Enzalutamide as a second generation antiandrogen for treatment of advanced prostate cancer

Prostate cancer (PCa) is the most common malignancy, and the third leading cancer-related cause of death among men of the Western world. Upon PCa progression into metastatic disease, androgen deprivation therapy is applied as the first-line treatment, and has been shown to be effective in most patients, leading to a decrease in serum prostate-specific antigen and relief of disease-related symptoms. However, advanced PCa almost inevitably progresses to a castration-resistant state, and is currently regarded as incurable. The large body of evidence indicates that PCa cells remain dependent on androgen receptor (AR) signaling even in an androgen-deprived environment. As such, development of drugs that target AR and AR signaling pathways have become one of the major milestones in treatment of castration-resistant PCa (CRPC). Nevertheless, currently available therapies that target AR signaling are still regarded as palliative and more potent therapies are in great need. Over the past few years, a wide range of novel therapies has entered clinical trial for treatment of CRPC, including androgen synthesis inhibitors (abiraterone acetate), chemotherapeutic agents (docetaxel and cabazitaxel), and immunotherapies (sipuleucel-T). In this context, enzalutamide (previously referred to as MDV3100) is a novel second generation antiandrogen that has been demonstrated to significantly improve survival in men with metastatic CRPC in several clinical trials. In this paper we summarize recently completed and ongoing clinical trials of enzalutamide, and briefly discuss the efficacy of the novel antiandrogen therapy and its limitations for treatment of CRPC

Overcoming Drug Resistance and Treating Advanced Prostate Cancer.

Most of the prostate cancers (PCa) in advanced stage will progress to castration-resistant prostate cancer (CRPC). Within CRPC group, 50-70% of the patients will develop bone metastasis in axial and other regions of the skeleton. Once PCa cells spread to the bone, currently, no treatment regimens are available to eradicate the metastasis, and cancer- related death becomes inevitable. In 2012, it is estimated that there will be 28,170 PCa deaths in the United States. Thus, PCa bone metastasis-associated clinical complications and treatment resistance pose major clinical challenges. In this review, we will present recent findings on the molecular and cellular pathways that are responsible for bone metastasis of PCa. We will address several novel mechanisms with a focus on the role of bone and bone marrow microenvironment in promoting PCa metastasis, and will further discuss why prostate cancer cells preferentially metastasize to the bone. Additionally, we will discuss novel roles of several key pathways, including angiogenesis and extracellular matrix remodeling in bone marrow and stem cell niches with their relationship to PCa bone metastasis and poor treatment response. We will evaluate how various chemotherapeutic drugs and radiation therapies may allow aggressive PCa cells to gain advantageous mutations leading to increased survival and rendering the cancer cells to become resistant to treatment. The novel concept relating several key survival and invasion signaling pathways to stem cell niches and treatment resistance will be reviewed. Lastly, we will provide an update of several recently developed novel drug candidates that target metastatic cancer microenvironments or niches, and discuss the advantages and significance provided by such therapeutic approaches in pursuit of overcoming drug resistance and treating advanced PCa

Calibration of the Mid-Infrared Tully-Fisher Relation

Distance measures on a coherent scale around the sky are required to address the outstanding cosmological problems of the Hubble Constant and of departures from the mean cosmic flow. The correlation between galaxy luminosities and rotation rates can be used to determine distances to many thousands of galaxies in a wide range of environments potentially out to 200 Mpc. Mid-infrared (3.6 microns) photometry with the Spitzer Space Telescope is particularly valuable as the source of the luminosities because it provides products of uniform quality across the sky. From a perch above the atmosphere, essentially the total magnitude of targets can be registered in exposures of a few minutes. Extinction is minimal and the flux is dominated by the light from old stars which is expected to correlate with the mass of the targets. In spite of the superior photometry, the correlation between mid-infrared luminosities and rotation rates extracted from neutral hydrogen profiles is slightly degraded from the correlation found with I band luminosities. A color correction recovers a correlation that provides comparable accuracy to that available at I band (~20% 1sigma in an individual distance) while retaining the advantages identified above. Without the color correction the relation between linewidth and [3.6] magnitudes is M^{b,i,k,a}_{[3.6]} = -20.34 - 9.74 (log W_{mx}^{i} -2.5). This description is found with a sample of 213 galaxies in 13 clusters that define the slope and 26 galaxies with Cepheid or tip of the red giant branch distances that define the zero point. A color corrected parameter M_{C_{[3.6]}} is constructed that has reduced scatter: M_{C_{[3.6]}} = -20.34 - 9.13 (log W_{mx}^{i} -2.5). Consideration of the 7 calibration clusters beyond 50 Mpc, outside the domain of obvious peculiar velocities, provides a preliminary Hubble Constant estimate of H_0=74+/-5 km/s/Mpc.Comment: Accepted for publication in The Astrophysical Journal, 14 pages, 11 figures, 4 table

MIR137 is an androgen regulated repressor of an extended network of transcriptional coregulators

Androgens and the androgen receptor (AR) play crucial roles in male development and the pathogenesis and progression of prostate cancer (PCa). The AR functions as a ligand dependent transcription factor which recruits multiple enzymatically distinct epigenetic coregulators to facilitate transcriptional regulation in response to androgens. Over-expression of AR coregulators is implicated in cancer. We have shown that over-expression of KDM1A, an AR coregulator, contributes to PCa recurrence by promoting VEGFA expression. However the mechanism(s) whereby AR coregulators are increased in PCa remain poorly understood. In this study we show that the microRNA hsa-miR-137 (miR137) tumor suppressor regulates expression of an extended network of transcriptional coregulators including KDM1A/LSD1/AOF1, KDM2A/JHDM1A/FBXL11, KDM4A/JMJD2A, KDM5B JARID1B/PLU1, KDM7A/JHDM1D/PHF8, MED1/TRAP220/DRIP205 and NCoA2/SRC2/TIF2. We show that expression of miR137 is increased by androgen in LnCaP androgen PCa responsive cells and that the miR137 locus is epigenetically silenced in androgen LnCaP:C4-2 and PC3 independent PCa cells. In addition, we found that restoration of miR137 expression down-regulates expression of VEGFA, an AR target gene, which suggests a role of miR137 loss also in cancer angiogenesis. Finally we show functional inhibition of mIR137 function enhanced androgen induction of PSA/KLK3 expression. Our data indicate that miR137 functions as an androgen regulated suppressor of androgen signaling by modulating expression of an extended network of transcriptional coregulators. Therefore, we propose that epigenetic silencing of miR137 is an important event in promoting androgen signaling during prostate carcinogenesis and progression

Regulation of vascular endothelial growth factor in prostate cancer

Prostate cancer (PCa) is the most common malignancy affecting men in the western world. Although radical prostatectomy and radiation therapy can successfully treat PCa in the majority of patients, up to ∼30% will experience local recurrence or metastatic disease. Prostate carcinogenesis and progression is typically an androgen-dependent process. For this reason, therapies for recurrent PCa target androgen biosynthesis and androgen receptor function. Such androgen deprivation therapies (ADT) are effective initially, but the duration of response is typically ≤24 months. Although ADT and taxane-based chemotherapy have delivered survival benefits, metastatic PCa remains incurable. Therefore, it is essential to establish the cellular and molecular mechanisms that enable localized PCas to invade and disseminate. It has long been accepted that metastases require angiogenesis. In the present review, we examine the essential role for angiogenesis in PCa metastases, and we focus in particular on the current understanding of the regulation of vascular endothelial growth factor (VEGF) in localized and metastatic PCa. We highlight recent advances in understanding the role of VEGF in regulating the interaction of cancer cells with tumor-associated immune cells during the metastatic process of PCa. We summarize the established mechanisms of transcriptional and post-transcriptional regulation of VEGF in PCa cells and outline the molecular insights obtained from preclinical animal models of PCa. Finally, we summarize the current state of anti-angiogenesis therapies for PCa and consider how existing therapies impact VEGF signaling

Cyclin A1 and P450 aromatase promote metastatic homing and growth of stem-like prostate cancer cells in the bone marrow

Bone metastasis is a leading cause of morbidity and mortality in prostate cancer (PCa). While cancer stem-like cells have been implicated as a cell of origin for PCa metastases, the pathways which enable metastatic development at distal sites remain largely unknown. In this study, we illuminate pathways relevant to bone metastasis in this disease. We observed that cyclin A1 (CCNA1) protein expression was relatively higher in PCa metastatic lesions in lymph node, lung, and bone/bone marrow. In both primary and metastatic tissues, cyclin A1 expression was also correlated with aromatase (CYP19A1), a key enzyme that directly regulates the local balance of androgens to estrogens. Cyclin A1 overexpression in the stem-like ALDHhigh subpopulation of PC3M cells, one model of PCa, enabled bone marrow integration and metastatic growth. Further, cells obtained from bone marrow metastatic lesions displayed self-renewal capability in colony forming assays. In the bone marrow, Cyclin A1 and aromatase enhanced local bone marrow-releasing factors, including androgen receptor, estrogen and matrix metalloproteinase MMP9 and promoted hte metastatic growth of PCa cells. Moreover, ALDHhigh tumor cells expressing elevated levels of aromatase stimulated tumor/host estrogen production and acquired a growth advantage in the presence of host bone marrow cells. Overall, these findings suggest that local production of steroids and MMPs in the bone marrow may provide a suitable microenvironment for ALDHhigh PCa cells to establish metastatic growths, offering new approaches to therapeutically target bone metastases

The role of PIP5K1α/pAKT and targeted inhibition of growth of subtypes of breast cancer using PIP5K1α inhibitor

Despite recent improvement in adjuvant therapies, triple-negative, and ER+ subtypes of breast cancer (BC) with metastatic potentials remain the leading cause of BC-related deaths. We investigated the role of phosphatidylinositol-4-phosphate 5-kinase alpha (PIP5Kα), a key upstream factor of PI3K/AKT, and the therapeutic effect of PIP5Kα inhibitor on subtypes of BC. The clinical importance of PIP5K1α and its association with survivals were analyzed using three BC cohorts from Nottingham (n = 913), KM plotter (n = 112) and TCGA (n = 817). Targeted overexpression or knockdown of PIP5K1α were introduced into BC cell lines. The effects of PIP5K1α and its inhibitor on growth and invasion of BC were confirmed by using in vitro assays including proliferation, migration, apoptosis and luciferase reporter assays and in vivo xenograft mouse models. All statistical tests were two-sided. PIP5K1α was associated with poor patient outcome in triple-negative BC (for PIP5K1α protein, p = 0.011 and for mRNA expression, p = 0.028, log-rank test). 29% of triple-negative BC had PIP5K1A gene amplification. Elevated level of PIP5K1α increased expression of pSer-473 AKT (p < 0.001) and invasiveness of triple-negative MDA-MB-231 cells (p < 0.001). Conversely, inhibition of PIP5K1α using its inhibitor ISA-2011B, or via knockdown suppressed growth and invasiveness of MDA-MB-231 xenografts (mean vehicle-treated controls = 2160 mm3, and mean ISA-2011B-treated = 600 mm3, p < 0.001). ISA-2011B-treatment reduced expression of pSer-473 AKT (p < 0.001) and its downstream effectors including cyclin D1, VEGF and its receptors, VEGFR1 and VEGFR2 (p < 0.001) in xenograft tumors. In ER+ cancer cells, PIP5K1α acted on pSer-473 AKT, and was in complexes with VEGFR2, serving as co-factor of ER-alpha to regulate activities of target genes including cyclin D1 and CDK1. Our study suggests that our developed PIP5K1α inhibitor has a great potential on refining targeted therapeutics for treatment of triple-negative and ER+ BC with abnormal PI3K/AKT pathways

MicroRNAs in the pathogenesis, diagnosis, prognosis and targeted treatment of cutaneous T-cell lymphomas

Cutaneous T-cell lymphoma (CTCL) represents a heterogeneous group of potentially devastating primary skin malignancies. Despite decades of intense research efforts, the pathogenesis is still not fully understood. In the early stages, both clinical and histopathological diagnosis is often difficult due to the ability of CTCL to masquerade as benign skin inflammatory dermatoses. Due to a lack of reliable biomarkers, it is also difficult to predict which patients will respond to therapy or progress towards severe recalcitrant disease. In this review, we discuss recent discoveries concerning dysregulated microRNA (miR) expression and putative pathological roles of oncogenic and tumor suppressive miRs in CTCL. We also focus on the interplay between miRs, histone deacetylase inhibitors, and oncogenic signaling pathways in malignant T cells as well as the impact of miRs in shaping the inflammatory tumor microenvironment. We highlight the potential use of miRs as diagnostic and prognostic markers, as well as their potential as therapeutic targets. Finally, we propose that the combined use of miR-modulating compounds with epigenetic drugs may provide a novel avenue for boosting the clinical efficacy of existing anti-cancer therapies in CTCL