Chromatin conformation changes in peripheral blood can detect prostate cancer and stratify disease risk groups.

BACKGROUND: Current diagnostic blood tests for prostate cancer (PCa) are unreliable for the early stage disease, resulting in numerous unnecessary prostate biopsies in men with benign disease and false reassurance of negative biopsies in men with PCa. Predicting the risk of PCa is pivotal for making an informed decision on treatment options as the 5-year survival rate in the low-risk group is more than 95% and most men would benefit from surveillance rather than active treatment. Three-dimensional genome architecture and chromosome structures undergo early changes during tumourigenesis both in tumour and in circulating cells and can serve as a disease biomarker. METHODS: In this prospective study we screened whole blood of newly diagnosed, treatment naïve PCa patients (n = 140) and cancer-free controls (n = 96) for the presence of 14,241 chromosomal loops in the loci of 425 genes. RESULTS: We have detected specific chromosome conformation changes in the loci of ETS1, MAP3K14, SLC22A3 and CASP2 genes in peripheral blood from PCa patients yielding PCa detection with 80% sensitivity and 80% specificity. Further analysis between PCa risk groups yielded prognostic validation sets consisting of HSD3B2, VEGFC, APAF1, BMP6, ERG, MSR1, MUC1, ACAT1 and DAPK1 genes that achieved 80% sensitivity and 93% specificity stratifying high-risk category 3 vs low risk category 1 and 84% sensitivity and 89% specificity stratifying high risk category 3 vs intermediate risk category 2 disease. CONCLUSIONS: Our results demonstrate specific chromosome conformations in the blood of PCa patients that allow PCa diagnosis and risk stratification with high sensitivity and specificity.

Field template-based design and biological evaluation of new sphingosine kinase 1 inhibitors.

PURPOSE: Sphingosine kinase 1 (SK1) is a protooncogenic enzyme expressed in many human tumours and is associated with chemoresistance and poor prognosis. It is a potent therapy target and its inhibition chemosensitises solid tumours. Despite recent advances in SK1 inhibitors synthesis and validation, their clinical safety and chemosensitising options are not well described. In this study, we have designed, synthesised and tested a new specific SK1 inhibitor with a low toxicity profile. METHODS: Field template molecular modelling was used for compound design. Lead compounds were tested in cell and mouse cancer models. RESULTS: Field template analysis of three known SK1 inhibitors, SKI-178, 12aa and SK1-I, was performed and compound screening identified six potential new SK1 inhibitors. SK1 activity assays in both cell-free and in vitro settings showed that two compounds were effective SK1 inhibitors. Compound SK-F has potently decreased cancer cell viability in vitro and sensitised mouse breast tumours to docetaxel (DTX) in vivo, without significant whole-body toxicity. CONCLUSION: Through field template screening, we have identified a new SK1 inhibitor, SK-F, which demonstrated antitumour activity in vitro and in vivo without overt toxicity when combined with DTX.

New FTY720-docetaxel nanoparticle therapy overcomes FTY720-induced lymphopenia and inhibits metastatic breast tumour growth.

PURPOSE: Combining molecular therapies with chemotherapy may offer an improved clinical outcome for chemoresistant tumours. Sphingosine-1-phosphate (S1P) receptor antagonist and sphingosine kinase 1 (SK1) inhibitor FTY720 (FTY) has promising anticancer properties, however, it causes systemic lymphopenia which impairs its use in cancer patients. In this study, we developed a nanoparticle (NP) combining docetaxel (DTX) and FTY for enhanced anticancer effect, targeted tumour delivery and reduced systemic toxicity. METHODS: Docetaxel, FTY and glucosamine were covalently conjugated to poly(lactic-co-glycolic acid) (PLGA). NPs were characterised by dynamic light scattering and electron microscopy. The cellular uptake, cytotoxicity and in vivo antitumor efficacy of CNPs were evaluated. RESULTS: We show for the first time that in triple negative breast cancer cells FTY provides chemosensitisation to DTX, allowing a four-fold reduction in the effective dose. We have encapsulated both drugs in PLGA complex NPs (CNPs), with narrow size distribution of ~ 100 nm and excellent cancer cell uptake providing sequential, sustained release of FTY and DTX. In triple negative breast cancer cells and mouse breast cancer models, CNPs had similar efficacy to systemic free therapies, but allowed an effective drug dose reduction. Application of CNPs has significantly reversed chemotherapy side effects such as weight loss, liver toxicity and, most notably, lymphopenia. CONCLUSIONS: We show for the first time the DTX chemosensitising effects of FTY in triple negative breast cancer. We further demonstrate that encapsulation of free drugs in CNPs can improve targeting, provide low off-target toxicity and most importantly reduce FTY-induced lymphopenia, offering potential therapeutic use of FTY in clinical cancer treatment.

Sphingosine kinase 1 contributes to leptin-induced STAT3 phosphorylation through IL-6/gp130 transactivation in oestrogen receptor-negative breast cancer.

Obesity is a known risk factor for breast cancer. We have recently identified that adipokine leptin regulates the expression of a proto-oncogenic enzyme sphingosine kinase 1 (SK1). Signal transducer and activator of transcription 3 (STAT3) has been linked to breast cancer progression and here we investigate the mechanism of leptin-induced STAT3 activation in ER-negative breast cancer. Gene and protein expression in human primary and secondary breast cancer tissues was analysed using quantitative real-time polymerase chain reaction (qRT-PCR) assay and immunofluorescence. Leptin-induced signalling was analysed in human ER-negative breast cancer cells using Western blotting, qRT-PCR and radiolabelling assays. Gene expression and receptor signalling was modified using small interfering RNA and neutralising antibodies. In human ER-negative breast tumours and lymph node metastases, the expression of leptin receptor significantly correlated with SK1. In ER-negative breast cancer cells, SK1 knockdown led to a significant reduction in leptin-induced STAT3 phosphorylation. Knockdown of another known activator of STAT3 signalling, gp130 also resulted in a significant decrease in leptin-induced STAT3 phosphorylation. ELISA assay showed that leptin produces a significant amount of IL-6 in an SK1-dependent manner. IL-6 neutralising antibodies significantly reduced p-STAT3. Immunofluorescent staining of human primary and secondary breast tumours showed significant correlation between SK1 and IL-6 (P < 0.001), SK1 and p-STAT3 (P < 0.01) and IL-6 and p-STAT3 (P < 0.01). Our findings demonstrate that leptin-induced STAT3 is partially cross activated through SK1-mediated IL6 secretion and gp130 activation. Positive correlations in human tissues suggest the potential significance of this pathway in ER-negative breast cancer.

Leptin induces upregulation of sphingosine kinase 1 in oestrogen receptor-negative breast cancer via Src family kinase-mediated, janus kinase 2-independent pathway.

INTRODUCTION: Obesity is a known risk factor for breast cancer. Sphingosine kinase 1 (SK1) is an oncogenic lipid kinase that is overexpressed in breast tumours and linked with poor prognosis, however, its role in obesity-driven breast cancer was never elucidated. METHODS: Human primary and secondary breast cancer tissues were analysed for SK1 and leptin receptor expression using quantitative real-time polymerase chain reaction (qRT-PCR) assay. Leptin-induced signalling was analysed in human oestrogen receptor (ER)-positive and negative breast cancer cells using Western blotting, qRT-PCR and radiolabelling assays. RESULTS: Our findings show for the first time that human primary breast tumours and associated lymph node metastases exhibit a strong correlation between SK1 and leptin receptor expression (Pearson R = 0.78 and R = 0.77, respectively, P <0.001). Both these genes are elevated in metastases of ER-negative patients and show a significant increase in patients with higher body mass index (BMI). Leptin induces SK1 expression and activation in ER-negative breast cancer cell lines MDAMB-231 and BT-549, but not in ER-positive cell lines. Pharmacological inhibition and gene knockdown showed that leptin-induced SK1 activity and expression are mediated by activation of extracellular signal-regulated kinases 1/2 (ERK1/2) and Src family kinase (SFK) pathways, but not by the major pathways downstream of leptin receptor (LEPR) - janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3). Src-homology 2 domain-containing phosphatase 2 (SHP2) appeared to be key to SK1 activation, and may function as an adaptor protein between SFKs and LEPR. Importantly, leptin-induced breast cancer cell proliferation was abrogated by SK1-specific small interfering RNA (siRNA). CONCLUSIONS: Overall, our findings demonstrate a novel SFK/ERK1/2-mediated pathway that links leptin signalling and expression of oncogenic enzyme SK1 in breast tumours and suggest the potential significance of this pathway in ER-negative breast cancer.

Circulating Chromosome Conformation Signatures Significantly Enhance PSA Positive Predicting Value and Overall Accuracy for Prostate Cancer Detection.

BACKGROUND: Prostate cancer (PCa) has a high lifetime prevalence (one out of six men), but currently there is no widely accepted screening programme. Widely used prostate specific antigen (PSA) test at cut-off of 3.0 ng/mL does not have sufficient accuracy for detection of any prostate cancer, resulting in numerous unnecessary prostate biopsies in men with benign disease and false reassurance in some men with PCa. We have recently identified circulating chromosome conformation signatures (CCSs, Episwitch® PCa test) allowing PCa detection and risk stratification in line with standards of clinical PCa staging. The purpose of this study was to determine whether combining the Episwitch PCa test with the PSA test will increase its diagnostic accuracy. METHODS: n = 109 whole blood samples of men enrolled in the PROSTAGRAM screening pilot study and n = 38 samples of patients with established PCa diagnosis and cancer-negative controls from Imperial College NHS Trust were used. Samples were tested for PSA, and the presence of CCSs in the loci encoding for of DAPK1, HSD3B2, SRD5A3, MMP1, and miRNA98 associated with high-risk PCa identified in our previous work. RESULTS: PSA > 3 ng/mL alone showed a low positive predicted value (PPV) of 0.14 and a high negative predicted value (NPV) of 0.93. EpiSwitch alone showed a PPV of 0.91 and a NPV of 0.32. Combining PSA and Episwitch tests has significantly increased the PPV to 0.81 although reducing the NPV to 0.78. Furthermore, integrating PSA, as a continuous variable (rather than a dichotomised 3 ng/mL cut-off), with EpiSwitch in a new multivariant stratification model, Prostate Screening EpiSwitch (PSE) test, has yielded a remarkable combined PPV of 0.92 and NPV of 0.94 when tested on the independent prospective cohort. CONCLUSIONS: Our results demonstrate that combining the standard PSA readout with circulating chromosome conformations (PSE test) allows for significantly enhanced PSA PPV and overall accuracy for PCa detection. The PSE test is accurate, rapid, minimally invasive, and inexpensive, suggesting significant screening diagnostic potential to minimise unnecessary referrals for expensive and invasive MRI and/or biopsy testing. Further extended prospective blinded validation of the new combined signature in a screening cohort with low cancer prevalence would be the recommended step for PSE adoption in PCa screening.

Development and Validation of Blood-Based Predictive Biomarkers for Response to PD-1/PD-L1 Checkpoint Inhibitors: Evidence of a Universal Systemic Core of 3D Immunogenetic Profiling across Multiple Oncological Indications.

BACKGROUND: Unprecedented advantages in cancer treatment with immune checkpoint inhibitors (ICIs) remain limited to only a subset of patients. Systemic analyses of the regulatory 3D genome architecture linked to individual epigenetic and immunogenetic controls associated with tumour immune evasion mechanisms and immune checkpoint pathways reveal a highly prevalent molecular profile predictive of response to PD-1/PD-L1 ICIs. A clinical blood test based on a set of eight (8) 3D genomic biomarkers has been developed and validated on the basis of an observational trial to predict response to ICI therapy. METHODS: The predictive eight biomarker set is derived from prospective observational clinical trials, representing 280 treatments with Pembrolizumab, Atezolizumab, Durvalumab, Nivolumab, and Avelumab in a broad range of indications: melanoma, lung, hepatocellular, renal, breast, bladder, colon, head and neck, bone, brain, lymphoma, prostate, vulvar, and cervical cancers. RESULTS: The 3D genomic eight biomarker panel for response to immune checkpoint therapy achieved a high accuracy of 85%, sensitivity of 93%, and specificity of 82%. CONCLUSIONS: This study demonstrates that a 3D genomic approach can be used to develop a predictive clinical assay for response to PD-1/PD-L1 checkpoint inhibition in cancer patients.

Monocytes acquire prostate cancer specific chromatin conformations upon indirect co-culture with prostate cancer cells.

Background: Three-dimensional chromosome loop conformations are powerful regulators of gene expression. These chromosome conformations can be detected both in tumour and in circulating cells and have significant disease biomarker potential. We have recently detected specific chromosome conformations in circulating cells of patients with prostate cancer (PCa) which were similar to ones found in their primary tumours, however, the possibility of horizontal transfer of chromosome conformations was not studied previously. Methods: Human monocytes (U937) were co-cultured in Boyden chambers through 0.4 uM membrane with or without PC-3 human PCa cells or their conditioned media and a custom DNA microarray for 900,000 chromosomal loops covering all coding loci and non-coding RNA genes was performed on each part of the co-culture system. Results: We have detected 684 PC-3 cell-specific chromosome conformations across the whole genome that were absent in naïve monocytes but appeared in monocytes co-cultured with PC-3 cells or with PC-3-conditioned media. Comparing PC3-specific conformations to the ones we have previously detected in systemic circulation of high-risk PCa patients revealed 9 positive loops present in both settings. Conclusions: Our results demonstrate for the first time a proof of concept for horizontal transfer of chromosome conformations without direct cell-cell contact. This carries high clinical relevance as we have previously observed chromatin conformations in circulating cells of patients with melanoma and PCa similar to ones in their primary tumours. These changes can be used as highly specific biomarkers for diagnosis and prognosis. Further studies are required to elucidate the specific mechanism of chromosome conformations transfer and its clinical significance in particular diseases.

IFN-γ, IL-17 and TGF-ß involvement in shaping the tumor microenvironment: The significance of modulating such cytokines in treating malignant solid tumors.

Multiple innate and adaptive immune effector cells and molecules partake in the recognition and destruction of cancer cells to protect against growing tumors, a concept that is known as cancer immunosurveillance. Unfortunately, cancer cells are capable of avoiding this process by immunoselection of poorly immunogenic tumor cells variants along with subversion of the immune system and thus shaping both the tumor and its microenvironment. Cytokines represent part of the complex pattern of the immune response which can assist the development of cancer as well as to eliminate it. Simultaneously, a large number of cytokines may be involved in the complex interactions between host and tumor cells where this dynamic cross-talk, between tumors and the immune system, can either regulate tumor growth or tumor growth, invasion and metastasis take place. In this review, we are stressing on the interface between infiltrated immune cells and tumor cells with the emphasis on the bidirectional activities of specific cytokines: IFN-γ, TGF-ß and IL-17 within the tumor microenvironment and their role in shaping it. In addition, the significance of modulating such cytokines in favor of anti-tumor response is discussed and merits the use of mixture of targeted modulators to overcome the network complexity of cytokines in the tumor microenvironment.

Eriobotrya japonica hydrophilic extract modulates cytokines in normal tissues, in the tumor of Meth-A-fibrosarcoma bearing mice, and enhances their survival time.

BACKGROUND: Cytokines play a key role in the immune response to developing tumors, and therefore modulating their levels and actions provides innovative strategies for enhancing the activity of antigen presenting cells and polarizing towards T helper 1 type response within tumor microenvironment. One of these approaches could be the employment of plant extracts that have cytokine immunomodulation capabilities. Previously, we have shown that the Eriobotrya japonica hydrophilic extract (EJHE) induces proinflammatory cytokines in vitro and in vivo. METHODS: The present study explored the in vivo immunomodulatory effect on interferon-gamma (IFN-γ), interleukin-17 (IL-17), and transforming growth factor-beta 1 (TGF-ß1) evoked by two water-extracts prepared from EJ leaves in the tissues of normal and Meth-A-fibrosarcoma bearing mice. RESULTS: Intraperitoneal (i.p.) administration of 10 µg of EJHE and EJHE-water residue (WR), prepared from butanol extraction, increased significantly IFN-γ production in the spleen (p < 0.01) and lung (p < 0.03) tissues at 6-48 hours and suppressed significantly TGF-ß1 production levels (p < 0.001) in the spleen for as long as 48 hours. The latter responses, however, were not seen in Meth-A fibrosarcoma-bearing mice. On the contrary, triple i.p. injections, 24 hours apart; of 10 µg EJHE increased significantly IFN-γ production in the spleen (p < 0.02) while only EJHE-WR increased significantly IFN-γ, TGF-ß1 and IL-17 (p < 0.03 - 0.005) production within the tumor microenvironment of Meth-A fibrosarcoma. In addition, the present work revealed a significant prolongation of survival time (median survival time 72 days vs. 27 days of control, p < 0.007) of mice inoculated i.p. with Meth-A cells followed by three times/week for eight weeks of i.p. administration of EJHE-WR. The latter prolonged survival effect was not seen with EJHE. CONCLUSIONS: The therapeutic value of EJHE-WR as an anticancer agent merits further investigation of understanding the effect of immunomodulators' constituents on the cellular components of the tissue microenvironment. This can lead to the development of improved strategies for cancer treatment and thus opening up a new frontier for future studies.

A case of severe dry eye disease with corneal melting as presenting complaint of acute myeloid leukaemia.

Dry eye syndrome is a common multifactorial disorder of the tear film and ocular surface. In rare cases, it may be caused by systemic diseases. Corneal melting is a complication of dry eye syndrome and is a potentially blinding condition. Here we report a case of a 67-year-old patient who attended her general practitioner for a year complaining of persistent dry eyes. Ophthalmological assessment showed severe dry eye syndrome with cornea melting in left eye. Blood test revealed anaemia and thrombocytopenia with circulating blasts. Bone marrow biopsy showed 15% myeloblasts with monosomy 7, compatible with acute myeloid leukaemia. Patient was started on intensive chemotherapy regime and was a candidate for allogenic bone marrow transplant. To our knowledge, this is the first case report demonstrating dry eye syndrome with sterile corneal melting as the possible presenting complaints of acute myeloid leukaemia. This case will serve as a useful reminder to general practitioners and accident and emergency doctors about the current guidelines regarding referral of persistently symptomatic patients with dry eye syndrome for further investigation in secondary care.

Sphingosine Kinase 1 in Breast Cancer-A New Molecular Marker and a Therapy Target.

It is now well-established that sphingosine kinase 1 (SK1) plays a significant role in breast cancer development, progression, and spread, whereas SK1 knockdown can reverse these processes. In breast cancer cells and tumors, SK1 was shown to interact with various pathways involved in cell survival and chemoresistance, such as nuclear factor-kappa B (NFκB), Notch, Ras/MAPK, PKC, and PI3K. SK1 is upregulated by estrogen signaling, which, in turn, confers cancer cells with resistance to tamoxifen. Sphingosine-1-phosphate (S1P) produced by SK1 has been linked to tumor invasion and metastasis. Both SK1 and S1P are closely linked to inflammation and adipokine signaling in breast cancer. In human tumors, high SK1 expression has been linked with poorer survival and prognosis. SK1 is upregulated in triple negative tumors and basal-like subtypes. It is often associated with high phosphorylation levels of ERK1/2, SFK, LYN, AKT, and NFκB. Higher tumor SK1 mRNA levels were correlated with poor response to chemotherapy. This review summarizes the up-to-date evidence and discusses the therapeutic potential for the SK1 inhibition in breast cancer, with emphasis on the mechanisms of chemoresistance and combination with other therapies such as gefitinib or docetaxel. We have outlined four key areas for future development, including tumor microenvironment, combination therapies, and nanomedicine. We conclude that SK1 may have a potential as a target for precision medicine, its high expression being a negative prognostic marker in ER-negative breast cancer, as well as a target for chemosensitization therapy.

Bradycardia and syncope as sole manifestations of a cranial lesion: a case report.

BACKGROUND: Bradycardia and syncope are known sequelae of brain lesions. However, in the absence of neurological signs and symptoms, bradycardia and syncope are often investigated purely from the cardiovascular perspective and central nervous system-related causes may be easily overlooked during differential diagnosis. CASE PRESENTATION: Here we report a case of a 69-year-old Caucasian man who presented to the emergency department after a fall. He had 1-year history of syncope and bradycardia with frequent ectopic beats shown on his electrocardiogram. He had no neurological symptoms. He was previously investigated as an out-patient and a diagnosis of idiopathic bradycardia with ventricular ectopic beats was made. On admission, cardiovascular investigations could not reveal the cause of his bradycardia. Computed tomography and magnetic resonance imaging scans of his head showed a localized mass in left basal ganglia consistent with infiltrating glioma. CONCLUSION: To the best of our knowledge this is the first case report demonstrating central nervous system-related bradycardia and syncope without other neurological symptoms. This case will serve as a useful reminder to general practitioners, accident and emergency doctors, and cardiologists.

Transcriptome-Wide Effects of Sphingosine Kinases Knockdown in Metastatic Prostate and Breast Cancer Cells: Implications for Therapeutic Targeting.

Sphingosine kinases 1 and 2 (SK1 and SK2) are proto-oncogenic isozymes expressed in many human tumors and associated with chemoresistance and poor prognosis. They are well-recognized therapy targets and their inhibition was shown to induce tumor volume reduction and chemosensitization in multiple cancer models. Oncogenic signaling is extremely complex and often cross-regulated. Designing molecular therapies and their combinations requires rational approaches to avoid redundant targeting or developing resistance. In this study, we have performed RNA transcriptome microarray analysis of two breast and two prostate metastatic cancer cell lines treated with siRNAs targeting SK1 or SK2. In prostate cancer cell lines SK1 knockdown (KD) has significantly changed expression of several genes including downregulation of NSUN2, G3BP2 and upregulation of ETS1. SK2 KD also affected expression of multiple genes including downregulation of CAPZA1 NSUN3 and ADPGK and upregulation of VDAC1, IBTK, ETS1, and MKNK2. Similarly, in breast cancer cells SK1 KD led to downregulation of NSUN2, NFATC3, CDK2, and G3BP2 and upregulation of GTF2B, TTC17, and RAB23. SK2 KD in breast cancer cells has decreased expression of ITGAV and CAPZA1 and increased expression of GTF2B and ST13. Gene-set enrichment analysis of known biochemical pathways showed that in prostate and breast cell lines SKs KD have altered multiple pathways. SK1 KD altered chromatin assembly, regulation of G1/S transition and mitosis, Wnt and MAP kinase signaling and cell motility. SK2 KD altered RAS protein signal transduction, regulation of MAP kinase and serine/threonine kinase activity, cell motility, small GTPase mediated signal transduction and phosphatidylinositol 3-kinase (PI3K) signaling. Through genome-wide microarray analysis, we have identified important molecular pathways affected by SK1 and SK2 KD. It appears that while KD of both genes leads to a decrease in individual pro-tumorigenic genes, there is a universal cellular response resulting in upregulation of several known pro-survival and pro-tumorigenic pathways such as MAPK, RAS, and PI3K, which may mediate cancer resistance to anti-SKs therapies. Our data point out to the potential advantage of certain molecular therapy combinations in targeting prostate and breast cancer. Further signaling studies are required to confirm the individual involvement of identified pathways.

An unusual case of disseminated intravascular coagulation.

The use of cardiac pacemakers is increasing worldwide. Infective endocarditis from a pacemaker lead is a rare, but one of the most severe complications of pacemaker insertion. The diagnosis of pacemaker-related infective endocarditis is usually delayed due to unspecific clinical signs and symptoms at presentation compared to native valve infective endocarditis. Several factors can increase the risk of cardiac pacemaker-related infective endocarditis including cachexia, malignancy, diabetes mellitus, immunosuppression and corticosteroid treatment. This case report is about a 70-year-old diabetic male who presented to the emergency department with disseminated intravascular coagulation (DIC), cardiac and liver failure. He was diagnosed with pacemaker infective endocarditis, which was ultimately fatal.

Core shell lipid-polymer hybrid nanoparticles with combined docetaxel and molecular targeted therapy for the treatment of metastatic prostate cancer.

Many prostate cancers relapse after initial chemotherapy treatment. Combining molecular and chemotherapy together with encapsulation of drugs in nanocarriers provides effective drug delivery and toxicity reduction. We developed core shell lipid-polymer hybrid nanoparticles (CSLPHNPs) with poly (lactic-co-glycolic acid) (PLGA) core and lipid layer containing docetaxel and clinically used inhibitor of sphingosine kinase 1 (SK1) FTY720 (fingolimod). We show for the first time that FTY720 (both free and in CSLPHNPs) re-sensitizes castrate resistant prostate cancer cells and tumors to docetaxel, allowing a four-fold reduction in effective dose. Our CSLPHNPs showed high serum stability and a long shelf life. CSLPHNPs demonstrated a steady uptake by tumor cells, sustained intracellular drug release and in vitro efficacy superior to free therapies. In a mouse model of human prostate cancer, CSLPHNPs showed excellent tumor targeting and significantly lower side effects compared to free drugs, importantly, reversing lymphopenia induced by FTY720. Overall, we demonstrate that nanoparticle encapsulation can improve targeting, provide low off-target toxicity and most importantly reduce FTY720-induced lymphopenia, suggesting its potential use in clinical cancer treatment.

Combination of RAD001 (everolimus) and docetaxel reduces prostate and breast cancer cell VEGF production and tumour vascularisation independently of sphingosine-kinase-1.

Resistance to docetaxel is a key problem in current prostate and breast cancer management. We have recently discovered a new molecular mechanism of prostate cancer docetaxel chemoresistance mediated by the mammalian target of rapamycin (mTOR)/sphingosine-kinase-1 (SK1) pathway. Here we investigated the influence of this pathway on vascular endothelial growth factor (VEGF) production and tumour vascularisation in hormone resistant prostate and breast cancer models. Immunofluorescent staining of tumour sections from human oestrogen receptor (ER)-negative breast cancer patients showed a strong correlation between phosphorylated P70S6 kinase (mTOR downstream target), VEGF and SK1 protein expression. In hormone-insensitive prostate (PC3) and breast (MDA-MB-231 and BT-549) cancer cell lines the mTOR inhibitor RAD001 (everolimus) has significantly inhibited SK1 and VEGF expression, while low dose (5 nM) docetaxel had no significant effect. In these cell lines, SK1 overexpression slightly increased the basal levels of VEGF, but did not block the inhibitory effect of RAD001 on VEGF. In a human prostate xenograft model established in nude mice, RAD001 alone or in combination with docetaxel has suppressed tumour growth, VEGF expression and decreased tumour vasculature. Overall, our data demonstrate a new mechanism of an independent regulation of SK1 and VEGF by mTOR in hormone-insensitive prostate and breast cancers.

The emerging role of FTY720 (Fingolimod) in cancer treatment.

FTY720 (Fingolimod) is a clinically approved immunomodulating therapy for multiple sclerosis that sequesters T-cells to lymph nodes through functional antagonism of sphingosine-1-phosphate 1 receptor. FTY720 also demonstrates a proven efficacy in multiple in vitro and in vivo cancer models, suggesting a potential therapeutic role in cancer patients. A potential anticancer mechanism of FTY720 is through the inhibition of sphingosine kinase 1, a proto-oncogene with in vitro and clinical cancer association. In addition, FTY720's anticancer properties may be attributable to actions on several other molecular targets. This study focuses on reviewing the emerging evidence regarding the anticancer properties and molecular targets of FTY720. While the clinical transition of FTY720 is currently limited by its immune suppression effects, studies aiming at FTY720 delivery and release together with identifying its key synergetic combinations and relevant patient subsets may lead to its rapid introduction into the clinic.

Histone deacetylases as new therapy targets for platinum-resistant epithelial ovarian cancer.

INTRODUCTION: In developed countries, ovarian cancer is the fourth most common cancer in women. Due to the non-specific symptomatology associated with the disease many patients with ovarian cancer are diagnosed late, which leads to significantly poorer prognosis. Apart from surgery and radiotherapy, a substantial number of ovarian cancer patients will undergo chemotherapy and platinum based agents are the mainstream first-line therapy for this disease. Despite the initial efficacy of these therapies, many women relapse; therefore, strategies for second-line therapies are required. Regulation of DNA transcription is crucial for tumour progression, metastasis and chemoresistance which offers potential for novel drug targets. METHODS: We have reviewed the existing literature on the role of histone deacetylases, nuclear enzymes regulating gene transcription. RESULTS AND CONCLUSION: Analysis of available data suggests that a signifant proportion of drug resistance stems from abberant gene expression, therefore HDAC inhibitors are amongst the most promising therapeutic targets for cancer treatment. Together with genetic testing, they may have a potential to serve as base for patient-adapted therapies.

Leptomeningeal carcinomatosis as the primary presentation of relapse in breast cancer.

Leptomeningeal metastasis (LM) is an uncommon presentation of relapse in breast cancer, which is associated with poor clinical outcomes and poor prognosis. Notably, LM most commonly occurs in breast cancer. The aim of the present review was to investigate the occurrence of LM as the primary presentation of relapse following remission in breast cancer patients and to determine whether specific histological subtypes are predisposed to meningeal metastases. In addition, the present review evaluated whether patients presenting with LM as the primary site of relapse exhibit differences in survival when compared with patients exhibiting metastasis to other sites. Cross-sectional studies have demonstrated that LM is commonly associated with other sites of distant metastasis including lung, liver and bone metastases. The histological breast cancer subtype most commonly associated with LM was invasive lobular carcinoma, while triple-negative breast cancer patients appear to be predisposed to the development of LM when considering the overall prevalence of histological breast cancer subtypes. At present, data regarding LM as the primary site of relapse are limited due to its rarity as the first site of metastasis in breast cancer. Case-controlled studies are required to investigate the incidence of LM as the primary site of recurrence in breast cancer patients as this would enable treatment standardization and identification of prognostic factors for improved survival.