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Urinary incontinence is a common postoperative complication of radical prostatectomy (RP). In order to improve postoperative urinary continence rate, we proposed a urethral reconstruction technique which can prevent functional urethra retracting and maintain urethral stability. This study aims to describe the novel technique of robotic-assisted radical prostatectomy (RARP) and compare it with standard vesicourethral anastomosis (VUA) in the early postoperative urinary continence.Based on the anatomy study, we proposed our novel urethral reconstruction technique. The technique is a continuous suture of the outer urethral rhabdosphincter and the levator ani muscle, the medial dorsal raphe and Denonvilliers fascia. A retrospective, single-center cohort of 75 patients undergoing RARP between August 2020 and February 2022 was analyzed, including 38 patients in the study group undergoing the novel urethral reconstruction technique and 37 patients in the control group undergoing the standard VUA.The two groups were comparable in all baseline characteristics. The continence rates in the study group were significantly higher than that in the control group at the day catheter was removed, 1st month and 3rd month after the catheter removal (71.1% vs 37.8%, p = 0.004; 76.3% vs 43.2%, p = 0.003; and 94.7% vs 78.4%, p = 0.037; respectively). No significant difference was observed in operation time (p = 0.241). Meantime, no increase in complications rate was observed in the study group.Our novel urethral reconstruction technique contributes to the early urinary continence after RARP effectively and safely.

The new generation androgen receptor (AR) pathway inhibitor enzalutamide can prolong the survival of patients with metastatic prostate cancer. However, resistance to enzalutamide inevitably develops in these patients, and the underlying mechanisms of this resistance are not fully defined. Here we demonstrate that the kinesin family member 15 (KIF15) contributes to enzalutamide resistance by enhancing the AR signaling in prostate cancer cells. KIF15 directly bound the N-terminus of AR/AR-V7 and prevented AR/AR-V7 proteins from degradation by increasing the protein association of ubiquitin-specific protease 14 (USP14) with AR/AR-V7. In turn, the transcriptionally active AR stimulated KIF15 expression. KIF15 inhibitors alone or in combination with enzalutamide significantly suppressed enzalutamide-resistant prostate cancer cell growth and xenograft progression. These findings highlight a key role of KIF15 in enabling prostate cancer cells to develop therapy resistance to enzalutamide and rationalize KIF15 as a potential therapeutic target.Significance:These findings demonstrate how reciprocal activation between KIF15 and AR contributes to enzalutamide resistance in prostate cancer and highlights cotargeting KIF15 and AR as a therapeutic strategy for these tumors.

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer arising mostly from adenocarcinoma via neuroendocrine transdifferentiation following androgen deprivation therapy. Mechanisms contributing to both NEPC development and its aggressiveness remain elusive. In light of the fact that hyperchromatic nuclei are a distinguishing histopathologic feature of NEPC, we utilized transcriptomic analyses of our patient-derived xenograft (PDX) models, multiple clinical cohorts, and genetically engineered mouse models to identify 36 heterochromatin-related genes that are significantly enriched in NEPC. Longitudinal analysis using our unique, first-in-field PDX model of adenocarcinoma-to-NEPC transdifferentiation revealed that, among those 36 heterochromatin-related genes, heterochromatin protein 1α (HP1α) expression increased early and steadily during NEPC development and remained elevated in the developed NEPC tumor. Its elevated expression was further confirmed in multiple PDX and clinical NEPC samples. HP1α knockdown in the NCI-H660 NEPC cell line inhibited proliferation, ablated colony formation, and induced apoptotic cell death, ultimately leading to tumor growth arrest. Its ectopic expression significantly promoted NE transdifferentiation in adenocarcinoma cells subjected to androgen deprivation treatment. Mechanistically, HP1α reduced expression of androgen receptor and RE1 silencing transcription factor and enriched the repressive trimethylated histone H3 at Lys9 mark on their respective gene promoters. These observations indicate a novel mechanism underlying NEPC development mediated by abnormally expressed heterochromatin genes, with HP1α as an early functional mediator and a potential therapeutic target for NEPC prevention and management.Significance: Heterochromatin proteins play a fundamental role in NEPC, illuminating new therapeutic targets for this aggressive disease. Cancer Res; 78(10); 2691–704. ©2018 AACR.

supplemary figures and figure legend

Supplementary materials and methods used in this study. Supplementary table with primer sequences. Figure S1, Histological feature of PDX models and heatmaps of PDX and clinical cohorts. Figure S2, IHC staining of HP1α in PDX models, and expression of Hp1α mRNA in NPp53 CRPC GEM models. Figure S3, Additional analyses of HP1α function in NEPC cells. Figure S4, Additional analyses of HP1α function in NE transdifferentiation. Figure S5, Additional analyses of the repressive function of HP1α on AR and REST expression. Figure S6, Additional analyses of the function of HP1α. Supplementary references.

Embryonal rhabdomyosarcoma (ERMS) is a major subtype of rhabdomyosarcoma, mainly affect children. There is seldom report for perineal ERMS in adults, since its rare location and the age.A 20-year old male adult was admitted due to the perineal mass.Diagnosis by histopathological examination of the biopsy sample was ERMS. Magnetic resonance imaging showed the tumor was found in the perineal region, with metastasis to pelvic cavity, right testis, lymph nodes and bone.The patient received Isophosphamide and Epirubicin for 4 cycles, followed by Irinotecan and Vindesine Sulfate for 2 cycles, then cisplatin, Dacarbazine and Apatinib for 3 cycles.The patient showed no response to chemotherapy.Perineal ERMS in adults is very rare. There is still no standard therapy for adult ERMS. Personalized therapy might be promising treatment for each individual.

Background Androgen deprivation therapy (ADT) remains the leading systemic therapy for locally advanced and metastatic prostate cancers (PCa). While a majority of PCa patients initially respond to ADT, the durability of response is variable and most patients will eventually develop incurable castration-resistant prostate cancer (CRPC). Our research objective is to identify potential early driver genes responsible for CRPC development. Methods We have developed a unique panel of hormone-naïve PCa (HNPC) patient-derived xenograft (PDX) models at the Living Tumor Laboratory. The PDXs provide a unique platform for driver gene discovery as they allow for the analysis of differentially expressed genes via transcriptomic profiling at various time points after mouse host castration. In the present study, we focused on genes with expression changes shortly after castration but before CRPC has fully developed. These are likely to be potential early drivers of CRPC development. Such genes were further validated for their clinical relevance using data from PCa patient databases. ZRSR2 was identified as a top gene candidate and selected for further functional studies. Results ZRSR2 is significantly upregulated in our PDX models during the early phases of CRPC development after mouse host castration and remains consistently high in fully developed CRPC PDX models. Moreover, high ZRSR2 expression is also observed in clinical CRPC samples. Importantly, elevated ZRSR2 in PCa samples is correlated with poor patient treatment outcomes. ZRSR2 knockdown reduced PCa cell proliferation and delayed cell cycle progression at least partially through inhibition of the Cyclin D1 (CCND1) pathway. Conclusion Using our unique HNPC PDX models that develop into CRPC after host castration, we identified ZRSR2 as a potential early driver of CRPC development.

Background: As distinct marker of proliferating cells, chromatin assembly factor-1 (CAF-1) was critical in DNA replication. CHAF1A, the major subunit in CAF-1 complex, has been shown to be highly expressed in some cancer types. However, there is paucity information about the clinical significance, molecule functions and co-expressed gene network of CHAF1A in breast cancer. Methods: Bioinformatic analysis of CHAF1A and its co-expression gene network were performed using various public databases. Results: Abnormally high expression of CHAF1A was found in 20 types of cancer tissues. Elevated expression of CHAF1A was positively correlated with breast cancer progression and poor patient outcome. Co-expression gene network analysis indicated that CHAF1A was associated with not only cell proliferation, DNA repair, apoptosis, but also cancer metabolism, immune system, drug resistance and so on. More importantly, higher expression of CHAF1A was positively correlated with immunosuppressive microenvironment and resistance to endocrine therapy and chemotherapy. Conclusions: The current study indicates that elevated expression of CHAF1A can be used as diagnosis and poor prognosis biomarker of breast cancer. Although higher expression of CHAF1A induced fast resistance to endocrine therapy and chemotherapy, it may be a potential therapeutic target and biomarker to predict the sensitivity of immunotherapy in breast cancer patients.

Progesterone receptor (PR) antagonists have been found to be effective for treating certain human cancers. However, the steroidal structure of PR antagonists could bind to other hormone receptors, thus leading to serious side effects. On the other hand, non-steroidal PR antagonists have rarely been evaluated for their anti-cancer efficacy. Therefore, identifying novel non-steroidal PR antagonists possessing potent anti-cancer efficacy would be an attractive project to pursue. In this study, we presented a new metal-free oxidative C H arylation method to rapidly synthesize a series of 6-aryl-6H-benzo[c]chromene derivatives. Multiple cancer cell lines were used for their anti-cancer activity screening. An extensive analysis of structure–activity relationships (SAR) of the derivatives revealed that compounds 32 and 34 markedly inhibited the proliferation of MCF-7 cells with IC50 values of 6.32 ± 0.52 μM and 5.71 ± 0.49 μM, respectively. Further investigation indicated that derivatives 32 and 34 could elevate the expression of p21 and decrease the expressions of CDK4 and cyclin D1, leading to cell cycle arrest at G0/G1 phase. In addition, derivatives 32 and 34 could induce apoptosis of MCF-7 cells in both dose- and time-dependent manners by activation of p53 pathway, i.e., activation of Cleaved Caspase-3, p53 and P-p53 as well as elevation of the Bax/Bcl-2 ratio. Docking of derivatives 32 and 34 into a PR homology model exhibited potent PR antagonistic activity indicating the 6-aryl-6H-benzo[c]chromene derivatives are promising PR antagonists. We envisioned that derivatives 32 and 34 might be potential anti-cancer drug candidates as novel therapeutic treatment for breast cancer.

The new generation androgen receptor (AR) pathway inhibitor enzalutamide can prolong the survival of patients with metastatic prostate cancer. However, resistance to enzalutamide inevitably develops in these patients, and the underlying mechanisms of this resistance are not fully defined. Here we demonstrate that the kinesin family member 15 (KIF15) contributes to enzalutamide resistance by enhancing the AR signaling in prostate cancer cells. KIF15 directly bound the N-terminus of AR/AR-V7 and prevented AR/AR-V7 proteins from degradation by increasing the protein association of ubiquitin-specific protease 14 (USP14) with AR/AR-V7. In turn, the transcriptionally active AR stimulated KIF15 expression. KIF15 inhibitors alone or in combination with enzalutamide significantly suppressed enzalutamide-resistant prostate cancer cell growth and xenograft progression. These findings highlight a key role of KIF15 in enabling prostate cancer cells to develop therapy resistance to enzalutamide and rationalize KIF15 as a potential therapeutic target. Significance: These findings demonstrate how reciprocal activation between KIF15 and AR contributes to enzalutamide resistance in prostate cancer and highlights cotargeting KIF15 and AR as a therapeutic strategy for these tumors.

Triple-negative breast cancer (TNBC) represents a subset of breast cancer characterized by high aggressiveness and poor prognosis. Currently, there is no curative therapeutic regimen for TNBC patients. In this study, molecular hybridization strategy is adopted by combining benzopyran and indole pharmacophores together, and a library of structurally simple 1,3,4,9-tetrahydropyrano[3,4-b]indoles was rapidly constructed. The structure-activity relationship studies indicated that compound 23 exhibited the most potent effect against the MDA-MB-231 cells with IC

Background Although androgen deprivation therapy is initially effective in controlling growth of hormone-naive prostate cancers (HNPCs) in patients, currently incurable castration-resistant prostate cancer (CRPC) inevitably develops. Objective To identify CRPC driver genes that may provide new targets to enhance CRPC therapy. Design, setting, and participants Patient-derived xenografts (PDXs) of HNPCs that develop CRPC following host castration were examined for changes in expression of genes at various time points after castration using transcriptome profiling analysis; particular attention was given to pre-CRPC changes in expression indicative of genes acting as potential CRPC drivers. Outcome measurements and statistical analysis The functionality of a potential CRPC driver was validated via its knockdown in cultured prostate cancer cells; its clinical relevance was established using data from prostate cancer patient databases. Results and limitations Eighty genes were found to be significantly upregulated at the CRPC stage, while seven of them also showed elevated expression prior to CRPC development. Among the latter, growth factor receptor bound protein 10 ( GRB10 ) was the most significantly and consistently upregulated gene. Moreover, elevated GRB10 expression in clinical prostate cancer samples correlated with more aggressive tumor types and poorer patient treatment outcome. GRB10 knockdown markedly reduced prostate cancer cell proliferation and activity of AKT, a well-established CRPC mediator. A positive correlation between AKT activity and GRB10 expression was also found in clinical cohorts. Conclusions GRB10 acts as a driver of CRPC and sensitizes androgen receptor pathway inhibitors, and hence GRB10 targeting provides a novel therapeutic strategy for the disease. Patient summary Development of castration-resistant prostate cancer (CRPC) is a major problem in the management of the disease. Using state-of-the-art patient-derived hormone-naive prostate cancer xenograft models, we found and validated the growth factor receptor bound protein 10 gene as a driver of CRPC, indicating that it may be used as a new molecular target to enhance current CRPC therapy.

Aneustat (OMN54) is a multivalent, botanical anticancer candidate therapeutic. A recent Phase-I clinical trial has indicated that it is well tolerated by patients and has immunomodulatory activity. In our study, using in vitro and in vivo prostate cancer models, we investigated Aneustat with regard to effects on (i) cancer-generated immunosuppression based on aerobic glycolysis leading to acidification of the tumor microenvironment, and (ii) immune-related processes such as macrophage differentiation and shifts in the intratumoral levels of host immune cells. Aneustat markedly reduced glucose consumption, lactic acid secretion, glycolysis-related gene expressions and proliferation of human LNCaP prostate cancer cells. In addition, Aneustat induced differentiation of RAW264.7 macrophages to the M1 anticancer phenotype. Treatment of LNCaP xenografts and first-generation patient-derived prostate cancer tissue xenografts with Aneustat in both cases led to a marked shift in intratumoral host (mouse/patient) immune cell levels: a higher ratio of cytotoxic CD8+ T/Treg cells, higher numbers of NK cells, lower numbers of Treg cells and MDSCs, i.e. changes favoring the host anticancer immune response. Taken together, the data indicate that Aneustat has immunomodulatory activity based on inhibition of aerobic glycolysis which in patients may lead to reduction of cancer-induced immunosuppression. Furthermore, first-generation patient-derived cancer tissue xenograft models may be used for screening compounds for immunomodulatory activity.

// Dong Lin 1,2,* , Susan L. Ettinger 1,* , Sifeng Qu 1,2 , Hui Xue 2 , Noushin Nabavi 1,2 , Stephen Yiu Chuen Choi 1,2 , Robert H. Bell 1 , Fan Mo 1 , Anne M. Haegert 1 , Peter W. Gout 2 , Neil Fleshner 3 , Martin E. Gleave 1 , Michael Pollak 4 , Colin C. Collins 1 and Yuzhuo Wang 1,2 1 The Vancouver Prostate Centre, Vancouver General Hospital and Department of Urologic Sciences, The University of British Columbia, Vancouver, British Columbia, Canada 2 Department of Experimental Therapeutics, BC Cancer Research Centre, Vancouver, British Columbia, Canada 3 Division of Urology, University of Toronto, Department of Urology, University Health Network, Princess Margaret Hospital, Toronto, Ontario, Canada 4 Lady Davis Research Institute and McGill University, Montreal, Quebec, Canada * Co-first Authors Correspondence to: Yuzhuo Wang, email: // Colin C. Collins, email: // Michael Pollak, email: // Keywords : prostate cancer; tumour heterogeneity; metabolic heterogeneity; patient-derived xenografts Received : January 20, 2017 Accepted : January 25, 2017 Published : February 09, 2017 Abstract To avoid over- or under-treatment of primary prostate tumours, there is a critical need for molecular signatures to discriminate indolent from aggressive, lethal disease. Reprogrammed energy metabolism is an important hallmark of cancer, and abnormal metabolic characteristics of cancers have been implicated as potential diagnostic/prognostic signatures. While genomic and transcriptomic heterogeneity of prostate cancer is well documented and associated with tumour progression, less is known about metabolic heterogeneity of the disease. Using a panel of high fidelity patient-derived xenograft (PDX) models derived from hormone-naive prostate cancer, we demonstrated heterogeneity of expression of genes involved in cellular energetics and macromolecular biosynthesis. Such heterogeneity was also observed in clinical, treatment-naive prostate cancers by analyzing the transcriptome sequencing data. Importantly, a metabolic gene signature of increased one-carbon metabolism or decreased proline degradation was identified to be associated with significantly decreased biochemical disease-free patient survival. These results suggest that metabolic heterogeneity of hormone-naive prostate cancer is of biological and clinical importance and motivate further studies to determine the heterogeneity in metabolic flux in the disease that may lead to identification of new signatures for tumour/patient stratification and the development of new strategies and targets for therapy of prostate cancer.

Centromere protein-A (CENP-A), a histone-H3 variant, plays an essential role in cell division by ensuring proper formation and function of centromeres and kinetochores. Elevated CENP-A expression has been associated with cancer development. This study aimed to establish whether elevated CENP-A expression can be used as a prognostic and predictive cancer biomarker. Molecular profiling of CENP-A in human cancers was investigated using genomic, transcriptomic and patient information from databases, including COSMIC, Oncomine, Kaplan-Meier plotter and cBioPortal. A network of CENP-A co-expressed genes was derived from cBioPortal and analyzed using Ingenuity Pathway Analysis (IPA) and Oncomine protocols to explore the function of CENP-A and its predictive potential. Transcriptional and post-transcriptional regulation of CENP-A expression was analyzed in silico. It was found that CENP-A expression was elevated in 20 types of solid cancer compared with normal counterparts. Elevated CENP-A expression highly correlated with cancer progression and poor patient outcome. Genomic analysis indicated that the elevated CENP-A expression was not due to alterations in the sequence or copy number of the CENP-A gene. Furthermore, CENP-A can be regulated by key oncogenic proteins and tumor-suppressive microRNAs. CENP-A co-expression network analysis indicated that CENP-A function is associated with cell cycle progression. Oncomine analysis showed a strong correlation between elevated CENP-A expression and oncolytic response of breast cancer patients to taxane-based chemotherapy. In conclusion, elevated CENP-A expression is coupled to malignant progression of numerous types of cancer. It may be useful as a biomarker of poor patient prognosis and as a predictive biomarker for taxane-based chemotherapy.

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer arising mostly from adenocarcinoma via neuroendocrine transdifferentiation following androgen deprivation therapy. Mechanisms contributing to both NEPC development and its aggressiveness remain elusive. In light of the fact that hyperchromatic nuclei are a distinguishing histopathologic feature of NEPC, we utilized transcriptomic analyses of our patient-derived xenograft (PDX) models, multiple clinical cohorts, and genetically engineered mouse models to identify 36 heterochromatin-related genes that are significantly enriched in NEPC. Longitudinal analysis using our unique, first-in-field PDX model of adenocarcinoma-to-NEPC transdifferentiation revealed that, among those 36 heterochromatin-related genes, heterochromatin protein 1α (HP1α) expression increased early and steadily during NEPC development and remained elevated in the developed NEPC tumor. Its elevated expression was further confirmed in multiple PDX and clinical NEPC samples. HP1α knockdown in the NCI-H660 NEPC cell line inhibited proliferation, ablated colony formation, and induced apoptotic cell death, ultimately leading to tumor growth arrest. Its ectopic expression significantly promoted NE transdifferentiation in adenocarcinoma cells subjected to androgen deprivation treatment. Mechanistically, HP1α reduced expression of androgen receptor and RE1 silencing transcription factor and enriched the repressive trimethylated histone H3 at Lys9 mark on their respective gene promoters. These observations indicate a novel mechanism underlying NEPC development mediated by abnormally expressed heterochromatin genes, with HP1α as an early functional mediator and a potential therapeutic target for NEPC prevention and management. Significance: Heterochromatin proteins play a fundamental role in NEPC, illuminating new therapeutic targets for this aggressive disease. Cancer Res; 78(10); 2691–704. ©2018 AACR.

Aneustat (OMN54) is a multivalent, botanical anticancer candidate therapeutic. A recent Phase-I clinical trial has indicated that it is well tolerated by patients and has immunomodulatory activity. In our study, using in vitro and in vivo prostate cancer models, we investigated Aneustat with regard to effects on (i) cancer-generated immunosuppression based on aerobic glycolysis leading to acidification of the tumor microenvironment, and (ii) immune-related processes such as macrophage differentiation and shifts in the intratumoral levels of host immune cells. Aneustat markedly reduced glucose consumption, lactic acid secretion, glycolysis-related gene expressions and proliferation of human LNCaP prostate cancer cells. In addition, Aneustat induced differentiation of RAW264.7 macrophages to the M1 anticancer phenotype. Treatment of LNCaP xenografts and first-generation patient-derived prostate cancer tissue xenografts with Aneustat in both cases led to a marked shift in intratumoral host (mouse/patient) immune cell levels: a higher ratio of cytotoxic CD8

Background: Docetaxel used for first-line treatment of advanced prostate cancer (PCa) is only marginally effective. We previously showed, using the LTL-313H subrenal capsule patient-derived metastatic PCa xenograft model, that docetaxel combined with Aneustat (OMN54), a multivalent plant-derived therapeutic, led to marked synergistic tumour growth inhibition. Here, we investigated the effect of docetaxel+Aneustat on metastasis. Methods: C4-2 cells were incubated with docetaxel, Aneustat and docetaxel+Aneustat to assess effects on cell migration. The LTL-313H model, similarly treated, was analysed for effects on lung micro-metastasis and kidney invasion. The LTL-313H gene expression profile was compared with profiles of PCa patients (obtained from Oncomine) and subjected to IPA to determine involvement of cancer driver genes. Results: Docetaxel+Aneustat markedly inhibited C4-2 cell migration and LTL-313H lung micro-metastasis/kidney invasion. Oncomine analysis indicated that treatment with docetaxel+Aneustat was associated with improved patient outcome. The drug combination markedly downregulated expression of cancer driver genes such as FOXM1 (and FOXM1-target genes). FOXM1 overexpression reduced the anti-metastatic activity of docetaxel+Aneustat. Conclusions: Docetaxel+Aneustat can inhibit PCa tissue invasion and metastasis. This activity appears to be based on reduced expression of cancer driver genes such as FOXM1. Use of docetaxel+Aneustat may provide a new, more effective regimen for therapy of metastatic PCa.

The current first‐line treatment for advanced metastatic prostate cancer, i.e. docetaxel‐based therapy, is only marginally effective. The aim of the present study was to determine whether such therapy can be improved by combining docetaxel with Aneustat (OMN54), a multivalent botanical drug candidate shown to have anti‐prostate cancer activity in preliminary in vitro experiments, which is currently undergoing a Phase‐I Clinical Trial. Human metastatic, androgen‐independent C4‐2 prostate cancer cells and NOD‐SCID mice bearing PTEN‐deficient, metastatic and PSA‐secreting, patient‐derived subrenal capsule LTL‐313H prostate cancer tissue xenografts were treated with docetaxel and Aneustat, alone and in combination. In vitro, Aneustat markedly inhibited C4‐2 cell replication in a dose‐dependent manner. When Aneustat was combined with docetaxel, the growth inhibitions of the drugs were essentially additive. In vivo, however, the combination of docetaxel and Aneustat enhanced anti‐tumor activity synergistically and very markedly, without inducing major host toxicity. Complete growth inhibition and shrinkage of the xenografts could be obtained with the combined drugs as distinct from the drugs on their own. Analysis of the gene expression of the xenografts using microarray indicated that docetaxel + Aneustat led to expanded anticancer activity, in particular to targeting of cancer hallmarks that were not affected by the single drugs. Our findings, obtained with a highly clinically relevant prostate cancer model, suggest, for the first time, that docetaxel‐based therapy of advanced human prostate cancer may be improved by combining docetaxel with Aneustat., Highlights First‐line, docetaxel‐based therapy of advanced prostate cancer is only marginally effective.The efficacy of docetaxel combined with Aneustat was determined in a metastatic xenograft model.Anti‐tumor activity was synergistically and markedly enhanced without major host toxicity.Gene expression analysis indicated docetaxel + Aneustat led to expanded anticancer activity.Docetaxel‐based therapy of advanced prostate cancer may be improved by combining docetaxel with Aneustat.

Centromere protein-A (CENP-A), a histone-H3 variant, plays an essential role in cell division by ensuring proper formation and function of centromeres and kinetochores. Elevated CENP-A expression has been associated with cancer development. This study aimed to establish whether elevated CENP-A expression can be used as a prognostic and predictive cancer biomarker. Molecular profiling of CENP-A in human cancers was investigated using genomic, transcriptomic and patient information from databases, including COSMIC, Oncomine, Kaplan-Meier plotter and cBioPortal. A network of CENP-A co-expressed genes was derived from cBioPortal and analyzed using Ingenuity Pathway Analysis (IPA) and Oncomine protocols to explore the function of CENP-A and its predictive potential. Transcriptional and post-transcriptional regulation of CENP-A expression was analyzed in silico. It was found that CENP-A expression was elevated in 20 types of solid cancer compared with normal counterparts. Elevated CENP-A expression highly correlated with cancer progression and poor patient outcome. Genomic analysis indicated that the elevated CENP-A expression was not due to alterations in the sequence or copy number of the CENP-A gene. Furthermore, CENP-A can be regulated by key oncogenic proteins and tumor-suppressive microRNAs. CENP-A co-expression network analysis indicated that CENP-A function is associated with cell cycle progression. Oncomine analysis showed a strong correlation between elevated CENP-A expression and oncolytic response of breast cancer patients to taxane-based chemotherapy. In conclusion, elevated CENP-A expression is coupled to malignant progression of numerous types of cancer. It may be useful as a biomarker of poor patient prognosis and as a predictive biomarker for taxane-based chemotherapy.

Prostate cancer is the most commonly diagnosed noncutaneous cancer and the leading cause of cancer-related death in North American men. Although androgen-deprivation therapy is initially effective in controlling the growth of hormone-naive prostate cancers (HNPC) in patients, currently incurable castration-resistant prostate cancer (CRPC) inevitably develops. Thus, we aim to identify CRPC driver genes that may provide new targets to enhance CRPC therapy. In this study, patient-derived xenografts (PDXs) of HNPCs that develop CRPC following host castration were examined for changes in expression of genes at various time points after castration using transcriptome profiling analysis; particular attention was given to pre-CRPC changes in expression indicative of genes acting as potential CRPC drivers. Eighty genes were found to be significantly upregulated at the CRPC stage while 7 of them also showed elevated expression prior to CRPC development. Among the latter, Growth Factor Receptor Bound Protein 10 (GRB10) was the most significantly and consistently upregulated gene. Moreover, we found GRB10 expression was elevated in clinical CRPC compared to HNPC in several clinical cohorts. Further investigation suggests that GRB10 is transcriptionally regulated by androgen receptor through an androgen-responsive element located in GRB10's intron. Functionally, we found that GRB10 knockdown markedly reduced prostate cancer cell proliferation and activity of AKT, a well-established CRPC mediator. Also, a positive correlation between AKT activity and GRB10 expression was found in clinical cohorts. In conclusion, GRB10 acts as a driver of CRPC and sensitizes AR pathway inhibitors, and hence GRB10-targeting provides a novel therapeutic strategy for the disease. Citation Format: Jun Hao, Xinpei Ci, Hui Xue, Rebecca Wu, Xin Dong, Fang Zhang, Sifeng Qu, Fan Zhang, Anne M. Haegert, Peter W. Gout, Colin Collins, Martin E. Gleave, Dong Lin, Yuzhuo Wang. Patient-derived hormone-naive prostate cancer xenograft models reveal GRB10 as an AR-repressed gene driving the development of castration-resistant prostate cancer [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 1918.

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer (PCa) arising mostly from adenocarcinoma via NE transdifferentiation following androgen deprivation therapy. However, mechanisms contributing to both NEPC development and its aggressiveness remain elusive. In light of the fact that hyperchromatic nuclei is a distinguishing histopathological feature of NEPC, we identified 36 heterochromatin-related genes that are significantly enriched in NEPC by transcriptomic analyses of our patient-derived xenograft (PDX) models, multiple clinical cohorts, and genetically engineered mouse models. Longitudinal analysis using our unique, first-in-field PDX model of adenocarcinoma-to-NEPC transdifferentiation revealed that, among those 36 heterochromatin-related genes, heterochromatin protein 1α (HP1α) expression is increased early and steadily during NEPC development and remain elevated in the developed NEPC tumor. Its elevated expression is further confirmed in multiple PDX and clinical NEPC samples. Functional studies showed that HP1α knockdown in the NCI-H660 NEPC cell line dramatically inhibits proliferation, completely ablates colony formation, and induces apoptotic cell death, ultimately leading to tumor growth arrest. Its ectopic expression significantly promotes NE transdifferentiation in adenocarcinoma cells subjected to androgen deprivation treatment. Mechanistically, HP1α reduces expression of androgen receptor (AR) and RE1 silencing transcription factor (REST), two crucial transcription factors silenced in NEPC, and enriches the repressive histone mark trimethylation of histone H3 at Lys9 (H3K9me3) on their respective gene promoters. These observations indicate a novel mechanism underlying NEPC development mediated by abnormally expressed heterochromatin genes, with HP1α as an early functional mediator and a potential therapeutic target for NEPC prevention and/or management. Citation Format: Xinpei Ci, Jun Hao, Xin Dong, Stephen Y. Choi, Hui Xue, Sifeng Qu, Ladan Fazli, Francesco Crea, Christopher Ong, Amina Zoubeidi, Housheng H. He, Martin E. Gleave, Colin C. Collins, Dong Lin, Yuzhuo Wang. A heterochromatin gene signature unveils HP1α mediating neuroendocrine prostate cancer development and aggressiveness [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 773.

Background: As the cancer hallmark, genetic instability caused by abnormal cell division, is characterized with the gain or loss of entire chromosomes. The specific histone-H3 variant, centromere protein-A (CENPA), plays essential role in regulating kinetochore assembly, centromere activity and chromosome stability during cell division. However, the biological function of CENPA in human cancer remains largely uncharacterized. This study aims to determine the prognostic value of CENPA expression in cancer patients and the potential therapeutic target in cancer treatment via the genotranscriptomic meta-analysis. Methods: In order to well address the issue, a comprehensive and unbiased genotranscriptomic meta-analysis of CENPA in human cancers was performed with the clinical patient information databases, i.e. COSMIC, Oncomine and cBioPortal. Results: Based on the analysis, it strongly indicated the widespread cancer promoting role of CENPA. There are no gene fusion, very low point mutation (0.15%) and very rare copy number variation (CNV) gain (0.09%) at the CENPA locus in 15214 patient samples across 33 cancer types. However, transcriptomic analyses indicated high correlation of increased CENPA mRNA levels in various solid cancer tissues compared with normal tissues. Furthermore, the poor clinical outcome among 51 clinical cohorts with different cancer types shows significantly correlation with CENPA up-regulation, especially in breast cancer. More importantly, the CENPA up-regulation is also significantly correlated with the metastasis progression and pathology-assessment in breast cancer patients. The high rank of metastatic related genes correlated with CENPA up-regulation is also confirmed in TCGA breast cancer cohorts. Conclusions: The current study highly indicates the essential cancer promoting role of CENPA in human cancer and its value as prognostic marker in clinical use. It also provides rationale for further investigation of CENPA as potential therapeutic target in breast cancer treatment. Citation Format: Xia Sun, Sifeng Qu. Genotranscriptomic meta-analysis of centromere protein A (CENPA): An essential role in human cancer progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 60. doi:10.1158/1538-7445.AM2015-60