Abstract Prostate cancer is the second leading cause of cancer-related deaths in men; specifically one in six men are diagnosed with prostate cancer in their lifetime. The use of serum prostate-specific antigen (PSA) levels has been lauded as a huge step forward in the diagnosis and treatment of prostate cancer, however since it's implemenatation as a biomarker it has become apparent that the numbers of deaths from prostate cancer has only decreased slightly. Therefore the identification of new biomarkers and treatments for highly invasive/metastatic prostate cancers is of a high priority. We sought to identify new biomarkers and drug targets by performing DNA microarray analysis of prostate tumour samples and normal prostate tissue samples. To further these goals we developed a specific array platform, this array was based upon extensive sequencing of prostate tumour samples and contains approximately 90,000 probesets many of which are specific to prostate cancer. We then utilized this technology to profile a series of fresh high Gleason score primary prostate tumour samples and normal prostate samples. We identified approximately 1,600 transcripts and many associated functionally relevant pathways that were significantly differentially expressed in the prostate tumour samples when compared with the normal prostate samples. Encouragingly we also identified several transcripts which are known to be specifically expressed in prostate cancer including prostate cancer antigen 3 (PCA3), α-methylacyl-coA-racemase AKA 2-methylacyl-CoA 2-epimerase (AMACR) and members of the olfactory receptor family 51, thereby demonstrating that this approach was producing reliable information. Additionally to these transcripts 34% of the 1,600 was annotated as being unique to the prostate cancer disease specific array when compared to available generic microarrays, thereby representing novel potential biomarkers and drug targets. Functional analysis of these unique transcripts annotated many to apoptotic processes, DNA repair and cellular proliferation amongst others. This content may be highly relevant to biomarker and target development for advanced prostate cancer. In conclusion we have developed a novel prostate cancer disease specific array, we have utilized this platform to profiled a series of prostate tumour and normal samples identifying several novel transcripts associated with advanced prostate cancer. Functional annotation of these unique transcripts associated many with processes know to be deregulated in cancer. We believe that this approach demonstrates the utility of this novel platform for the discovery of clinical biomarkers and novel drug targets from tumour tissue. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1153.
<p>Related to Figure 6: Western blots and immunofluorescence images of PDLIM2 and b-catenin phospho-Ser675 expression and localization in BT549 cells overexpressing HA-PDLIM2 are included. Graph depicting measurements of cell migration in HA-PDLIM2-expressing BT549 is shown. The effects of suppression of PDLIM2 on b-catenin and b1-integrin levels in HCC1806 and MDA-MB-231-LUC2 are shown. Further analyses of effects of loss of adhesion and also, serum starvation, on PDLIM2 and active b-catenin subcellular localization in TN Breast cell lines are also shown.</p>
Abstract Introduction: Blockade of PD-1/PD-L1 has shown potent antitumor activity but these therapies are limited to certain diseases with higher intrinsic somatic mutation burden. A key research priority is now optimising response to these agents in diseases with limited clinical response. Activation of the cGAS-STING innate immune pathway has been identified as synergistic with anti-PD-1 therapy, and also a means of overcoming resistance to IO (immune-oncology therapy). We have reported activation of the cGAS-STING immune pathway as a result of cytosolic DNA released in response to intrinsic and extrinsic DNA damage, and that upregulation of PD-L1 in response to DNA damage is dependent on STING. Therefore, activating the STING pathway as a combination treatment with IO therapy could result in improved clinical responses. Experimental procedures: We perform qPCR analysis of the STING target genes, CXCL10/CCL5 after treatment with different classes of chemotherapy. We perform immunofluorescence to determine dsDNA translocation to the cytosol and the requirement of STING for this, an siRNA screening approach was used to identify the key nucleases involved in cytosolic dsDNA translocation and chemokines expression. Results: We observed increased expression of CXCL10/CCL5 gene expression following treatment with the topoisomerase I (irinotecan) and II (Doxorubicin and Etoposide) inhibitors. This chemokine expression was associated with increased expression of dsDNA in the cytosol. Using an siRNA approach, depletion of STING and the DNA nuclease MUS81 demonstrated abrogation of CXCL10/CCL5 expression following treatment with Doxorubicin. Conclusions: Here, we show that topoisomerase I and II inhibitors are the most potent chemotherapy at activating the cGAS-STING pathway and associated expression of interferon-dependent chemokines. We propose that combination therapies of topoisomerase I and II inhibitors with IO therapy will be effective in tumours which have had limited clinical response to single agent IO therapy. Citation Format: Richard D. Wilkinson, David I. Johnston, Eileen E. Parkes, Nuala McCabe, Richard D. Kennedy. Exploring the effect of chemotherapies on STING-dependent cytokine release [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;78(13 Suppl):Abstract nr 3787.
<p>Related to Figures 2 and 3: Shows counts of distribution of IHC scores of PDLIM2 staining in RATHER cohort based on TNBC subtype. Includes analysis of TNBC subtypes of tissues in the RATHER cohorts in relation to PDLIM2 expression, a Kaplan Meier plot of breast cancer specific survival in relation to TNBC subtype, and correlation plot of PDLIM2 mRNA and protein expression in the RATHER cohorts. Examples of nuclear PDLIM2 expression in stromal/infiltrating cells are also shown.</p>
<p>Related to Figure 2: Shows data for distribution of IHC scores of PDLIM2 staining in TNBC tissues and examples of PDLIM2 IHC images of normal tissue. Includes Kaplan Meier curves and clinicopathological analysis of RATHER cohorts in relation to PDLIM2 expression.</p>
Understanding the cellular target structure and thereby proposing the best delivery system to achieve sustained release of drugs has always been a significant area of focus in biomedical research for translational benefits. Specific targeting of the receptors expressed on the target cell represents an effective strategy for increasing the pharmacological efficacy of the administered drug. Liposomes offer enhanced conveyance as a potential carrier of biomacromolecules such as anti-cancer proteins, drugs and siRNA for targeting tumour cell death. Commonly used liposomal constructs for various therapies are Doxil, Myocet, DepoCyt and Abraxanes. However, recent strategy of using multifunctional liposomes for the sustained release of drugs with increased plasma residence time and monoclonal antibody-based targeting of tumours coupled with imaging modalities have attracted enormous scientific attention. The ability of liposomes coated with specific ligands such as Apo-E derived RGD R9 and Tat peptide, to reverse the conceptualisation of drug resistance and cross the blood brain barrier, provides promising future for their use as an efficient drug delivery system. By outlining the recent advancements and innovations in the established concept of liposomal drug delivery, this review will focus on the multifunctional liposomes as an emerging novel lipid based drug delivery system.
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