ORCID Profile
0000-0002-1893-9812
Current Organisations
Monash University
,
University of Melbourne
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Gene Expression (incl. Microarray and other genome-wide approaches) | Endocrinology | Signal Transduction | Genetics
Health Related to Ageing | Expanding Knowledge in the Biological Sciences |
Publisher: Elsevier BV
Date: 2018
DOI: 10.1016/J.JBIOR.2017.10.010
Abstract: The PIM kinases are proto-oncogenes which have been shown to facilitate cell survival and proliferation to drive malignancy and resistance post-therapy. They are able to suppress cell death signals, sustain PI3K/AKT/mTORC1 pathway activity and regulate the MYC oncogenic program. Recent work has revealed PIM kinase essentiality for advanced tumour maintenance and described tumour sensitivity to small molecule inhibitors targeting PIM kinase in multiple malignancies.
Publisher: American Association for Cancer Research (AACR)
Date: 15-06-2022
DOI: 10.1158/1538-7445.AM2022-2155
Abstract: Advanced prostate cancer is characterised by mutations and lifications of genes involved in regulating protein synthesis. PTEN-loss stimulates activity of the mTOR pathway, while lification of MYC leads to increased ribosome biogenesis and elevated mRNA translation rate. Our previous work has demonstrated the efficacy of co-targeting ribosome biogenesis, via inhibition of RNA Pol I activity, and 4E-BP1 phosphorylation to suppress prostate cancer growth in vivo in GEMM of PCa and in patient-derived xenografts (Rebello et al., Clinical Cancer Research, 2016 Lawrence et al., European Urology, 2018). In a collaboration with Pimera Inc., we investigated the efficacy of their new lead RNA Pol I inhibitor PMR-116 in models of prostate cancer. PMR-116 is well tolerated in vivo in mice and can be given at 300mg/kg weekly. Using the Hi-MYC mouse model of PCa we show that dosing 6 month old mice once weekly for 4 weeks can decrease the incidence of invasive lesions by up to 85% compared to vehicle control while reverting glands to patterns of low grade intraepithelial neoplasia. PMR-116 rapidly inhibits proliferation in the Hi-MYC model with a 50% decrease in Ki67 observed 12 hours after oral administration. Conversely, PMR-116 showed minimal anti-tumour efficacy in the PTEN-null model of PCa suggesting that elevated MYC signalling may be required for optimal response. To further validate our promising GEMM results in more clinically relevant human-derived models, we used patient-derived xenografts lines we established from multidrug-resistant, metastatic PCa (Lawrence et al, European Urology, 2018). PMR-116 treatment decreased tumour volume in all PDX tested including complete response in a line in which tumour volume decreased by ~90% compared to baseline. We believe this new RNA Pol I inhibitor shows promising results in a wide range of preclinical models and may exert higher efficacy in tumours expressing high levels of MYC. PMR-116 is currently in Phase I dose escalation trial in patient with solid tumours (ACTRN12620001146987). Citation Format: Alisee Huglo, Richard Rebello, Mitchell Lawrence, Gail Risbridger, Denis Drygin, Mustapha Haddach, Katherine Hannan, Ross Hannan, Luc Furic. PMR-116, a novel inhibitor of ribosome biogenesis with antitumor activity in preclinical models of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022 2022 Apr 8-13. Philadelphia (PA): AACR Cancer Res 2022 (12_Suppl):Abstract nr 2155.
Publisher: American Association for Cancer Research (AACR)
Date: 14-11-2016
DOI: 10.1158/1078-0432.CCR-16-0124
Abstract: Purpose: The MYC oncogene is frequently overexpressed in prostate cancer. Upregulation of ribosome biogenesis and function is characteristic of MYC-driven tumors. In addition, PIM kinases activate MYC signaling and mRNA translation in prostate cancer and cooperate with MYC to accelerate tumorigenesis. Here, we investigate the efficacy of a single and dual approach targeting ribosome biogenesis and function to treat prostate cancer. Experimental Design:The inhibition of ribosomal RNA (rRNA) synthesis with CX-5461, a potent, selective, and orally bioavailable inhibitor of RNA polymerase I (Pol I) transcription, has been successfully exploited therapeutically but only in models of hematologic malignancy. CX-5461 and CX-6258, a pan-PIM kinase inhibitor, were tested alone and in combination in prostate cancer cell lines, in Hi-MYC- and PTEN-deficient mouse models and in patient-derived xenografts (PDX) of metastatic tissue obtained from a patient with castration-resistant prostate cancer. Results: CX-5461 inhibited anchorage-independent growth and induced cell-cycle arrest in prostate cancer cell lines at nanomolar concentrations. Oral administration of 50 mg/kg CX-5461 induced TP53 expression and activity and reduced proliferation (MKI67) and invasion (loss of ductal actin) in Hi-MYC tumors, but not in PTEN-null (low MYC) tumors. While 100 mg/kg CX-6258 showed limited effect alone, its combination with CX-5461 further suppressed proliferation and dramatically reduced large invasive lesions in both models. This rational combination strategy significantly inhibited proliferation and induced cell death in PDX of prostate cancer. Conclusions: Our results demonstrate preclinical efficacy of targeting the ribosome at multiple levels and provide a new approach for the treatment of prostate cancer. Clin Cancer Res 22(22) 5539–52. ©2016 AACR.
Publisher: Springer Science and Business Media LLC
Date: 29-04-2012
DOI: 10.1038/NI.2291
Publisher: Bioscientifica
Date: 26-09-2019
Publisher: American Society of Clinical Oncology (ASCO)
Date: 03-2015
DOI: 10.1200/JCO.2015.33.7_SUPPL.13
Abstract: 13 Background: Whole genome and matching normal tissue analyses in prostate cancer patients have shown that widespread genomic changes occur in multiple distant regions of the genome simultaneously (Baca et al., Cell. 2013). The inherent genomic instability in prostate cancers causes activation of pathways involved in DNA damage, which could be a prognostic and potentially predictive marker for treatment with agents impacting DNA repair (e.g. PARP inhibitors). Using a published dataset, a “DNA damage signature” was generated to test its role as a potential prognostic marker. Methods: A 10-gene signature was generated, using the top 9 genes (MXD3, ZMYND19, BANF1, TOMM40, UBE2S, SNRPF, RPP21, CDK2AP2 and H2AFX) correlated with H2AFX expression, which is known to be unregulated upon DNA damage. TP53 was added due to its significant role in this pathway. This signature was then assessed in The Cancer Genome Atlas dataset (TCGA, unpublished data at NCI) as a discovery set and then validated in the MSK dataset (Taylor et al., 2010) using mutation, copy number, mRNA and proteomic data. Results: Genes in the signature were altered in 31% (77/246) of patients, by lification and over expression compared to normal. The most frequent alterations were found in TP53 (15%), MXD3 (7%), BANF1 (7%), UBE28 (7%) and CDK2AF2 (7%). Analysis of protein changes associated with alteration in genomic signature showed upregulation of FOXO3, BCL2L1, BAK1 and PCNA (P .05). There were significant correlations between the signature and Gleason score (p=0.0015), PTEN (p=0.003) & RAD51 gene expression (p .001), but not with ERG,PSA, PIK3CA or BRCA2. Patients with alterations were associated with poor disease free survival (DFS) (p=0.002). When expression was assessed in the validation set, 73%(62/85) s les showed altered gene signatures and those with alterations also had poor DFS (p=0.003). Conclusions: The DNA damage signature can be used to define a group of patients with poor outcome and has the potential to be used as prognostic marker in treatment decisions in early prostate cancer patients.
Publisher: Proceedings of the National Academy of Sciences
Date: 02-08-2010
Abstract: Translational regulation plays a critical role in the control of cell growth and proliferation. A key player in translational control is eIF4E, the mRNA 5′ cap-binding protein. Aberrant expression of eIF4E promotes tumorigenesis and has been implicated in cancer development and progression. The activity of eIF4E is dysregulated in cancer. Regulation of eIF4E is partly achieved through phosphorylation. However, the physiological significance of eIF4E phosphorylation in mammals is not clear. Here, we show that knock-in mice expressing a nonphosphorylatable form of eIF4E are resistant to tumorigenesis in a prostate cancer model. By using a genome-wide analysis of translated mRNAs, we show that the phosphorylation of eIF4E is required for translational up-regulation of several proteins implicated in tumorigenesis. Accordingly, increased phospho-eIF4E levels correlate with disease progression in patients with prostate cancer. Our findings establish eIF4E phosphorylation as a critical event in tumorigenesis. These findings raise the possibility that chemical compounds that prevent the phosphorylation of eIF4E could act as anticancer drugs.
Publisher: Springer Netherlands
Date: 2014
Publisher: MDPI AG
Date: 23-07-2020
Abstract: Expression of ATP-binding cassette (ABC) transporters has long been implicated in cancer chemotherapy resistance. Increased expression of the ABCC subfamily transporters has been reported in prostate cancer, especially in androgen-resistant cases. ABCC transporters are known to efflux drugs but, recently, we have demonstrated that they can also have a more direct role in cancer progression. The pharmacological potential of targeting ABCC1, however, remained to be assessed. In this study, we investigated whether the blockade of ABCC1 affects prostate cancer cell proliferation using both in vitro and in vivo models. Our data demonstrate that pharmacological inhibition of ABCC1 reduced prostate cancer cell growth in vitro and potentiated the effects of Docetaxel in vitro and in mouse models of prostate cancer in vivo. Collectively, these data identify ABCC1 as a novel and promising target in prostate cancer therapy.
Publisher: Cold Spring Harbor Laboratory
Date: 08-02-2017
DOI: 10.1101/106922
Abstract: mRNA translation plays an evolutionarily conserved role in homeostasis and when dysregulated results in various disorders. Optimal and universally applicable analytical methods to study transcriptome-wide changes in translational efficiency are therefore critical for understanding the complex role of translation regulation under physiological and pathological conditions. Techniques used to interrogate translatomes, including polysome- and ribosome-profiling, require adjustment for changes in total mRNA levels to capture bona fide alterations in translational efficiency. Herein, we present the anota2seq algorithm for such analysis using data from ribosome- or polysome-profiling quantified by DNA-microarrays or RNA sequencing, which outperforms current methods for identification of changes in translational efficiency. In contrast to available analytical methods, anota2seq also allows capture of an underappreciated mode for regulation of gene expression whereby translation acts as a buffering mechanism which maintains constant protein levels despite fluctuations in mRNA levels (“translational buffering”). Application of anota2seq shows that insulin affects gene expression at multiple levels, in a largely mTOR-dependent manner. Moreover, insulin induces levels of a subset of mRNAs independently of mTOR that undergo translational buffering upon mTOR inhibition. Thus, the universal anota2seq algorithm allows efficient and hitherto unprecedented interrogation of translatomes and enables studies of translational buffering which represents an unexplored mechanism for regulating of gene expression.
Publisher: Cold Spring Harbor Laboratory
Date: 28-12-2018
DOI: 10.1101/507574
Abstract: Estrogen receptor alpha (ERα) activity is associated with increased cancer cell proliferation. Studies aiming to understand the impact of ERα on cancer-associated phenotypes have largely been limited to its transcriptional activity. Herein, we demonstrate that ERα coordinates its transcriptional output with selective modulation of mRNA translation. Importantly, translational perturbations caused by depletion of ERα largely manifest as “translational offsetting” of the transcriptome, whereby amounts of translated mRNA and protein levels are maintained constant despite changes in mRNA abundance. Transcripts whose levels, but not polysome-association, are reduced following ERα depletion lack features which limit translational efficiency including structured 5’UTRs and miRNA target sites. In contrast, mRNAs induced upon ERα depletion whose polysome-association remains unaltered are enriched in codons requiring U34-modified tRNAs for efficient decoding. Consistently, ERα regulates levels of U34-modification enzymes, whereas altered expression of U34-modification enzymes disrupts ERα dependent translational offsetting. Altogether, we unravel a hitherto unprecedented mechanism of ERα-dependent orchestration of transcriptional and translational programs, and highlight that translational offsetting may be a pervasive mechanism of proteome maintenance in hormone-dependent cancers.
Publisher: American Association for Cancer Research (AACR)
Date: 31-05-2018
DOI: 10.1158/2159-8290.CD-17-0867
Abstract: Genetic alterations that potentiate PI3K signaling are frequent in prostate cancer, yet how different genetic drivers of the PI3K cascade contribute to prostate cancer is unclear. Here, we report PIK3CA mutation/ lification correlates with poor survival of patients with prostate cancer. To interrogate the requirement of different PI3K genetic drivers in prostate cancer, we employed a genetic approach to mutate Pik3ca in mouse prostate epithelium. We show Pik3caH1047R mutation causes p110α-dependent invasive prostate carcinoma in vivo. Furthermore, we report that PIK3CA mutation and PTEN loss coexist in patients with prostate cancer and can cooperate in vivo to accelerate disease progression via AKT–mTORC1/2 hyperactivation. Contrasting single mutants that slowly acquire castration-resistant prostate cancer (CRPC), concomitant Pik3ca mutation and Pten loss caused de novo CRPC. Thus, Pik3ca mutation and Pten deletion are not functionally redundant. Our findings indicate that PIK3CA mutation is an attractive prognostic indicator for prostate cancer that may cooperate with PTEN loss to facilitate CRPC in patients. Significance: We show PIK3CA mutation correlates with poor prostate cancer prognosis and causes prostate cancer in mice. Moreover, PIK3CA mutation and PTEN loss coexist in prostate cancer and can cooperate in vivo to accelerate tumorigenesis and facilitate CRPC. Delineating this synergistic relationship may present new therapeutic rognostic approaches to overcome castration/PI3K–AKT–mTORC1/2 inhibitor resistance. Cancer Discov 8(6) 764–79. ©2018 AACR. See related commentary by Triscott and Rubin, p. 682. This article is highlighted in the In This Issue feature, p. 663
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22522815.V1
Abstract: Supplementary Methods, Figures, and Tables
Publisher: Springer Science and Business Media LLC
Date: 22-03-2023
DOI: 10.1038/S41467-023-37161-0
Abstract: In heterogeneous head and neck cancer (HNC), subtype-specific treatment regimens are currently missing. An integrated analysis of patient HNC subtypes using single-cell sequencing and proteome profiles reveals an epithelial-mesenchymal transition (EMT) signature within the epithelial cancer-cell population. The EMT signature coincides with PI3K/mTOR inactivation in the mesenchymal subtype. Conversely, the signature is suppressed in epithelial cells of the basal subtype which exhibits hyperactive PI3K/mTOR signalling. We further identify YBX1 phosphorylation, downstream of the PI3K/mTOR pathway, restraining basal-like cancer cell proliferation. In contrast, YBX1 acts as a safeguard against the proliferation-to-invasion switch in mesenchymal-like epithelial cancer cells, and its loss accentuates partial-EMT and in vivo invasion. Interestingly, phospho-YBX1 that is mutually exclusive to partial-EMT, emerges as a prognostic marker for overall patient outcomes. These findings create a unique opportunity to sensitise mesenchymal cancer cells to PI3K/mTOR inhibitors by shifting them towards a basal-like subtype as a promising therapeutic approach against HNC.
Publisher: American Association for Cancer Research (AACR)
Date: 12-2010
DOI: 10.1158/1535-7163.MCT-10-0413
Abstract: Enzastaurin (LY317615.HCl) is currently in a phase III registration trial for diffuse large B-Cell lymphoma and numerous phase II clinical trials. Enzastaurin suppresses angiogenesis and induces apoptosis in multiple human tumor cell lines by inhibiting protein kinase C (PKC) and phosphoinositide 3-kinase (PI3K)/AKT pathway signaling. PI3K/AKT pathway signaling liberates eukaryotic translation initiation factor 4E (eIF4E) through the hierarchical phosphorylation of eIF4E binding proteins (4E-BP). When hypophosphorylated, 4E-BPs associate with eIF4E, preventing eIF4E from binding eIF4G, blocking the formation of the eIF4F translation initiation complex. Herein, we show that enzastaurin treatment impacts signaling throughout the AKT/mTOR pathway leading to hypophosphorylation of 4E-BP1 in cancer cells of erse lineages (glioblastoma, colon carcinoma, and B-cell lymphoma). Accordingly, enzastaurin treatment increases the amount of eIF4E bound to 4E-BP1 and decreases association of eIF4E with eIF4G, thereby reducing eIF4F translation initiation complex levels. We therefore chose to evaluate whether this effect on 4E-BP1 was involved in enzastaurin-induced apoptosis. Remarkably, enzastaurin-induced apoptosis was blocked in cancer cells depleted of 4E-BP1 by siRNAs, or in 4EBP1/2 knockout murine embryonic fibroblasts cells. Furthermore, eIF4E expression was increased and 4E-BP1 expression was decreased in cancer cells selected for reduced sensitivity to enzastaurin-induced apoptosis. These data highlight the importance of modulating 4E-BP1 function, and eIF4F complex levels, in the direct antitumor effect of enzastaurin and suggest that 4E-BP1 function may serve as a promising determinant of enzastaurin activity. Mol Cancer Ther 9(12) 3158–63. ©2010 AACR.
Publisher: EMBO
Date: 26-09-2019
Publisher: American Chemical Society (ACS)
Date: 03-02-2016
DOI: 10.1021/ACS.JMEDCHEM.5B01439
Abstract: The sphingosine kinase (SK) inhibitor, SKI-II, has been employed extensively in biological investigations of the role of SK1 and SK2 in disease and has demonstrated impressive anticancer activity in vitro and in vivo. However, interpretations of results using this pharmacological agent are complicated by several factors: poor SK1/2 selectivity, additional activity as an inducer of SK1-degradation, and off-target effects, including its recently identified capacity to inhibit dihydroceramide desaturase-1 (Des1). In this study, we have delineated the structure-activity relationship (SAR) for these different targets and correlated them to that required for anticancer activity and determined that Des1 inhibition is primarily responsible for the antiproliferative effects of SKI-II and its analogues. In the course of these efforts, a series of novel SK1, SK2, and Des1 inhibitors have been generated, including compounds with significantly greater anticancer activity.
Publisher: MDPI AG
Date: 16-02-2017
DOI: 10.3390/GENES8020071
Publisher: Cold Spring Harbor Laboratory
Date: 10-02-2022
DOI: 10.1101/2022.02.09.479805
Abstract: Hexanucleotide expansion mutations in C9ORF72 are a cause of familial amyotrophic lateral sclerosis. We previously reported that long arginine-rich dipeptide repeats (DPR), mimicking abnormal proteins expressed from the hexanucleotide expansion, caused translation stalling when expressed in cell culture models. Whether this stalling provides a mechanism of pathogenicity remains to be determined. Here we explored the molecular features of DPR-induced stalling and examined whether known regulatory mechanisms of ribosome quality control (RQC) are involved to sense and resolve the stalls. We demonstrate that arginine-containing DPRs lead to stalling in a length dependent manner, with lengths longer than 40 repeats invoking severe translation arrest. Mutational screening of 40×Gly-Xxx DPRs shows that stalling is most pronounced where Xxx are positively charged amino acids (Arg or Lys). Through a genome-wide knockout screen we find that genes regulating stalling on polyadenosine mRNA coding for poly-Lys, a canonical RQC substrate, respond differently to the readthrough of arginine-rich DPRs. Indeed, we find evidence that DPR-mediated stalling has no natural regulatory responses even though the stalls may be sensed, as evidenced by an upregulation of RQC gene expression. These findings therefore implicate arginine-rich DPR-mediated stalled ribosomes as posing a particular danger to cellular health and viability.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 06-02-2019
DOI: 10.1126/SCITRANSLMED.AAU5758
Abstract: Metabolism alterations are hallmarks of cancer, but the involvement of lipid metabolism in disease progression is unclear. We investigated the role of lipid metabolism in prostate cancer using tissue from patients with prostate cancer and patient-derived xenograft mouse models. We showed that fatty acid uptake was increased in human prostate cancer and that these fatty acids were directed toward biomass production. These changes were mediated, at least partly, by the fatty acid transporter CD36, which was associated with aggressive disease. Deleting
Publisher: American Association for Cancer Research (AACR)
Date: 10-2014
DOI: 10.1158/1538-7445.AM2014-2106
Abstract: Prostate cancer, a hormone-dependent disease of aging men, occurs as the relative levels of estrogen compared to testosterone are increasing. Indeed, high doses of estrogen, in combination with androgens, can initiate prostate cancer. This effect is attributed to the activity of the estrogen receptor α (ERα), but a paucity of suitable models means that the precise role of ERα in prostate cancer is still poorly understood. In this study we observed increased ERα expression in three different models of prostate cancer, PTEN null mice, Hi-Myc mice, and high grade human tumor specimens. Within the PTEN null prostate, there was a consistent pattern of ERα expression: low in benign glands, moderate in tumors within the dorsal, lateral and ventral lobes, and high in tumors within the anterior prostate. This pattern significantly correlated with the levels of the proliferative marker Ki67. There was also a significant correlation between ERα and Ki67 within in idual malignant glands in the anterior prostate. Furthermore, we demonstrated that ERα sustained the in vitro proliferation of cells derived from a PTEN null tumor in 2D and 3D assays. There was a significant decrease in proliferation in cells treated with TPSF, a non-competitive ERα antagonist, or with ERα-specific shRNA. Loss of ERα caused a significant decrease in the levels of MYC and other ERα target genes. It also reduced the activity of both the PI3K and MAPK pathways as measured by decreased levels of phosphorylated erk1/2, S6 kinase and other downstream factors. This effect was reversed in rescue experiments with expression constructs for both full length ERα, capable of genomic and non-genomic actions, and membrane-only ERα, only able to trigger rapid non-genomic signalling. Collectively, these results demonstrate that ERα levels increase in prostate cancer, which promotes proliferation through classical genomic and rapid non-genomic signalling. Citation Format: Itsuhiro Takizawa, Mitchell Lawrence, Helen Pearson, John Pedersen, Normand Pouliot, Australian Prostate Cancer BioResource, Patrick Humbert, Luc Furic, Gail Risbridger. Estrogen receptor alpha drives proliferation of prostate cancer through PI3K and MAPK signaling. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research 2014 Apr 5-9 San Diego, CA. Philadelphia (PA): AACR Cancer Res 2014 (19 Suppl):Abstract nr 2106. doi:10.1158/1538-7445.AM2014-2106
Publisher: Impact Journals, LLC
Date: 25-06-2015
Publisher: Wiley
Date: 16-09-2013
DOI: 10.1002/PROS.22720
Abstract: Contribution of stromal Hedgehog (Hh) signaling is evident in the prostate gland in mice, but needs translation to human tissues if Hh therapeutics are to be used effectively. Our goal was to determine if primary human prostate fibroblasts contain cilia, and respond to prostate Hh signaling. Primary human prostate cancer-associated (CAFs), and adjacent non-malignant (NPFs) fibroblasts isolated from human tissue specimens were analyzed using immunofluorescence, real-time PCR, and available array data. Cell culture and tissue recombination were used to determine responsiveness of human fibroblasts to Hh pathway manipulation and the paracrine effects of stromal Hh signaling, respectively. Prostatic fibroblasts were capable of forming primary cilia, with the capacity for active Hh signaling as seen by Smo co-localization to the tip of the primary cilium. Expression of genes known to represent a signature of active Hh signaling in the prostate (especially Fgf5 and Igfbp6) were increased in CAFs compared to NPFs. The level of canonical Hh genes and prostate Hh signature genes were rarely synchronous with lower doses of Purmorphamine/BMS-833923 regulating canonical transcription factors, and higher doses effecting prostate Hh signature genes. Grafts consisting of NPFs with constitutively active Hh signaling induced increased proliferation and dedifferentiation of adjacent non-malignant BPH-1 epithelial cells. These data show that human prostatic fibroblasts have the capacity for Hh signaling and manipulation. Increased expression of a signature of prostatic Hh genes in the prostate tumor microenvironment suggests a role in the epithelial transformations driving prostate cancer (PCa).
Publisher: Bioscientifica
Date: 26-09-2019
Publisher: American Association for Cancer Research (AACR)
Date: 03-2011
DOI: 10.1158/0008-5472.CAN-10-3298
Abstract: Activation of the translation initiation factor 4E (eIF4E) promotes malignant transformation and metastasis. Signaling through the AKT-mTOR pathway activates eIF4E by phosphorylating the inhibitory 4E binding proteins (4E-BP). This liberates eIF4E and allows binding to eIF4G. eIF4E can then be phosphorylated at serine 209 by the MAPK-interacting kinases (Mnk), which also interact with eIF4G. Although dispensable for normal development, Mnk function and eIF4E phosphorylation promote cellular proliferation and survival and are critical for malignant transformation. Accordingly, Mnk inhibition may serve as an attractive cancer therapy. We now report the identification of a potent, selective and orally bioavailable Mnk inhibitor that effectively blocks 4E phosphorylation both in vitro and in vivo. In cultured cancer cell lines, Mnk inhibitor treatment induces apoptosis and suppresses proliferation and soft agar colonization. Importantly, a single, orally administered dose of this Mnk inhibitor substantially suppresses eIF4E phosphorylation for at least 4 hours in human xenograft tumor tissue and mouse liver tissue. Moreover, oral dosing with the Mnk inhibitor significantly suppresses outgrowth of experimental B16 melanoma pulmonary metastases as well as growth of subcutaneous HCT116 colon carcinoma xenograft tumors, without affecting body weight. These findings offer the first description of a novel, orally bioavailable MNK inhibitor and the first preclinical proof-of-concept that MNK inhibition may provide a tractable cancer therapeutic approach. Cancer Res 71(5) 1849–57. ©2011 AACR.
Publisher: American Association for Cancer Research (AACR)
Date: 14-03-2017
DOI: 10.1158/1538-7445.TRANSCONTROL16-IA10
Abstract: Recent findings by our group have been instrumental in the development of the novel selective inhibitors of RNA Polymerase I (Pol I) (Drygin et al., Cancer Research, 2011 Bywater et al. Cancer Cell, 2012). This work has led to the fundamental discovery that ribosomal gene transcription by Pol I is not simply a “housekeeping” process in cancer cells but is highly regulated to maintain their viability (Bywater et al. Nature Reviews Cancer, 2013). Strikingly, inhibition of Pol I transcription shows a profound selectivity for malignant over normal cells in preclinical studies. As with the majority of targeted therapies, despite initial favorable responses to approaches that target ribosome synthesis and/or function in MYC-driven lymphoma models, resistant disease emerges. It is increasingly clear that maximizing the inhibition of key signaling networks as a whole improves anti-tumor response. The well-established reliance of MYC-driven malignancies on elevated rates of ribosome biogenesis, mTORC1/eIF4E-driven protein synthesis, and cell growth makes them vulnerable to therapeutic strategies that target the ribosome. Thus we hypothesized that the simultaneous targeting of the ribosome at multiple points would antagonize the development of acquired resistance and consequently prolong survival in MYC-driven cancer models. We will present data to demonstrate that targeting both ribosome synthesis and function through the combination of novel inhibitors of RNA polymerase I transcription, and PI3K/AKT/mTOR signaling inhibitors or PIM Kinase inhibitors provides a significant increase in survival compared to treatment with single agents (Devlin et al., Cancer Discovery 2016 Rebello et al., Clinical Cancer Res. 2016). We will also discuss the molecular mechanism by which multipoint targeting of the ribosome synergizes to increase survival. Finally we will discuss our collaboration with Pimera, Inc. to develop highly selective second generation RNA Pol I inhibitors. The lead compound PMR-116 is showing exceptional activity in transgenic models of malignancy, including MLL-ENL AML and Vk*MYC driven multiple myeloma. We anticipate this compound will enter the clinic in 2017. Citation Format: Ross D. Hannan, Nadine Hein, Katherine M. Hannan, Gretchen Poortinga, Elaine Sanij, Jirawas Sornkom, Kylee MacLachlan, Andrew Cuddihy, Carleen Cullinane, Luc Furic, Denis Drygin, Mustapha Haddach, Simon Harrison, Grant McArthur, Richard B. Pearson. Drugging the ribosome at the level of synthesis and translation to treat solid and hematologic cancers. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy 2016 Oct 27-30 San Francisco, CA. Philadelphia (PA): AACR Cancer Res 2017 (6 Suppl):Abstract nr IA10.
Publisher: Impact Journals, LLC
Date: 13-08-2019
Publisher: Rockefeller University Press
Date: 15-05-2019
Abstract: PTEN loss stimulates prostate tumor progression by sustaining AKT activation. Nowak et al. (2019. J. Cell Biol. 0.1083/jcb.201902048) surprisingly show that the AKT-suppressing phosphatase PHLPP2 promotes disease progression in the context of dual PTEN and p53 loss by increasing MYC stability.
Publisher: Springer Science and Business Media LLC
Date: 09-06-2014
DOI: 10.1038/ONC.2014.146
Publisher: Public Library of Science (PLoS)
Date: 10-07-2012
Publisher: Elsevier BV
Date: 06-2018
Publisher: EDP Sciences
Date: 06-2005
Publisher: Cold Spring Harbor Laboratory
Date: 19-12-2007
DOI: 10.1261/RNA.720308
Abstract: Messenger RNAs are associated with multiple RNA-binding proteins to form ribonucleoprotein (mRNP) complexes. These proteins are important regulators of the fate of their target mRNAs. In human cells, Staufen1 and Staufen2 proteins, coded by two different genes, are double-stranded RNA-binding proteins involved in several cellular functions including mRNA localization, translation, and decay. Although 51% identical, these proteins are nevertheless found in different RNA particles. In addition, differential splicing events generate Staufen2 isoforms that only differ at their N-terminal extremities. In this paper, we used a genome-wide approach to identify and compare the mRNA targets of mammalian Staufen proteins. The mRNA content of Staufen mRNPs was identified by probing DNA microarrays with probes derived from mRNAs isolated from immunopurified Staufen-containing complexes following transfection of HEK293T cells with Stau1 55 -HA, Stau2 59 -HA, or Stau2 62 -HA expressors. Our results indicate that 7% and 11% of the cellular RNAs expressed in HEK293T cells are found in Stau1- and in Stau2-containing mRNPs, respectively. A comparison of Stau1- and Stau2-containing mRNAs identifies a relatively low percentage of common mRNAs the percentage of common mRNAs highly increases when mRNAs in Stau2 59 -HA- and Stau2 62 -containing mRNPs are compared. There is a predominance of mRNAs involved in cell metabolism, transport, transcription, regulation of cell processes, and catalytic activity. All these subsets of mRNAs are mostly distinct from those associated with FMRP or IMP, although some mRNAs overlap. Consistent with a model of post-transcriptionnal gene regulation, our results show that Stau1- and Stau2-mRNPs associate with distinct but overlapping sets of cellular mRNAs.
Publisher: Springer New York
Date: 2011
Publisher: Wiley
Date: 09-07-2014
DOI: 10.1002/PATH.4386
Abstract: Prostate cancer is hormone-dependent and regulated by androgens as well as oestrogens. The tumour microenvironment also provides regulatory control, but the balance and interplay between androgens and oestrogens at the human prostate tumour interface is unknown. This study reveals a central and dominant role for oestrogen in the microenvironment, fuelling a pro-tumourigenic loop of inflammatory cytokines involving recruitment of mast cells by carcinoma-associated fibroblasts (CAFs). Mast cell numbers were increased in human PCa clinical specimens, specifically within the peritumoural stroma. Human mast cells were also shown to express ERα and ERβ, with oestradiol directly stimulating mast cell proliferation and migration as well as altered cytokine/chemokine expression. There was a significant shift in the oestrogen:androgen balance in CAFs versus normal prostatic fibroblasts (NPFs), with a profound increase to ER:AR expression. Androgen signalling is also reduced in CAFs, while ERα and ERβ transcriptional activity is not, allowing oestrogen to dictate hormone action in the tumour microenvironment. Gene microarray analyses identified CXCL12 as a major oestrogen-driven target gene in CAFs, and CAFs recruit mast cells via CXCL12 in a CXCR4-dependent manner. Collectively, these data reveal multicellular oestrogen action in the tumour microenvironment and show dominant oestrogen, rather than androgen, signalling at the prostatic tumour interface.
Publisher: Elsevier BV
Date: 11-2018
Publisher: American Association for Cancer Research (AACR)
Date: 04-2013
DOI: 10.1158/1538-7445.AM2013-3575
Abstract: Introduction The prostate is an organ where the dual actions of estrogen receptors (ERα and ERβ)are just beginning to be understood and appreciated in a physiological context. Steroid receptors can act outside of the nucleus by interacting with cytoplasmic or membrane bound proteins and activating or inhibiting signaling pathways in a ligand dependent or independent manner. However, our understanding of this non-nuclear activity remains partial. Here, we attempt to uncover how estrogens regulate post-transcriptional gene expression programs in prostate cancer. The rationale for studying impacts on post-transcriptional gene expression programs downstream of a transcription factor is that there is often no direct correlation between the level of an mRNA and the corresponding protein product. Additionally, several intracellular signaling pathways affected by estrogen signaling (e.g MAPK and PI3K pathways) directly regulate gene expression post-transcriptionally. One post-transcriptional mechanism that is tightly regulated by various intracellular signaling pathways is mRNA translation initiation - a highly controlled step that is regulated on multiple levels and is commonly deregulated in cancer. Many factors acting on mRNAs in cis and/or in trans, including RNA-binding proteins, RNA secondary structures or modifications of the cap structure by methylation can have strong impact on the efficiency of mRNA translation. Thus, estrogen signaling, by directly and indirectly affecting intracellular signaling can potentially regulate translational activity of its transcriptional targets. Approach We used prostate derived cell lines to assess how estrogens regulate proliferation and survival as a function of their ability to modulate transcription and translation. We performed polysome-microarray approach where the cytoplasmic mRNA population is separated based on the number of associated ribosomes followed by quantification of mRNA levels in pools of actively translating mRNAs. Using prostate cell lines, epithelial and stromal in origin, we first characterized the level of transcription and translation in unstimulated conditions to obtain a snapshot of the translational activity of each mRNA in baseline conditions. Secondly, we tested the impact on transcription and translation following stimulation for 2 hours with estradiol or with an ERβ-specific agonist (8β-VE2). We are currently validating ERα/β translational targets and identifying regulatory RNA sequences that enable ER-induced translational control. Conclusion We endeavor to determine how the gene expression programs regulated by ERα and ERβ are integrated at the transcriptional and translational level to direct proliferation, growth and survival in prostate tumors. Citation Format: Luc Furic, Ola Larsson, Ivan Topisirovic, Mark Frydenberg, John Pedersen, Gail Risbridger. Integration of estradiol signaling at the translational and transcriptional level in prostate cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research 2013 Apr 6-10 Washington, DC. Philadelphia (PA): AACR Cancer Res 2013 (8 Suppl):Abstract nr 3575. doi:10.1158/1538-7445.AM2013-3575
Publisher: Informa UK Limited
Date: 20-03-2017
Publisher: Elsevier BV
Date: 2023
Publisher: American Association for Cancer Research (AACR)
Date: 15-07-2016
DOI: 10.1158/1538-7445.AM2016-4809
Abstract: MYC-driven malignancies are associated with elevated rates of ribosome biogenesis and mTORC1/eIF4E-driven protein synthesis suggesting they may be vulnerable to therapeutic strategies that target the ribosome. We investigated the therapeutic efficacy of targeting multiple nodes of the network controlling the ribosome in mouse models of MYC-driven lymphoma (Eì-Myc) and prostate cancer (HI-MYC). Simultaneous inhibition of ribosomal RNA synthesis and repression of protein translation was achieved by utilizing the novel RNA polymerase I inhibitor CX-5461 and PI3K/AKT/mTORC1 and PIM 1 signaling inhibitors. Combined inhibition of ribosome biogenesis and function significantly improved therapeutic outcomes in lymphoma and prostate cancer models. CX-5461 and Everolimus (mTORC1 inhibitor) co-treatment more than doubled the survival of Eì-Myc lymphoma-bearing mice. While both classes of inhibitor suppress rDNA transcription, they treat MYC-driven malignancy through distinct molecular mechanisms facilitating their combinatorial effects. In contrast to CX-5461, PI3K/AKT/mTOR pathway inhibitors did not activate a nucleolar stress response and p53-dependent apoptosis but instead induce B-lymphoma cell death via the upregulation of the BH3-only protein BMF (Devlin et al Cancer Discovery 2015 Oct 21. pii: CD-14-0673. [Epub ahead of print]). PIM kinase has been shown to regulate eIF4Edriven protein synthesis on prostate cancer cell lines. Co-treatment of HI-MYC mice with CX-5461 and the PIM kinase inhibitor CX-6258 reverted highly invasive disease to low-grade prostate intraepithelial neoplasia. These findings demonstrate that MYC driven tumors are addicted to multiple regulatory steps associated with ribosome synthesis and function and coordinated targeting of these addictions provides an effective new therapeutic approach to treat MYC driven cancers. Citation Format: Jennifer R. Devlin, Richard J. Rebello, Katherine M. Hannan, Carleen Cullinane, Denis Drygin, Gail P. Risbridger, Luc Furic, Ross D. Hannan, Richard B. Pearson. Combination therapy targeting ribosome biogenesis and mRNA translation provides a novel and potent therapeutic approach to treat MYC-driven malignancy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research 2016 Apr 16-20 New Orleans, LA. Philadelphia (PA): AACR Cancer Res 2016 (14 Suppl):Abstract nr 4809.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2014
Publisher: Elsevier BV
Date: 07-2014
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22522815
Abstract: Supplementary Methods, Figures, and Tables
Publisher: Informa UK Limited
Date: 15-11-2021
Publisher: American Association for Cancer Research (AACR)
Date: 15-07-2016
DOI: 10.1158/1538-7445.AM2016-5181
Abstract: Background: The MYC oncogene is commonly over-expressed in prostate cancer (PC). Upregulation of ribosome biogenesis and function is a characteristic feature of MYC-driven tumors. Accordingly, inhibition of ribosomal RNA (rRNA) synthesis with CX-5461, a potent, selective and orally bioavailable inhibitor of RNA polymerase I (Pol I) transcription has been successfully exploited therapeutically in models of hematological malignancy characterized by elevated MYC expression. Additionally, PIM kinases activate MYC signaling and mRNA translation in PC and cooperate with MYC to accelerate tumorigenesis. Here we investigate the efficacy of a dual approach targeting ribosome biogenesis and function to treat PC by combining CX-5461 with the pan-PIM kinase inhibitor CX-6258 in murine and human models Methods: The efficacy of CX-5461 and CX-6258, alone and in combination, was tested in PC cell lines, in the Hi-MYC mouse model of PC (n = 8-11 per group) and in PC metastatic tissues. Primary cell lines derived from Hi-MYC mice were used to analyze signaling events underpinning therapeutic efficacy. Triplicate experiments were analyzed with ANOVA followed by Dunnett's post hoc test. All statistical tests were two-sided. Results: CX-5461 reduced anchorage independent growth and induced cell cycle arrest in human PC cell lines and in primary prostatic epithelial cells from Hi-MYC mice (P& .001). CX-5461 treatment of Hi-MYC mice induced p53 expression and activity and significantly reduced prostate epithelial cell proliferation (P = 0.02) and invasion. While CX-6258 showed little effect alone, its combination with CX-5461 further suppressed proliferation (P = 0.01), dramatically reduced the incidence of large invasive lesions from 64% to 9% and preserved prostate ductal architecture. This promising combination strategy prevented the growth of PDX tissue characterized by elevated MYC and resistance to conventional therapy (P = 0.04). Conclusions: Our results demonstrate preclinical efficacy of combination therapies targeting the ribosome at multiple levels and provide a new approach for treatment of PC with high MYC activity. Citation Format: Richard J. Rebello, Eric Kusnadi, Don Cameron, Analia Lesmana, Denis Drygin, Ashlee K. Clark, Laura Porter, Shahneen Sandhu, Gail P. Risbridger, Richard B. Pearson, Ross D. Hannan, Luc Furic. Dual inhibition of RNA Pol I transcription and PIM kinase as a new therapy to treat prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research 2016 Apr 16-20 New Orleans, LA. Philadelphia (PA): AACR Cancer Res 2016 (14 Suppl):Abstract nr 5181.
Publisher: American Association for Cancer Research (AACR)
Date: 04-01-2022
DOI: 10.1158/1538-7445.AM2023-5614
Abstract: [177Lu]Lu-PSMA-617 (LuPSMA) radionuclide therapy improves overall survival in mCRPC, and was recently approved by the FDA. Nevertheless, owing to the heterogeneous nature of mCRPC, responses to LuPSMA therapy can be variable, and resistance is inevitable. As a result, biomarkers linked to clinical outcome with LuPSMA are urgently required. Using plasma ctDNA, we present the first comprehensive genomic analysis of a prospective cohort of mCRPC patients treated with LuPSMA. Targeted sequencing of 78 genes was performed on baseline plasma and matched buffy coat s les from patients who received LuPSMA on a prospective registry (NCT04769817). Reportable alterations included pathogenic single-nucleotide and copy number variants. Association between alterations and clinical outcomes were assessed using log rank, cox proportional, and chi-squared analyses. Clinical data collected included PSA decline by ≥50% or ≥90% (PSA50-response rate, PSA50-RR and PSA90-RR), and PSA progression free survival (PSA-PFS). In total, 100 patients (median age 74 years, range 52-90) received a median of 4 cycles of LuPSMA. 83 patients had detectable ctDNA (median fraction 17%, range 0-94%) with PSA50-RR 50%, PSA90-RR 22%, and a median PSA-PFS of 7.2 months. Patients with an AR or PTEN aberration had significantly shorter PSA-PFS (HR 0.50 and 0.59, respectively Table), as did patients with any PI3K pathway aberration (HR 0.56). Additionally, patients with a high ctDNA burden had significantly worse PSA-PFS (HR 0.42, Table). There were no significant differences in PSA-RR based on deleterious genomic changes. Our data reveal that aberrations in the AR and PI3K pathways, along with pre-treatment ctDNA fraction, whilst not linked to PSA-RR, are prognostic for durability of response to LuPSMA. If validated in larger cohorts, these data will help to optimise the use of LuPSMA by improving patient selection and enhancing prognostication. Analysis of clinical endpoints based on deleterious genomic changes in ctDNA n PSA-PFS (months, wild type (wt) vs variant) PSA-PFS HR (95% CI, wt vs variant) PSA50-RR (wt vs variant) PSA90-RR (wt vs variant) Exonic AR variants 47 8.1 vs 6.0 p=0.005 0.50 (0.30-0.83) p=0.006 58% vs 40% p=0.09 23% vs 21% p=0.8 Any AR variant (intronic and upstream enhancer regions included) 49 8.1 vs 6.0 p=0.007 0.53 (0.31-0.83) p=0.008 60% vs 41% p=0.09 24% vs 20% p=0.7 RB1 variant 19 7.9 vs 5.5 p=0.2 0.67 (0.39-1.2) p=0.2 51% vs 42% p=0.5 23% vs 21% p=0.9 PTEN variant 25 7.8 vs 6.3 p=0.04 0.59 (0.36-1.00) p=0.045 50% vs 48% p=0.9 22% vs 24% p=0.8 TP53 variant 43 8.1 vs 6.7 p=0.1 0.67 (0.42-1.1) p=0.1 52% vs 47% p=0.6 20% vs 26% p=0.5 BRCA2 variant 10 7.7 vs 5.1 p=0.2 0.63 (0.29-1.30) p=0.2 51% vs 40% p=0.7 20% vs 40% p=0.1 PIK3CA variant 8 7.7 vs 4.1 p=0.08 0.48 (0.20-1.1) p=0.09 52% vs 13% p=0.06 23% vs 13% p=0.5 PI3K pathway variant 35 7.8 vs 5.5 p= 0.02 0.56 (0.34-0.91) p=0.02 55% vs 40% p=0.2 22% vs 23% p=0.9 ctDNA fraction ≥20% 43 9.0 vs 5.1 p=0.0002 0.42 (0.26-0.67) p& .001 55% vs 42% p=0.2 21% vs 23% p=0.8 Citation Format: Heidi Fettke, Louise Kostos, James Buteau, Jason A. Steen, Elizabeth Medhurst, Mo B. Haskali, Declan Murphy, Maria Docanto, Patricia Bukczynska, Nicole Ng, Shahneen Sandhu, Siavash Foroughi, Luc Furic, Tu Nguyen-Dumont, Michael S. Hofman, Arun A. Azad. Genomic aberrations in circulating tumor DNA (ctDNA) and clinical outcomes from [177Lu]Lu-PSMA-617 in metastatic castration-resistant prostate cancer (mCRPC). [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023 Part 1 (Regular and Invited Abstracts) 2023 Apr 14-19 Orlando, FL. Philadelphia (PA): AACR Cancer Res 2023 (7_Suppl):Abstract nr 5614.
Publisher: Springer Science and Business Media LLC
Date: 19-08-2021
DOI: 10.1038/S41467-021-25175-5
Abstract: Preclinical testing is a crucial step in evaluating cancer therapeutics. We aimed to establish a significant resource of patient-derived xenografts (PDXs) of prostate cancer for rapid and systematic evaluation of candidate therapies. The PDX collection comprises 59 tumors collected from 30 patients between 2012–2020, coinciding with availability of abiraterone and enzalutamide. The PDXs represent the clinico-pathological and genomic spectrum of prostate cancer, from treatment-naïve primary tumors to castration-resistant metastases. Inter- and intra-tumor heterogeneity in adenocarcinoma and neuroendocrine phenotypes is evident from bulk and single-cell RNA sequencing data. Organoids can be cultured from PDXs, providing further capabilities for preclinical studies. Using a 1 x 1 x 1 design, we rapidly identify tumors with exceptional responses to combination treatments. To govern the distribution of PDXs, we formed the Melbourne Urological Research Alliance (MURAL). This PDX collection is a substantial resource, expanding the capacity to test and prioritize effective treatments for prospective clinical trials in prostate cancer.
Publisher: American Society for Clinical Investigation
Date: 19-09-2019
Publisher: Wiley
Date: 17-05-2007
Publisher: Elsevier BV
Date: 07-2016
Publisher: Elsevier BV
Date: 11-2009
DOI: 10.1016/J.CCR.2009.09.025
Abstract: eIF4E, the mRNA 5' cap-binding translation initiation factor, is overexpressed in numerous cancers and is implicated in mechanisms underlying oncogenesis and senescence. 4E-BPs (eIF4E-binding proteins) inhibit eIF4E activity, and thereby act as suppressors of eIF4E-dependent pathways. Here, we show that tumorigenesis is increased in p53 knockout mice that lack 4E-BP1 and 4E-BP2. However, primary fibroblasts lacking 4E-BPs, but expressing p53, undergo premature senescence and resist oncogene-driven transformation. Thus, the p53 status governs 4E-BP-dependent senescence and transformation. Intriguingly, the 4E-BPs engage in senescence via translational control of the p53-stabilizing protein, Gas2. Our data demonstrate a role for 4E-BPs in senescence and tumorigenesis and highlight a p53-mediated mechanism of senescence through a 4E-BP-dependent pathway.
Publisher: MDPI AG
Date: 11-03-2021
Abstract: Mast cells (MCs) are important cellular components of the tumor microenvironment and are significantly associated with poor patient outcomes in prostate cancer and other solid cancers. The promotion of tumor progression partly involves heterotypic interactions between MCs and cancer-associated fibroblasts (CAFs), which combine to potentiate a pro-tumor extracellular matrix and promote epithelial cell invasion and migration. Thus far, the interactions between MCs and CAFs remain poorly understood. To identify molecular changes that may alter resident MC function in the prostate tumor microenvironment, we profiled the transcriptome of human prostate MCs isolated from patient-matched non-tumor and tumor-associated regions of fresh radical prostatectomy tissue. Transcriptomic profiling revealed a distinct gene expression profile of MCs isolated from prostate tumor regions, including the downregulation of SAMD14, a putative tumor suppressor gene. Proteomic profiling revealed that overexpression of SAMD14 in HMC-1 altered the secretion of proteins associated with immune regulation and extracellular matrix processes. To assess MC biological function within a model of the prostate tumor microenvironment, HMC-1-SAMD14+ conditioned media was added to co-cultures of primary prostatic CAFs and prostate epithelium. HMC-1-SAMD14+ secretions were shown to reduce the deposition and alignment of matrix produced by CAFs and suppress pro-tumorigenic prostate epithelial morphology. Overall, our data present the first profile of human MCs derived from prostate cancer patient specimens and identifies MC-derived SAMD14 as an important mediator of MC phenotype and function within the prostate tumor microenvironment.
Publisher: Bioscientifica
Date: 07-2020
DOI: 10.1530/ERC-20-0092
Abstract: Identifying the factors stimulating prostate cancer cells migration and invasion has the potential to bring new therapeutic targets to the clinic. Cysteine-rich secretory protein 3 (CRISP3) is one of the most highly upregulated proteins during the transition of a healthy human prostatic epithelium to prostate cancer. Here we show using a genetically engineered mouse model of prostate cancer that CRISP3 production greatly facilitates disease progression from carcinoma in situ to invasive prostate cancer in vivo . This interpretation was confirmed using both human and mouse prostate cancer cell lines, which showed that exposure to CRISP3 enhanced cell motility and invasion. Further, using mass spectrometry, we show that CRISP3 induces changes in abundance of a subset of cell-cell adhesion proteins, including LASP1 and TJP1 both in vivo and in vitro . Collectively, these data identify CRISP3 as being pro-tumorigenic in the prostate and validate it as a potential target for therapeutic intervention.
Publisher: Springer New York
Date: 2011
Publisher: Wiley
Date: 30-06-2003
DOI: 10.1046/J.1471-4159.2003.01883.X
Abstract: Staufen is an RNA-binding protein, first identified for its role in oogenesis and CNS development in Drosophila. Two mammalian homologs of Staufen have been identified and shown to bind double-stranded RNA and tubulin, and to function in the somatodendritic transport of mRNA in neurons. Here, we examined whether Staufen proteins are expressed in skeletal muscle in relation to the neuromuscular junction. Immunofluorescence experiments revealed that Staufen1 (Stau1) and Staufen2 (Stau2) accumulate preferentially within the postsynaptic sarcoplasm of muscle fibers as well as at newly formed ectopic synapses. Western blot analyses showed that the levels of Stau1 and Stau2 are greater in slow muscles than in fast-twitch muscles. Muscle denervation induced a significant increase in the expression of Stau1 and Stau2 in the extrasynaptic compartment of both fast and slow muscles. Consistent with these observations, we also demonstrated that expression of Stau1 and Stau2 is increased during myogenic differentiation and that treatment of myotubes with agrin and neuregulin induces a further increase in the expression of both Staufen proteins. We propose that Stau1 and Stau2 are key components of the postsynaptic apparatus in muscle, and that they contribute to the maturation and plasticity of the neuromuscular junction.
Publisher: Oxford University Press (OUP)
Date: 30-03-2019
DOI: 10.1093/NAR/GKZ223
Abstract: mRNA translation plays an evolutionarily conserved role in homeostasis and when dysregulated contributes to various disorders including metabolic and neurological diseases and cancer. Notwithstanding that optimal and universally applicable methods are critical for understanding the complex role of translational control under physiological and pathological conditions, approaches to analyze translatomes are largely underdeveloped. To address this, we developed the anota2seq algorithm which outperforms current methods for statistical identification of changes in translation. Notably, in contrast to available analytical methods, anota2seq also allows specific identification of an underappreciated mode of gene expression regulation whereby translation acts as a buffering mechanism which maintains protein levels despite fluctuations in corresponding mRNA abundance (‘translational buffering’). Thus, the universal anota2seq algorithm allows efficient and hitherto unprecedented interrogation of translatomes which is anticipated to advance knowledge regarding the role of translation in homeostasis and disease.
Publisher: Elsevier BV
Date: 02-2018
Publisher: Elsevier BV
Date: 07-2012
Publisher: The Company of Biologists
Date: 15-08-2002
Abstract: Mammalian Staufen2 (Stau2) is involved in mRNA transport in neurons. Here,we report that Stau2 is a double-stranded RNA-binding protein that is mainly expressed in the brain. We show that Stau2 is found in the somatodendritic compartment of neurons. In dendrites, Stau2 is aligned on in idual tracts and colocalizes with microtubules. Stau2 is expressed as at least three splice isoforms, which can be observed in several subcellular complexes. Although a 62 kDa isoform (Stau262) fractionates in ribosome-free fractions of light density, Stau259 and Stau252 are found in high-density complexes. These complexes are resistant to EDTA and to non-ionic detergent. For the first time, we also provide evidence for an interaction of some Stau2 isoforms with ribosomes, thus pointing to an interesting new role for Stau2 in translation. EDTA treatment, which dissociates ribosome subunits,does not release Stau2 from the subunits, suggesting that Stau2-ribosome associations are not mediated mainly by mRNA intermediates. Although Stau2 has many features in common with its paralogue Stau1, it does not colocalize with Stau1-containing particles, indicating that these proteins are components of different complexes in dendrites. Our findings suggest that members of the Staufen family share evolutionarily conserved properties and highlight the complexity of Staufen-mediated RNA transport in neurons.
Publisher: American Association for Cancer Research (AACR)
Date: 07-2018
DOI: 10.1158/1538-7445.AM2018-3743
Abstract: The estrogen receptor α (ERα) activities are complex: in the cytoplasm ERα can directly stimulate survival signalling at the cell membrane, while in the nucleus ERα activates and represses the transcription of target genes. We recently showed that in prostate cancer ERα expression is associated with increased proliferation and higher clinical grade. Here we explore the role of ERα in coordinating transcription and mRNA translation. Unexpectedly, loss of ERα expression leads to decoupling of transcription and translation events. Namely, mRNAs whose levels are induced by ERα loss exhibit reduced translation efficiency and, vice versa, mRNAs whose levels are reduced by ERα loss exhibit enhanced translation efficiency. Such regulation is manifested at the protein level and targets a range of key cellular functions including translation and metabolism. Our detailed mechanistic assessment reveal that while ERα-regulated microRNA levels contribute to global changes in mRNA levels, translational buffering is explained by changes in ribosome processivity and elongation rate. Overall, we have recently identified a process by which ERα drastically impacts the translation of a subset of mRNAs in cancer cells. We propose that this new regulatory pathway plays a major role in mediating biological effects of ERα in neoplastic tissues. Moreover, our findings have important implications in understanding alterations in gene expression programs following treatment with ERα antagonists. Citation Format: Julie Lorent, Vincent van Hoef, Richard Rebello, Mitchell Lawrence, Ivan Topisirovic, Ola Larsson, Luc Furic. Translational regulation by ERα in hormone-dependent cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018 2018 Apr 14-18 Chicago, IL. Philadelphia (PA): AACR Cancer Res 2018 (13 Suppl):Abstract nr 3743.
Publisher: Bioscientifica
Date: 26-09-2019
Publisher: American Association for Cancer Research (AACR)
Date: 14-03-2017
DOI: 10.1158/1538-7445.TRANSCONTROL16-B23
Abstract: Background: Prostate epithelium is exquisitely sensitive to the overexpression of the proto-oncogene MYC which causes neoplastic transformation. Indeed, MYC protein is almost universally overexpressed in metastatic castration-resistant prostate cancer (CRPC) making targeting MYC an attractive option for treating advanced stage disease. Unfortunately, the development of therapeutic agents directly targeting MYC has been largely unsuccessful, thus emphasizing the need to indirectly target MYC activity through inhibition of downstream cellular processes it regulates. One of the main effects of MYC in cancer cells is to accelerate proliferative growth via stimulation of high levels of ribosome biogenesis. Accordingly, the control of protein synthesis rate has emerged as the “Achilles' heel” of a wide array of tumors. MYC also regulates and cooperates with PIM kinases to increase the activity of the eIF4F translation initiation complex and MYC-driven tumors are addicted to eIF4E. Here, we investigate the efficacy of a single and dual approach targeting ribosome biogenesis and function to treat prostate cancer (PC). Experimental design: We employed numerous models of PC, including a novel CRPC patient derived xenograft system, which showed the pre-clinical efficacy of therapies that combine to target MYC directed signaling to the ribosome. The inhibition of ribosomal RNA (rRNA) synthesis with CX-5461, a potent, selective and orally bioavailable inhibitor of RNA polymerase I (Pol I) transcription has been successfully exploited therapeutically, but only in models of hematological malignancy. CX-5461 and CX-6258, a pan-PIM kinase inhibitor, were tested alone and in combination in PC cell lines, in Hi-MYC and PTEN-deficient mouse models and in patient derived xenografts (PDX) of metastatic tissue obtained from a castration-resistant PC patient. Results: CX-5461 inhibited anchorage-independent growth and induced cell cycle arrest in PC cell lines at nanomolar concentrations. Oral administration of 50 mg/kg CX-5461 induced p53 expression and activity and reduced proliferation (Ki-67) and invasion (loss of ductal actin) in Hi-MYC tumors, but not in PTEN null (low MYC) tumors. While 100 mg/kg CX-6258 showed limited effect alone, its combination with CX-5461 further suppressed proliferation and dramatically reduced large invasive lesions in both models. This rational combination strategy significantly inhibited proliferation and induced cell death in PDX of PC. Conclusion: Our results demonstrate preclinical efficacy of targeting the ribosome at multiple levels and provide a new approach for the treatment of PC. In addition, a key conclusion of our study is that the androgen receptor (AR) presence or activity has no significant impact on the therapeutic activity of our novel combination therapy. Therefore, we believe our new exciting combination therapy could be used in the clinic in combination with current anti-androgens or as salvage therapy in multi-drug resistant CRPC. Citation Format: Richard J. Rebello, Eric Kusnadi, Don P. Cameron, Helen B. Pearson, Analia Lesmana, Jennifer R. Devlin, Denis Drygin, Ashlee K. Clark, Laura Porter, John Pedersen, Shahneen Sandhu, Gail P. Risbridger, Richard B. Pearson, Ross D. Hannan, Luc Furic. Inhibition of ribosomal RNA synthesis as a new therapeutic approach to treat advanced prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy 2016 Oct 27-30 San Francisco, CA. Philadelphia (PA): AACR Cancer Res 2017 (6 Suppl):Abstract nr B23.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-02-2023
DOI: 10.1200/JCO.2023.41.6_SUPPL.TPS280
Abstract: TPS280 Background: [ 177 Lu]Lu-PSMA-I& T (LuPSMA) is a small molecule radioligand that delivers radiation via beta-particulate emission to cells expressing prostate-specific membrane antigen (PSMA). Despite a survival benefit in mCRPC, responses for many are not durable, with the majority of pts developing progressive osseous disease. Due to the lack of crossfire radiation in micrometastatic disease, small cancer cell clusters in the bone marrow may not receive an adequate dose of radiation from 177 Lu to induce cytotoxic double-stranded DNA breaks. Alpha-emitters have a shorter path length (≤100 µm) and higher linear energy transfer, making them better suited for treating micrometastatic disease. As a calcium-mimetic, radium-223 ( 223 Ra) is a bone-specific alpha-emitter which targets osteoblastic bone metastases. We hypothesise that the combination of LuPSMA with 223 Ra will be well tolerated and lead to improved response durability. Methods: This phase I/II, single-arm, single-centre study will enrol 36 patients with mCRPC who have progressed on a prior second-generation antiandrogen. Up to 6 cycles of LuPSMA (7.4 GBq) and 223 Ra (28 kBq/kg - 55 kBq/kg) will be given intravenously every 6 weeks, along with background androgen deprivation and bone protective therapy. Key eligibility criteria include a diagnosis of mCRPC with at least two untreated bone metastases visible on bone scintigraphy and PSMA-positive disease on PSMA PET/CT (SUVmax ≥20). Sites of FDG-positive disease must be either PSMA-positive or have increased uptake on bone scan. Other eligibility criteria include an ECOG status of 0-2, and adequate bone marrow and organ function. Patients treated with more than one line of chemotherapy for metastatic prostate cancer are not eligible. Blood s les and biopsies will be taken at baseline, on treatment, and at progression to develop tumor- and immune-based biomarkers that predict treatment response and associated survival benefit. A traditional 3+3 dose-escalation model will be utilized initially, escalating the dose of 223 Ra. The dose of LuPSMA will remain fixed. The co-primary objectives of this study are to determine the maximum tolerated dose of 223 Ra when combined with LuPSMA, and the 50% PSA response rate. Secondary objectives include measuring the frequency and severity of adverse events, assessment of efficacy through overall, radiographic and PSA progression-free survival, overall survival, objective tumor response rate, and evaluation of pain and health-related quality of life. Enrolment commenced in September 2022 and will continue for 24 months. Clinical trial information: NCT05383079 .
Publisher: Elsevier BV
Date: 06-2018
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-02-2023
DOI: 10.1200/JCO.2023.41.6_SUPPL.TPS281
Abstract: TPS281 Background: [ 177 Lu]Lu-PSMA is an effective class of therapy for men with metastatic castration-resistant prostate cancer (mCRPC) however, progression is inevitable. The limited durability of response is partially explained by the presence of micrometastatic deposits. Single tumor cells and micrometastases are energy-sheltered deposits receiving low absorbed radiation, due to the ~0.7mm mean path-length of Lutetium-177 ( 177 Lu). Terbium-161 ( 161 Tb) has abundant emission of Auger electrons that deposit a higher concentration of radiation over a shorter path, particularly to single tumor cells and micrometastases. 161 Tb has shown superior in-vitro and in-vivo results in comparison with 177 Lu. We hypothesize that [ 161 Tb]Tb-PSMA-I& T will deliver effective radiation to sites of metastatic prostate cancer with an acceptable safety profile. Methods: This single-center, single-arm, phase I/II trial will recruit 30 to 36 men with progressive mCRPC. The phase I dose-escalation is designed with a 3+3 model to establish the safest dose of [ 161 Tb]Tb-PSMA-I& T (dose levels: 4.4, 5.5 and 7.4 GBq). The maximum tolerated dose (MTD) will be defined as the highest dose level at which a dose-limiting toxicity occurs in less than 1/3 or 2/6 participants. The phase II dose-expansion will include 24 participants at the MTD. Up to six cycles of [ 161 Tb]Tb-PSMA-I& T will be administered intravenously every six weeks, with each subsequent dose for each patient reduced by 0.4GBq. Key eligibility criteria include a diagnosis of mCRPC with progression after at least one line of taxane chemotherapy and a second-generation anti-androgen, PSMA-positive disease on PSMA PET/CT (SUVmax ≥20), no sites of discordance on FDG PET/CT, adequate bone marrow, hepatic and renal function, ECOG performance status ≤2, and no prior treatment with another radioisotope. The co-primary objectives are to establish the MTD of [ 161 Tb]Tb-PSMA-I& T, and safety profile [CTCAE v5.0]. Secondary objectives include measuring absorbed radiation dose [Gray], evaluating anti-tumour activity [PSA 50% response rate, radiographic and PSA progression-free survival, overall survival, objective response rate], and evaluation of pain [BPI-SF] and health-related quality of life [FACT-P and FACT-RNT] over the first 12 months after treatment commences. Exploratory objectives include ctDNA analysis at baseline, during treatment and at progression, and optional tissue biopsies, to determine biomarkers of treatment response and resistance. Patient enrolment began in October 2022, with recruitment expected to continue for 24 months. Clinical trial information: NCT05521412 .
Publisher: Portland Press Ltd.
Date: 12-12-2005
DOI: 10.1042/BJ20050694
Abstract: Mammalian Stau1 (Staufen1), a modular protein composed of several dsRBDs (double-stranded RNA-binding domains), is probably involved in mRNA localization. Although Stau1 is mostly described in association with the rough endoplasmic reticulum and ribosomes in the cytoplasm, recent studies suggest that it may transit through the nucleus/nucleolus. Using a sensitive yeast import assay, we show that Stau1 is actively imported into the nucleus through a newly identified bipartite nuclear localization signal. As in yeast, the bipartite nuclear localization signal is necessary for Stau1 nuclear import in mammalian cells. It is also required for Stau1 nucleolar trafficking. However, Stau1 nuclear transit seems to be regulated by mechanisms that involve cytoplasmic retention and/or facilitated nuclear export. Cytoplasmic retention is mainly achieved through the action of dsRBD3, with dsRBD2 playing a supporting role in this function. Similarly, dsRBD3, but not its RNA-binding activity, is critical for Stau1 nucleolar trafficking. The function of dsRBD3 is strengthened or stabilized by the presence of dsRBD4 but prevented by the interdomain between dsRBD2 and dsRBD3. Altogether, these results suggest that Stau1 nuclear trafficking is a highly regulated process involving several determinants. The presence of Stau1 in the nucleus/nucleolus suggests that it may be involved in ribonucleoprotein formation in the nucleus and/or in other nuclear functions not necessarily related to mRNA transport.
Publisher: American Association for Cancer Research (AACR)
Date: 19-08-2021
DOI: 10.1158/1535-7163.MCT-20-0932
Abstract: Monotherapy with PARP inhibitors is effective for the subset of castrate-resistant prostate cancer (CRPC) with defects in homologous recombination (HR) DNA repair. New treatments are required for the remaining tumors, and an emerging strategy is to combine PARP inhibitors with other therapies that induce DNA damage. Here we tested whether PARP inhibitors are effective for HR-proficient CRPC, including androgen receptor (AR)-null tumors, when used in combination with CX-5461, a small molecule that inhibits RNA polymerase I transcription and activates the DNA damage response, and has antitumor activity in early phase I trials. The combination of CX-5461 and talazoparib significantly decreased in vivo growth of patient-derived xenografts of HR-proficient CRPC, including AR-positive, AR-null, and neuroendocrine tumors. CX-5461 and talazoparib synergistically inhibited the growth of organoids and cell lines, and significantly increased the levels of DNA damage. Decreased tumor growth after combination therapy was maintained for 2 weeks without treatment, significantly increasing host survival. Therefore, combination treatment with CX-5461 and talazoparib is effective for HR-proficient tumors that are not suitable for monotherapy with PARP inhibitors, including AR-null CRPC. This expands the spectrum of CRPC that is sensitive to PARP inhibition.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-02-2023
DOI: 10.1200/JCO.2023.41.6_SUPPL.TPS278
Abstract: TPS278 Background: [ 177 Lu]Lu-PSMA-617 was recently FDA-approved for use in the post-taxane, post-antiandrogen setting in pts with mCRPC. Despite conferring a survival benefit, for many the treatment response is short, and progression is inevitable. One of the likely mechanisms limiting the durability of responses to [ 177 Lu]Lu-PSMA-617 is heterogeneity in tumor PSMA expression. This can be screened for visually using PSMA and FDG PET/CT scans and inspecting for discordant disease, however, micrometastatic disease is unable to be evaluated in this way. In addition, [ 177 Lu]Lu-PSMA-617 may not effectively target micrometastatic disease due to the longer path length of beta emitters. Cabazitaxel has radiosensitizing properties that may enhance the cytotoxic effect of [ 177 Lu]Lu-PSMA-617, whilst also treating any PSMA-negative disease. We hypothesize that the combination of [ 177 Lu]Lu-PSMA-617 and cabazitaxel will be well tolerated and lead to more durable responses. Methods: This single-centre, single-arm phase I/II trial will enrol 32-38 pts with mCRPC to evaluate the safety and preliminary efficacy of cabazitaxel and [ 177 Lu]Lu-PSMA-617 in combination. Up to 6 doses of [ 177 Lu]Lu-PSMA-617 (7.4 GBq) will be administered intravenously every 6 weeks. Cabazitaxel will be given concurrently (dose range 12.5mg/m 2 - 20mg/m 2 ), on Day 2 and Day 23 of each 6-week cycle. The dose of cabazitaxel will be escalated using a traditional 3+3 design. Key eligibility criteria include a diagnosis of mCRPC with PSMA-positive disease on PSMA PET/CT (SUVmax ≥15), with no evidence of diffuse marrow disease or sites of discordance on FDG PET/CT. Pts must have progressed after prior docetaxel and a second-generation antiandrogen, have adequate bone marrow and organ function and an ECOG performance status of 0-1. The primary objective is to establish the maximum tolerated dose of cabazitaxel and [ 177 Lu]Lu-PSMA-617. Secondary objectives include measuring the frequency and severity of adverse events, assessment of efficacy through PSA 50% response rate, radiographic and PSA progression-free survival, overall survival, objective tumor response rate, and evaluation of pain and health-related quality of life over the first 12 months. Bloods will be taken at baseline, during treatment and at progression for ctDNA analysis, the results of which will be correlated with baseline pt and disease characteristics, and response outcomes, to determine biomarkers of treatment response and resistance. Pt recruitment commenced in August 2022 and will continue for 18 months. Clinical trial information: NCT05340374 .
Publisher: Oxford University Press (OUP)
Date: 18-01-2018
Abstract: What is the role of epididymal cysteine-rich secretory proteins (CRISPs) in male fertility? While epididymal CRISPs are not absolutely required for male fertility, they are required for optimal sperm function. CRISPs are members of the CRISP, Antigen 5 and Pathogenesis related protein 1 (CAP) superfamily and are characterized by the presence of an N-terminal CAP domain and a C-terminal CRISP domain. CRISPs are highly enriched in the male reproductive tract of mammals, including in the epididymis. Within humans there is one epididymal CRISP, CRISP1, whereas in mice there are two, CRISP1 and CRISP4. In order to define the role of CRISPs within the epididymis, Crisp1 and Crisp4 knockout mouse lines were produced then interbred to produce Crisp1 and 4 double knockout (DKO) mice, wherein the expression of all epididymal CRISPs was ablated. In idual and DKO models were then assessed, relative to their own strain-specific wild type littermates for fertility, and sperm output and functional competence at young (10-12 weeks of age) and older ages (22-24 weeks). Crisp1 and 4 DKO and control mice were also compared for their ability to bind to the zona pellucida and achieve fertilization. Knockout mouse production was achieved using modified embryonic stem cells and standard methods. The knockout of in idual genes was confirmed at a mRNA (quantitative PCR) and protein (immunochemistry) level. Fertility was assessed using breeding experiments and a histological assessment of testes and epididymal tissue. Sperm functional competence was assessed using a computer assisted sperm analyser, induction of the acrosome reaction using progesterone followed by staining for acrosome contents, using immunochemical and western blotting to assess the ability of sperm to manifest tyrosine phosphorylation under capacitating conditions and using sperm-zona pellucida binding assays and IVF methods. A minimum of three biological replicates were used per assay and per genotype. While epididymal CRISPs are not absolutely required for male fertility, their production results in enhanced sperm function and, depending on context, CRISP1 and CRISP4 act redundantly or autonomously. Specifically, CRISP1 is the most important CRISP in the establishment of normally motile sperm, whereas CRISP4 acts to enhance capacitation-associated tyrosine phosphorylation, and CRISP1 and CRISP4 act together to establish normal acrosome function. Both are required to achieve optimal sperm-egg interaction. The presence of immune infiltrates into the epididymis of older, but not younger, DKO animals also suggests epididymal CRISPs function to produce an immune privileged environment for maturing sperm within the epididymis. Caution should be displayed in the translation of mouse-derived data into the human wherein the histology of the epididymis is someone what different. The mice used in the study were housed in a specific pathogen-free environment and were thus not exposed to the full range of environmental challenges experienced by wild mice or humans. As such, the role of CRISPs in the maintenance of an immune privileged environment, for ex le, may be understated. The combined deletion of Crisp1 and Crisp4 in mice is equivalent to the removal of all CRISP expression in humans. As such, these data suggest that mammalian CRISPs, including that in humans, function to enhance sperm function and thus male fertility. These data also suggest that in the presence of an environmental challenge, CRISPs help to maintain an immune privileged environment and thus, protect against immune-mediated male infertility. Not applicable. This study was funded by the National Health and Medical Research Council, the Victorian Cancer Agency and a scholarship from the Chinese Scholarship Council. The authors have no conflicts of interest to declare.
Publisher: American Association for Cancer Research (AACR)
Date: 07-2019
DOI: 10.1158/1538-7445.AM2019-155
Abstract: Cysteine-rich secretory protein 3 (CRISP3) is one of the most highly up-regulated proteins during the transition from a healthy human prostatic epithelium to prostate cancer. The role of CRISP3 within this process has not however, been defined. Here we show using a genetically engineered mouse model of prostate cancer, that CRISP3 production greatly facilitates disease progression from carcinoma in situ to invasive prostate cancer in vivo. This observation was further validated using both human and mouse prostate cancer cell lines, which showed that exposure to CRISP3 enhanced cell motility and invasion. Further,using mass spectrometry, we showed that this activity is induced, at least in part, via changes in cell-cell adhesion proteins, including LASP1 and TJP1 both in vivo and in vitro. Collectively, these data identify CRISP3 as being pro-tumorigenic in the prostate and validate it as a bona fide marker of aggressive prostate cancer and a potential target for therapeutic intervention. Citation Format: Luc Furic, Marianna Volpert, Jinghua Hu, Anne O'Connor, Richard J. Rebello, Shivakumar Keerthikumar, Jemma Evans, Jo Merriner, John Pedersen, Gail P. Risbridger, Peter McIntyre, Moira K. O'Bryan. Cysteine-rich secretory protein 3 expression leads to invasive prostate cancer by modulating cell motility [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019 2019 Mar 29-Apr 3 Atlanta, GA. Philadelphia (PA): AACR Cancer Res 2019 (13 Suppl):Abstract nr 155.
Publisher: Elsevier BV
Date: 2022
Publisher: Impact Journals, LLC
Date: 26-11-2014
Abstract: While high doses of estrogen, in combination with androgens, can initiate prostate cancer (PCa) via activation of the estrogen receptor α (ERα), the role of ERα in PCa cells within established tumors is largely unknown. Here we show that expression of ERα is increased in high grade human PCa. Similarly, ERα is elevated in mouse models of aggressive PCa driven by MYC overexpression or deletion of PTEN. Within the prostate of PTEN-deficient mice, there is a progressive pattern of ERα expression: low in benign glands, moderate in tumors within the dorsal, lateral and ventral lobes, and high in tumors within the anterior prostate. This expression significantly correlates with the proliferation marker Ki67. Furthermore, in vitro knockdown of ERα in cells derived from PTEN-deficient tumors causes a significant and sustained decrease in proliferation. Depletion of ERα also reduces the activity of the PI3K and MAPK pathways, both downstream targets of non-genomic ERα action. Finally, ERα knockdown reduces the levels of the MYC protein and lowers the sensitivity of cellular proliferation to glucose withdrawal, which correlates with decreased expression of the glucose transporter GLUT1. Collectively, these results demonstrate that ERα orchestrates proliferation and metabolism to promote the neoplastic growth of PCa cells.
Publisher: Elsevier BV
Date: 2005
DOI: 10.1016/J.CELL.2004.11.050
Abstract: Mammalian Staufen (Stau)1 is an RNA binding protein that is thought to function in mRNA transport and translational control. Nonsense-mediated mRNA decay (NMD) degrades abnormal and natural mRNAs that terminate translation sufficiently upstream of a splicing-generated exon-exon junction. Here we describe an mRNA decay mechanism that involves Stau1, the NMD factor Upf1, and a termination codon. Unlike NMD, this mechanism does not involve pre-mRNA splicing and occurs when Upf2 or Upf3X is downregulated. Stau1 binds directly to Upf1 and elicits mRNA decay when tethered downstream of a termination codon. Stau1 also interacts with the 3'-untranslated region of ADP-ribosylation factor (Arf)1 mRNA. Accordingly, downregulating either Stau1 or Upf1 increases Arf1 mRNA stability. These findings suggest that Arf1 mRNA is a natural target for Stau1-mediated decay, and data indicate that other mRNAs are also natural targets. We discuss this pathway as a means for cells to downregulate the expression of Stau1 binding transcripts.
Publisher: MDPI AG
Date: 29-06-2021
Abstract: Breast and prostate cancer are the second and third leading causes of death amongst all cancer types, respectively. Pathogenesis of these malignancies is characterised by dysregulation of sex hormone signalling pathways, mediated by the estrogen receptor-α (ER) in breast cancer and androgen receptor (AR) in prostate cancer. ER and AR are transcription factors whose aberrant function drives oncogenic transcriptional programs to promote cancer growth and progression. While ER/AR are known to stimulate cell growth and survival by modulating gene transcription, emerging findings indicate that their effects in neoplasia are also mediated by dysregulation of protein synthesis (i.e., mRNA translation). This suggests that ER/AR can coordinately perturb both transcriptional and translational programs, resulting in the establishment of proteomes that promote malignancy. In this review, we will discuss relatively understudied aspects of ER and AR activity in regulating protein synthesis as well as the potential of targeting mRNA translation in breast and prostate cancer.
Publisher: MDPI AG
Date: 2009
DOI: 10.3747/CO.V16I1.406
Abstract: Cancer cells are characterized by aberrant growth arising from deregulated signalling pathways. The mammalian target of rapamycin (mtor) pathway integrates multiple growth signals coming from both intracellular and extracellular cues. In this short review, we summarize what is known about the efficacy of targeting the mtor pathway to treat cancer patients, and we explain the rationale behind promising new inhibitors that could show more potent tumour growth inhibition than did the first generation of these drugs.
Publisher: Frontiers Media SA
Date: 18-11-2022
DOI: 10.3389/FMED.2022.1059122
Abstract: [ 177 Lu]Lu-PSMA is a radioligand therapy used in metastatic castration-resistant prostate cancer (mCRPC). Despite a survival benefit, the responses for many patients receiving [ 177 Lu]Lu-PSMA are not durable, and all patients eventually develop progressive disease. The bone marrow is the most common site of progression. Micrometastases in this area likely receive an inadequate dose of radiation, as the emitted beta-particles from 177 Lu travel an average range of 0.7 mm in soft tissue, well beyond the diameter of micrometastases. Radium-223 ( 223 Ra) is a calcium-mimetic and alpha-emitting radionuclide approved for use in men with mCRPC with bone metastases. The range of emitted alpha particles in soft tissue is much shorter (≤100 μm) with high linear energy transfer, likely more lethal for osseous micrometastases. We anticipate that combining a bone-specific alpha-emitter with [ 177 Lu]Lu-PSMA will improve eradication of micrometastatic osseous disease, and thereby lead to higher and longer responses. This is a single-center, single-arm phase I/II trial evaluating the combination of 223 Ra and [ 177 Lu]Lu-PSMA-I& T in men with mCRPC. Thirty-six patients will receive 7.4 GBq of [ 177 Lu]Lu-PSMA-I& T, concurrently with 223 Ra in escalating doses (28 kBq/kg – 55kBq/kg), both given intravenously every six weeks for up to six cycles. Eligible patients will have at least two untreated bone metastases visible on bone scintigraphy, and PSMA-positive disease on PSMA PET scan. Patients must have adequate bone marrow and organ function and be willing to undergo tumor biopsies. Patients with discordant disease visible on FDG PET scan (defined as FDG positive disease with minimal or no PSMA expression and no uptake on bone scan) will be excluded. Other key exclusion criteria include the presence of diffuse marrow disease, prior treatment with 223 Ra or [ 177 Lu]Lu-PSMA, or more than one prior line of chemotherapy for prostate cancer. The co-primary objectives of this study are to determine the maximum tolerated dose of 223 Ra when combined with [ 177 Lu]Lu-PSMA-I& T and the 50% PSA response rate. The AlphaBet trial is a phase I/II study combining 223 Ra with [ 177 Lu]Lu-PSMA-I& T in patients with mCRPC. We aim to enroll the first patient in Q3 2022, and recruitment is anticipated to continue for 24 months. NCT05383079.
Start Date: 03-2012
End Date: 10-2015
Amount: $375,000.00
Funder: Australian Research Council
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