共查询到20条相似文献,搜索用时 31 毫秒
1.
Yafeng Ma Alison Luk Francis P. Young David Lynch Wei Chua Bavanthi Balakrishnar Paul de Souza Therese M. Becker 《International journal of molecular sciences》2016,17(8)
Androgen receptor splice variant V7 (AR-V7) was recently identified as a valuable predictive biomarker in metastatic castrate-resistant prostate cancer. Here, we report a new, sensitive and accurate screen for AR-V7 mRNA expression directly from circulating tumor cells (CTCs): We combined EpCAM-based immunomagnetic CTC isolation using the IsoFlux microfluidic platform with droplet digital polymerase chain reaction (ddPCR) to analyze total AR and AR-V7 expression from prostate cancer patients CTCs. We demonstrate that AR-V7 is reliably detectable in enriched CTC samples with as little as five CTCs, even considering tumor heterogeneity, and confirm detection of AR-V7 in CTC samples from advanced prostate cancer (PCa) patients with AR-V7 detection limited to castrate resistant disease status in our sample set. Sensitive molecular analyses of circulating tumor cells (CTCs) or circulating tumor nucleic acids present exciting strategies to detect biomarkers, such as AR-V7 from non-invasive blood samples, so-called blood biopsies. 相似文献
2.
3.
4.
Haozhe Zhang Yi Zhou Zengzhen Xing Rajiv Kumar Sah Junqi Hu Hailiang Hu 《International journal of molecular sciences》2022,23(21)
All aspects of prostate cancer evolution are closely related to androgen levels and the status of the androgen receptor (AR). Almost all treatments target androgen metabolism pathways and AR, from castration-sensitive prostate cancer (CSPC) to castration-resistant prostate cancer (CRPC). Alterations in androgen metabolism and its response are one of the main reasons for prostate cancer drug resistance. In this review, we will introduce androgen metabolism, including how the androgen was synthesized, consumed, and responded to in healthy people and prostate cancer patients, and discuss how these alterations in androgen metabolism contribute to the resistance to anti-androgen therapy. 相似文献
5.
Friedemann Zengerling Wolfgang Streicher Andres J. Schrader Mark Schrader Bianca Nitzsche Marcus V. Cronauer Michael H?pfner 《International journal of molecular sciences》2012,13(9):11530-11542
Recent evidence suggests that the development of castration resistant prostate cancer (CRPCa) is commonly associated with an aberrant, ligand-independent activation of the androgen receptor (AR). A putative mechanism allowing prostate cancer (PCa) cells to grow under low levels of androgens, is the expression of constitutively active, C-terminally truncated AR lacking the AR-ligand binding domain (LBD). Due to the absence of a LBD, these receptors, termed ARΔLBD, are unable to respond to any form of anti-hormonal therapies. In this study we demonstrate that the multikinase inhibitor sorafenib inhibits AR as well as ARΔLBD-signalling in CRPCa cells. This inhibition was paralleled by proteasomal degradation of the AR- and ARΔLBD-molecules. In line with these observations, maximal antiproliferative effects of sorafenib were achieved in AR and ARΔLBD-positive PCa cells. The present findings warrant further investigations on sorafenib as an option for the treatment of advanced AR-positive PCa. 相似文献
6.
Emma J. Montgomery Enming Xing Moray J. Campbell Pui-Kai Li James S. Blachly Allan Tsung Christopher C. Coss 《International journal of molecular sciences》2022,23(22)
Hepatocellular carcinoma (HCC) is the predominant type of liver cancer and a leading cause of cancer-related death globally. It is also a sexually dimorphic disease with a male predominance both in HCC and in its precursors, non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH). The role of the androgen receptor (AR) in HCC has been well documented; however, AR-targeted therapies have failed to demonstrate efficacy in HCC. Building upon understandings of AR in prostate cancer (PCa), this review examines the role of AR in HCC, non-androgen-mediated mechanisms of induced AR expression, the existence of AR splice variants (AR-SV) in HCC and concludes by surveying current AR-targeted therapeutic approaches in PCa that show potential for efficacy in HCC in light of AR-SV expression. 相似文献
7.
Matteo Rosellini Matteo Santoni Veronica Mollica Alessandro Rizzo Alessia Cimadamore Marina Scarpelli Nadia Storti Nicola Battelli Rodolfo Montironi Francesco Massari 《International journal of molecular sciences》2021,22(4)
Prostate cancer is the most frequent malignancy in the worldwide male population; it is also one of the most common among all the leading cancer-related death causes. In the last two decades, the therapeutic scenario of metastatic castration-resistant prostate cancer has been enriched by the use of chemotherapy and androgen receptor signaling inhibitors (ARSI) and, more recently, by immunotherapy and poly(ADP–ribose) polymerase (PARP) inhibitors. At the same time, several trials have shown the survival benefits related to the administration of novel ARSIs among patients with non-castration-resistant metastatic disease along with nonmetastatic castration-resistant cancer too. Consequently, the therapeutic course of this malignancy has been radically expanded, ensuring survival benefits never seen before. Among the more recently emerging agents, the so-called “antibody–drug conjugates” (ADCs) are noteworthy because of their clinical practice changing outcomes obtained in the management of other malignancies (including breast cancer). The ADCs are novel compounds consisting of cytotoxic agents (also known as the payload) linked to specific antibodies able to recognize antigens expressed over cancer cells’ surfaces. As for prostate cancer, researchers are focusing on STEAP1, TROP2, PSMA, CD46 and B7-H3 as optimal antigens which may be targeted by ADCs. In this paper, we review the pivotal trials that have currently changed the therapeutic approach to prostate cancer, both in the nonmetastatic castration-resistant and metastatic settings. Therefore, we focus on recently published and ongoing trials designed to investigate the clinical activity of ADCs against prostate malignancy, characterizing these agents. Lastly, we briefly discuss some ADCs-related issues with corresponding strategies to overwhelm them, along with future perspectives for these promising novel compounds. 相似文献
8.
Elena Ferrari Valeria Naponelli Saverio Bettuzzi 《International journal of molecular sciences》2021,22(11)
The members of the Lemur Tyrosine Kinases (LMTK1-3) subfamily constitute a group of three membrane-anchored kinases. They are known to influence a wide variety of key cellular events, often affecting cell proliferation and apoptosis. They have been discovered to be involved in cancer, in that they impact various signalling pathways that influence cell proliferation, migration, and invasiveness. Notably, in the context of genome-wide association studies, one member of the LMTK family has been identified as a candidate gene which could contribute to the development of prostate cancer. In this review, of published literature, we present evidence on the role of LMTKs in human prostate cancer and model systems, focusing on the complex network of interacting partners involved in signalling cascades that are frequently activated in prostate cancer malignancy. We speculate that the modulators of LMTK enzyme expression and activity would be of high clinical relevance for the design of innovative prostate cancer treatment. 相似文献
9.
Radu Costin Bizga Nicolescu Zoe R. Maylin Dr. Francisco Javier Pérez-Areales Dr. Jessica Iegre Prof. Hardev S. Pandha Dr. Mohammad Asim Prof. David R. Spring 《ChemMedChem》2023,18(2):e202200548
Androgen receptor targeted therapies for prostate cancer have serious limitations in advanced stages of the disease. While resistance to the FDA-approved enzalutamide is extensively documented, novel therapies based on epichlorohydrin scaffolds (EPI) are currently in clinical trials, but display suboptimal pharmacokinetics. Herein, we report the synthesis and biological characterisation of a novel class of compounds designed through covalently linking enzalutamide and EPI-001 through various triazole based linkers. The compounds display an 18 to 53 fold improvement in the cell killing potency towards C4-2b prostate cancer (PCa) cells compared to the gold standards of therapy, enzalutamide and EPI-001. The most promising compounds were proven to exhibit their toxicity exclusively through androgen receptor (AR) mediated pathways. This work sets the basis for the first class of hybrid AR inhibitors which successfully combine two drug moieties – EPI-001 and enzalutamide – into the same molecule. 相似文献
10.
11.
12.
James Farrell Gyorgy Petrovics David G. McLeod Shiv Srivastava 《International journal of molecular sciences》2013,14(8):15510-15531
Prostate cancer is the most common non-skin cancer and the second leading cause of cancer-related death for men in the United States. Prostate cancer incidence and associated mortality are highest in African American men in comparison to other races. The observed differences in incidence and disease aggressiveness at presentation support a potential role for different pathways of prostate carcinogenesis between African American and Caucasian men. This review focuses on some of the recent molecular biology discoveries, which have been investigated in prostate carcinogenesis and their likely contribution to the known discrepancies across race and ethnicity. Key discussion points include the androgen receptor gene structure and function, genome-wide association studies and epigenetics. The new observations of the ethnic differences of the ERG oncogene, the most common prostate cancer gene, are providing new insights into ERG based stratification of prostate cancers in the context of ethnically diverse patient populations. This rapidly advancing knowledge has the likely potential to benefit clinical practice. Current and future work will improve the ability to sub-type prostate cancers by molecular alterations and lead to targeted therapy against this common malignancy. 相似文献
13.
14.
Chunli Wang Lingzu Kong Seokmin Kim Sunyoung Lee Sechan Oh Seona Jo Inhwan Jang Tae-Don Kim 《International journal of molecular sciences》2022,23(18)
Interleukin-7 (IL-7) is a multipotent cytokine that maintains the homeostasis of the immune system. IL-7 plays a vital role in T-cell development, proliferation, and differentiation, as well as in B cell maturation through the activation of the IL-7 receptor (IL-7R). IL-7 is closely associated with tumor development and has been used in cancer clinical research and therapy. In this review, we first summarize the roles of IL-7 and IL-7Rα and their downstream signaling pathways in immunity and cancer. Furthermore, we summarize and discuss the recent advances in the use of IL-7 and IL-7Rα as cancer immunotherapy tools and highlight their potential for therapeutic applications. This review will help in the development of cancer immunotherapy regimens based on IL-7 and IL-7Rα, and will also advance their exploitation as more effective and safe immunotherapy tools. 相似文献
15.
Alessandra Bosutti Barbara Dapas Gabriele Grassi Rossana Bussani Fabrizio Zanconati Fabiola Giudici Cristina Bottin Nicola Pavan Carlo Trombetta Bruna Scaggiante 《International journal of molecular sciences》2022,23(8)
Although the eukaryotic elongation factor eEF1A1 plays a role in various tumours, there is little information on its prognosis/therapeutic value in prostate carcinoma. In high-grade and castration-resistant prostate carcinoma (CRPC), the identification of novel therapeutic markers/targets remains a priority. The expression of eEF1A1 protein was determined in formalin-fixed, paraffin-embedded prostate cancer and hyperplasia tissue by IHC. The role of eEF1A1 was investigated in a cellular model using a DNA aptamer (GT75) we previously developed. We used the aggressive CRPC cancer PC-3 and non-tumourigenic PZHPV-7 lines. Cytotoxicity was measured by the MTS assay and eEF1A1 protein levels by in-cell Western assays. The mRNA levels of eEF1A1 were measured by qPCR and ddPCR. Higher expression of eEF1A1 was found in Gleason 7–8 compared with 4–6 tissues (Gleason ≥ 7, 87% versus Gleason ≤ 6, 54%; p = 0.033). Patients with a high expression of eEF1A1 had a worse clinical outcome. In PC-3, but not in PZHPV-7, GT75 decreased cell viability and increased autophagy and cell detachment. In PC-3 cells, but not in PZHPV-7, GT75 mainly co-localised with the fraction of eEF1A1 bound to actin. Overexpression of the eEF1A1 protein can identify aggressive forms of prostate cancer. The targeting of eEF1A1 by GT75 impaired cell viability in PC-3 cancer cells but not in PZHPV-7 non-tumourigenic cells, indicating a specific role for the protein in cancer survival. The eEF1A1–actin complexes appear to be critical for the viability of PC-3 cancer cells, suggesting that eEF1A1 may be an attractive target for therapeutic strategies in advanced forms of prostate cancer. 相似文献
16.
Pamela McCall Claire E. Adams Jennifer M. Willder Lindsay Bennett Tahir Qayyum Clare Orange Mark A. Underwood Joanne Edwards 《International journal of molecular sciences》2013,14(8):16656-16671
We previously reported that AR phosphorylation at serine 213 was associated with poor outcome and may contribute to prostate cancer development and progression. This study investigates if specific AR phosphorylation sites have differing roles in the progression of hormone naïve prostate cancer (HNPC) to castrate resistant disease (CRPC). A panel of phosphospecific antibodies were employed to study AR phosphorylation in 84 matched HNPC and CRPC tumours. Immunohistochemistry measured Androgen receptor expression phosphorylated at serine residues 94 (pAR94), 308 (pAR308), 650(pAR650) and 791 (pAR791). No correlations with clinical parameters were observed for pAR94 or pAR650 in HNPC or CRPC tumours. In contrast to our previous observation with serine 213, high pAR308 is significantly associated with a longer time to disease specific death (p = 0.011) and high pAR791 expression significantly associated with a longer time to disease recurrence (p = 0.018) in HNPC tumours and longer time to death from disease recurrence (p = 0.040) in CRPC tumours. This observation in CRPC tumours was attenuated in high apoptotic tumours (p = 0.022) and low proliferating tumours (p = 0.004). These results demonstrate that understanding the differing roles of AR phosphorylation is necessary before this can be exploited as a target for castrate resistant prostate cancer. 相似文献
17.
Milena Rondón-Lagos Victoria E. Villegas Nelson Rangel Magda Carolina Sánchez Peter G. Zaphiropoulos 《International journal of molecular sciences》2016,17(8)
17β-Estradiol (E2) plays a pivotal role in the development and progression of breast cancer. As a result, blockade of the E2 signal through either tamoxifen (TAM) or aromatase inhibitors is an important therapeutic strategy to treat or prevent estrogen receptor (ER) positive breast cancer. However, resistance to TAM is the major obstacle in endocrine therapy. This resistance occurs either de novo or is acquired after an initial beneficial response. The underlying mechanisms for TAM resistance are probably multifactorial and remain largely unknown. Considering that breast cancer is a very heterogeneous disease and patients respond differently to treatment, the molecular analysis of TAM’s biological activity could provide the necessary framework to understand the complex effects of this drug in target cells. Moreover, this could explain, at least in part, the development of resistance and indicate an optimal therapeutic option. This review highlights the implications of TAM in breast cancer as well as the role of receptors/signal pathways recently suggested to be involved in the development of TAM resistance. G protein—coupled estrogen receptor, Androgen Receptor and Hedgehog signaling pathways are emerging as novel therapeutic targets and prognostic indicators for breast cancer, based on their ability to mediate estrogenic signaling in ERα-positive or -negative breast cancer. 相似文献
18.
Helen Saxby Stergios Boussios Christos Mikropoulos 《International journal of molecular sciences》2022,23(9)
Stereotactic ablative body radiotherapy (SABR) is currently used as a salvage intervention for men with oligometastatic prostate cancer (PC), and increasingly so since the results of the Stereotactic Ablative Body Radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers (SABR-COMET) trial reported a significant improvement in overall survival with SABR. The addition of androgen deprivation therapy (ADT) to localised prostate radiotherapy improves survival as it sensitises PC to radiotherapy-induced cell death. The importance of the androgen receptor (AR) gene pathway in the development of resistance to radiotherapy is well established. In this review paper, we will examine the data to determine how we can overcome the upregulation of the AR pathway and suggest a strategy for improving outcomes in men with oligometastatic hormone-sensitive PC. 相似文献
19.
20.
Thanakorn Pungsrinont Julia Kallenbach Aria Baniahmad 《International journal of molecular sciences》2021,22(20)
Androgen deprivation therapy (ADT) and androgen receptor (AR)-targeted therapy are the gold standard options for treating prostate cancer (PCa). These are initially effective, as localized and the early stage of metastatic disease are androgen- and castration-sensitive. The tumor strongly relies on systemic/circulating androgens for activating AR signaling to stimulate growth and progression. However, after a certain point, the tumor will eventually develop a resistant stage, where ADT and AR antagonists are no longer effective. Mechanistically, it seems that the tumor becomes more aggressive through adaptive responses, relies more on alternative activated pathways, and is less dependent on AR signaling. This includes hyperactivation of PI3K-AKT-mTOR pathway, which is a central signal that regulates cell pro-survival/anti-apoptotic pathways, thus, compensating the blockade of AR signaling. The PI3K-AKT-mTOR pathway is well-documented for its crosstalk between genomic and non-genomic AR signaling, as well as other signaling cascades. Such a reciprocal feedback loop makes it more complicated to target individual factor/signaling for treating PCa. Here, we highlight the role of PI3K-AKT-mTOR signaling as a resistance mechanism for PCa therapy and illustrate the transition of prostate tumor from AR signaling-dependent to PI3K-AKT-mTOR pathway-dependent. Moreover, therapeutic strategies with inhibitors targeting the PI3K-AKT-mTOR signal used in clinic and ongoing clinical trials are discussed. 相似文献