was highly expressed in metastatic prostate cancer cells in bone. Here we show that p45-sErbB3 stimulates calvarial bone to secrete factors that increase the invasiveness of prostate cancer cells in Boyden chamber invasion assay. We used gene array analysis to identify p45-sErbB3 regulated osteoblast genes that may enhance the invasiveness of PC-3 cells and found that p45-sErbB3 stimulated the expression of osteonectin, biglycan, and type I collagen in mouse calvaria. We further showed that recombinant osteonectin increases the invasiveness of PC-3 cells and osteonectin neutralizing antibody blocked p45-sErbB3 mediated invasiveness. These results suggest that p45-sErbB3 enhances the invasiveness of PC-3 cells is due, at least in part, to the stimulation of the secretion of osteonectin from bone. Thus, p45-sErbB3 mediates the bi-directional interaction between PCa cells and bone through osteonectin. Sample 1: non-treated calvaria RNA, Group 1 Sample 2: sErbB3 (100ng/ml) treated calvaria RNA, Group 2 Array: GE-supper array MM026 (total 96 genes, with 10 housekeeping genes) (service from SuperArray Bioscience Corporation: http://www.superarray.com
2008-05-01 | E-GEOD-8001 | biostudies-arrayexpress
Project description:The main objective of the current study is to determine, using transcriptomic analysis on patient derived-xenograft models, whether differentially aggressive PCa tumors predispose their microenvironment (stroma) to a metastatic gene expression pattern. Transcriptomic profiling (RNA Sequencing) was performed on PCa PDX models representing different disease stages; BM18 (androgen dependent bone metastasis) and LAPC9 (androgen independent bone metastasis).
| EGAS00001004770 | EGA