bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract IA18: MYCN amplification and ATRX mutations are incompatible in neuroblastoma
Authors: Zeineldin Maged , Federico Sara , Chen Xiang , Xu Beisi , Stewart Elizabeth , Naranjo Arlene , Hogarty Michael D. , Dyer Michael A.
Published: February 2019

Age and stage of disease at diagnosis are associated with outcome in neuroblastoma. A previous study identified ATRX point mutations and in-frame deletions in older patients with stage 4 disease. To validate the frequency of ATRX mutations and assess the relation of mutations and known prognostic variables, we collaborated with the Children’s Oncology Group and sequenced the entire ATRX genomic locus in 475 neuroblastoma tumor samples to validate the frequency of ATRX mutations and assess the relation of mutations and known prognostic variables. Older age at diagnosis, stage 4 disease, and unfavorable histology were significantly associated with mutations in the ATRX gene; MYCN amplification was mutually exclusive from ATRX mutations. To directly test if ATRX mutations and MYCN amplification are incompatible in neuroblastoma, we mutated the ATRX gene in MYCN amplified neuroblastoma cell lines and ectopically expressed MYCN in ATRX mutant neuroblastoma cell lines. Both approaches showed that ATRX and MYCN amplification are incompatible in neuroblastoma in culture and in vivo. To gain a better understanding of the underlying molecular and cellular mechanisms of this incompatibility, we performed a series of experiments including telomere analysis, epigenetic profiling, electron microscopic analysis of dying cells, and metabolic profiling. We discovered that induction of MYCN expression in ATRX mutant neuroblastoma cells leads to metabolic reprogramming, mitochondrial dysfunction, increased reactive oxygen species, and replicative stress. We propose that this leads to synthetic lethality in ATRX mutant neuroblastomas because of the underlying replicative stress in those cells as a result of dysfunction of this essential histone chaperone complex.

Citation Format: Maged Zeineldin, Sara Federico, Xiang Chen, Beisi Xu, Elizabeth Stewart, Arlene Naranjo, Michael D. Hogarty, Michael A. Dyer. MYCN amplification and ATRX mutations are incompatible in neuroblastoma [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr IA18.
Abstract IA23: Metabolic complexity in cancer cells and tumors
Authors: DeBerardinis Ralph J.
Published: February 2019

Metabolism is dynamic and responds to a wide range of cell-intrinsic and cell-extrinsic factors. In cancer, cell-intrinsic influences on metabolism include somatically acquired mutations in oncogenes and tumor suppressor genes, many of which regulate metabolic activity. Cell-extrinsic factors include nutrient access, which may become limiting due to inadequate vasculature and intense fuel utilization, and metabolic interactions with stromal and immune cells. A major challenge in cancer metabolism research is to understand how these various factors culminate in the metabolic phenotype of an intact tumor, and ultimately to identify which altered pathways represent potential therapeutic targets. We have taken two parallel approaches to understand metabolic complexity in human cancer. The first uses a combination of multiparametric imaging and intraoperative stable isotope infusions to assess metabolic fluxes in patients with solid tumors, and to compare fluxes between tumors and adjacent benign tissue. Genomic, histologic, and metabolic analysis of tumor samples allows us to correlate various intrinsic and extrinsic factors to specific aspects of the metabolic phenotype. The second approach uses standardized culture conditions to assess cell-intrinsic heterogeneity of metabolic preferences and dependencies in large panels of human cancer cell lines. This approach has uncovered liabilities associated with specific molecular subtypes of non-small cell and small cell lung cancer. I will discuss the application of these two approaches to metabolic heterogeneity in human cancer, with an emphasis on features relevant to intact tumors and therapeutic liabilities.

Citation Format: Ralph J. DeBerardinis. Metabolic complexity in cancer cells and tumors [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr IA23.
Abstract PR09: Cancer-specific retargeting of BAF complexes by a prion-like domain
Authors: Boulay Gaylor , Sandoval Gabriel J. , Riggi Nicolo , Iyer Sowmya , Buisson Rémi , Naigles Beverly , Awad Mary E. , Rengarajan Shruthi , Volorio Angela , McBride Matthew J. , Broye Liliane C. , Zou Lee , Stamenkovic Ivan , Kadoch Cigall , Rivera Miguel N.
Published: February 2019

Alterations in transcriptional regulators can orchestrate oncogenic gene expression programs in cancer. Here we show that the BAF chromatin-remodeling complex, which is mutated in over 20% of human tumors, interacts with EWSR1, a member of a family of proteins with prion-like domains (PrLD) that are frequent partners in oncogenic fusions with transcription factors. In Ewing sarcoma, we find that the BAF complex is recruited by the EWS-FLI1 fusion protein to tumor-specific enhancers and contributes to target gene activation. This process is a neomorphic property of EWS-FLI1 compared to wild-type FLI1 and depends on tyrosine residues that are necessary for phase transitions of the EWSR1 prion-like domain. Furthermore, fusion of short fragments of EWSR1 to FLI1 is sufficient to recapitulate BAF complex retargeting and EWS-FLI1 activities. Our studies thus demonstrate that the physical properties of prion-like domains can retarget critical chromatin regulatory complexes to establish and maintain oncogenic gene expression programs.

Citation Format: Gaylor Boulay, Gabriel J. Sandoval, Nicolo Riggi, Sowmya Iyer, Rémi Buisson, Beverly Naigles, Mary E. Awad, Shruthi Rengarajan, Angela Volorio, Matthew J. McBride, Liliane C. Broye, Lee Zou, Ivan Stamenkovic, Cigall Kadoch, Miguel N. Rivera. Cancer-specific retargeting of BAF complexes by a prion-like domain [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr PR09.
Abstract A002: Comparison of circulating microRNAs in plasma before and after radical prostatectomy among men treated for prostate cancer
Authors: McDonald Alicia C. , Raman Jay D. , Shen Jing , Liao Jason , Vira Manish
Published: February 2019

Introduction: MicroRNAs (miRNAs) have been linked to advanced prostate cancer; however, their role as circulating biomarkers of prostate cancer (PC) status has yet to be determined. We examined whether circulating miRNAs in plasma could be employed as biomarkers of disease among men treated for PC by radical prostatectomy (RP).

Methods: Men with clinically localized PC scheduled for a RP were recruited. Demographics, medical history, clinical information, pre-RP blood, and post-RP blood within 1 year after RP were collected. Pre- and post-RP blood were processed into plasma and the expression of the 16 most statistically significant PC circulating miRNAs in plasma identified from our previous study (miR- 381, 34a, 523, 365, 122, 375, 1255b, 34b, 450b-5p, 639, 885-5p, 1260, 150, 378, 671-3p, 148a) were examined using real-time PCR. Wilcoxon signed ranked test was used to compare the median expression of these miRNAs between pre- and post-RP plasma.

Results: There were 29 men, aged 43 to 77 years, included. Majority were white men (79.3%). The median preoperative serum PSA was 6.3 ng/mL. Majority had a pathologic Gleason score of 7 (3+4) (56%) and a pathologic tumor stage of T3 (60.7%). There was no statistically significant difference in miRNA expression between pre- and post-RP plasma.

Conclusion: No difference in miRNA expression before and immediately after RP was observed, possibly due to the lack of impact of tumor removal on miRNA expression and the timing of plasma collections. Future studies that examine post-RP plasma miRNA expression over time with PC recurrence are warranted.

Citation Format: Alicia C. McDonald, Jay D. Raman, Jing Shen, Jason Liao, Manish Vira. Comparison of circulating microRNAs in plasma before and after radical prostatectomy among men treated for prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A002.
Abstract A016: KDM4B promotes castration-resistant prostate cancer by regulating alternative splicing of the androgen receptor
Authors: Liu Zhi-Ping
Published: February 2019

Emergence of constitutively active androgen receptor variant AR-V7 is associated with poor survival of castration-resistant prostate cancer (CRPC). AR-V7 can be generated by the inclusion of cryptic exon CE3 via alternative splicing, but the mechanism of AR-V7 activation remains elusive. Here, we show that histone lysine demethylase KDM4B promotes CRPC via generation of AR-V7. Genetic inactivation of KDM4B in CRPC cells suppressed xenograft growth and abolished tumor AR-V7 expression. Pharmacologic inhibition of KDM4B inhibited tumor growth and sensitized CRPC cells to current antiandrogen therapy. Mechanistically, KDM4B promotes AR-V7 as a trans-acting splicing factor and couples the spliceosome to the chromatin. Our study defines KDM4B-regulated alternative splicing as a pivotal mechanism for generating AR-V7 and a contributing factor for CRPC, providing insight for mechanistic targeting of CRPC.

Citation Format: Zhi-Ping Liu. KDM4B promotes castration-resistant prostate cancer by regulating alternative splicing of the androgen receptor [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A016.
Abstract A019: Heme-oxygenase 1 drives the metabolic fate in prostate cancer
Authors: Arciuch Valeria G. Antico , Cascardo Florencia , Velazquez Florencia , Vickers Sofia Lage , Anselmino Nicolas , Labanca Estefania , Cotignola Javier , Gueron Geraldine , Navone Nora , Vazquez Elba
Published: February 2019

Prostate cancer (PCa) is the second leading cause of cancer-associated death in men. Energetic metabolism alterations have become a new hallmark of cancer, since variations in a single gene can orchestrate changes in metabolic pathways and confer an adaptive advantage. Heme-oxygenase 1 (HO-1) exerts an antitumoral role in PCa inhibiting cell proliferation, migration, tumor growth, and angiogenesis. The aim of this work was to assess the role of HO-1 in the metabolic signature of PCa.

Through RNA-Seq we found a set of metabolic genes deregulated under pharmacologic induction (hemin treatment) or genetic induction of HO-1 in PC3 cells. STAR and ATP5L2 were upregulated, while HMGCS2, PRODH, and ACOT12 were downregulated. These genes encode for steroid hormone metabolism, ATP synthesis, ketogenesis, proline and lipid metabolism. The analysis of the deregulated genes (2-fold) by Gene Ontology revealed alterations in several metabolic pathways such as steroid, proline and lipid metabolism, and ATP synthesis. Functional analysis highlighted a decrease in oxygen consumption rate and ATP production under hemin treatment. Furthermore, HO-1 induction led to a decrease in the extracellular lactate levels.

Bone is the only site of PCa progression, and bone cells are able to produce factors that favor progression. However, the molecular nature of this interaction remains elusive. Our results performed on cocultures of PC3 cells (treated or not with hemin) with Raw264.7 (preosteoclastic) or MC3T3 (preosteoblastic) cells demonstrate that HO-1 directs the metabolic fate of bone precursor cells due to the deregulation of glycolytic genes. HO-1 induction in PC3 cells downregulated PKM2 and LDHA expression in cocultured Raw264.7 and MC3T3 cells (p< 0.05).

Based on our results, we propose HO-1 as a key regulator of the metabolic status of PCa cells and a powerful mediator capable of redefining the metabolic signature of bone precursor cells, thus favoring the establishment of a less aggressive phenotype.

Citation Format: Valeria G. Antico Arciuch, Florencia Cascardo, Florencia Velazquez, Sofia Lage Vickers, Nicolas Anselmino, Estefania Labanca, Javier Cotignola, Geraldine Gueron, Nora Navone, Elba Vazquez. Heme-oxygenase 1 drives the metabolic fate in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A019.
Abstract A020: Integrative analysis of the proteome in primary and advanced prostate cancer
Authors: Latonen Leena , Afyounian Ebrahim , Jylhä Antti , Nättinen Janika , Aapola Ulla , Annala Matti , Kivinummi Kati , Tammela Teuvo , Beuerman Roger W. , Uusitalo Hannu , Nykter Matti , Visakorpi Tapio
Published: February 2019

To fully understand the output of alterations in cancer genomes and transcriptomes, we need to know how these aberrations are translated into the functional protein units in cells. We assessed proteomic changes during disease formation and progression in prostate cancer by performing high-throughput mass spectrometry on clinical tissue samples of benign prostatic hyperplasia (BPH), untreated primary prostate cancer (PC), and castration-resistant prostate cancer (CRPC). With SWATH-MS quantitation-based proteomics we found that each of these sample groups show a distinct protein profile. By integrative analysis of this mass spectrometry dataset with genetic, epigenetic, and transcriptional data from the same samples, we show that, especially in CRPC, gene copy number, DNA methylation, and RNA expression levels do not reliably predict proteomic changes. From our analysis, we have identified sets of novel expression changes occurring primarily at the protein level, in addition to identification of several miRNA-target correlations present at protein but not at mRNA level. We find novel expression changes in previously unrecognized pathways in prostate cancer that are likely to affect disease development and progression. For example, we identify two metabolic shifts in the citric acid cycle (TCA cycle), one occurring during primary cancer development and the second during castration resistance, having implications on drug targeting against cancer metabolism. Our proteogenomic analysis of prostate cancer uncovers robustness against genomic and transcriptomic aberrations during disease progression, reveals new disease mechanisms, and significantly extends understanding of prostate cancer biology.

Citation Format: Leena Latonen, Ebrahim Afyounian, Antti Jylhä, Janika Nättinen, Ulla Aapola, Matti Annala, Kati Kivinummi, Teuvo Tammela, Roger W. Beuerman, Hannu Uusitalo, Matti Nykter, Tapio Visakorpi. Integrative analysis of the proteome in primary and advanced prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A020.
Abstract A022: Role of metallothionein in the pathogenesis of prostate cancer
Authors: Hamid Sobia , Anees Mariam
Published: February 2019

Metallothionein (MT) is a metal binding protein of low molecular weight. It is involved in metal homeostasis, cell differentiation, proliferation, and detoxification of heavy metals. Neoplastic transformation in prostate cancer is attributed to elevated levels of metallothionein. We studied the expression of MT in prostate tissues.

Immunohistochemistry (IHC) of 35 prostate cancer patients was performed to evaluate the expression of MT and then correlated with the expression profiles of epithelial TRAIL (Tumor necrosis factor related apoptosis inducing ligand), stromal TRAIL, decoy receptors (DcR1 and DcR2), death receptors (DR4 and DR5), nuclear factor κB (NF-κB), and FLICE inhibitory protein (FLIP). We also correlated expression patterns of these proteins using Pearson correlation with clinical histopathologic factors and determined their influence on overall survival of patients. Elevated levels of MT were observed in cancer tissues as compared to benign controls. Expression levels of epithelial TRAIL, DcR1, DcR2, DR4, DR5, NF-κB, and FLIP were also enhanced in cancer tissue samples. Age at diagnosis was significantly associated with stage (R= -0.467, p=0.046), MT (R= -0.419, p=0.012), DcR1 (R= 0.355, p=0.036) and sTRAIL (R= 0.553, p= 0.001). NF-κB significantly correlated with DR5 expression (R= 0.408, p = 0.015) in tumor tissues. Better survival was observed in patients with MT negative expression (p=0.467). Elevated levels of MT in prostate cancer patients and its positive correlation with FLIP and DcR1 depict its role as an antiapoptotic moiety. Further exploration of the role of MT in prostate cancer pathogenesis could help in establishing MT as a potential therapeutic target.

Citation Format: Sobia Hamid, Mariam Anees. Role of metallothionein in the pathogenesis of prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A022.
Abstract A031: Androgen deprivation therapy-induced TGFBI signaling promotes EMT and bone metastasis of prostate cancer
Authors: Liu Yen-Nien , Chen Wei-Yu , Tsai Yuan-Chin , Yeh Hsiu-Lien , Suau Florent , Huang Jiaoti
Published: February 2019

Metastatic progression in patients with prostate cancer is common despite pharmacologic inhibition of androgen receptor signaling. This drug resistance is associated with increased signaling through the transforming growth factor-β (TGF-β) signaling pathway. We found the type I/II/IV collagen-binding protein transforming growth factor-β (TGF-β)-induced (TGFBI) is an important factor in the epithelial-to-mesenchymal transition (EMT) and malignant progression of prostate cancer. We identified that an androgen-responsive gene, SPDEF, navigates between AR and TGFβ signaling during prostate cancer progression to metastasis though a physical interaction with the promoter region of the TGFBI gene. We show that loss of AR-regulated SPDEF induces TGFBI expression in prostate cancer cells, leading to drastic and aggressive physiologic changes. Furthermore, we confirmed the negative correlation between SPDEF and TGFβ singling in prostate cancer patients and demonstrated that ADT can reduce SPDEF and increase TGFβ signaling. Our results support an inhibitory role of the AR on TGFβ signaling through SPDEF-mediated suppression of TGFBI, and that disruption of this pathway promotes metastatic progression in prostate cancer.

Citation Format: Yen-Nien Liu, Wei-Yu Chen, Yuan-Chin Tsai, Hsiu-Lien Yeh, Florent Suau, Jiaoti Huang. Androgen deprivation therapy-induced TGFBI signaling promotes EMT and bone metastasis of prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A031.
Abstract A060: Repression of microRNA-338/421 by EZH2 represents a novel mechanism for SPINK1-positive prostate cancers
Authors: Bhatia Vipul , Yadav Anjali , Tiwari Ritika , Nigam Shivansh , Goel Apul , Ateeq Bushra
Published: February 2019

Prostate cancer (PCa) is a clinically heterogeneous disease marked by variability in patient prognosis. The intratumoral and interpatient heterogeneity formed the basis of molecular stratification of the disease. Overexpression of Serine Peptidase Inhibitor, Kazal type-1 (SPINK1), was found to be the second most recurrent (~10-15%) PCa subtype, after highly recurrent (~50%) androgen-driven TMPRSS2-ERG genetic rearrangement. Unlike amplification of ERBB2 in breast cancer, SPINK1 overexpression has not been associated with gene amplification or rearrangement. Nonetheless, molecular mechanism underlying its upregulation in cancer is poorly understood and remains a matter of conjecture.

Using in silico microRNA prediction tools, we shortlisted three miRNAs, of which miR-338-5p and miR-421 revealed an inverse correlation with SPINK1 in The Cancer Genome Atlas (TCGA) prostate adenocarcinoma RNA-Seq dataset (n=106), which was validated in our PCa specimens (n=20). Here, we showed that miR-338-5p and miR-421 post-transcriptionally regulate SPINK1 by binding to its 3′ UTR. We established that miR-338-5p and miR-421 mediate several cellular responses against SPINK1-positive cancer by inducing S-phase cell-cycle arrest, inhibiting epithelial-to-mesenchymal transition (EMT), cancer stemness, and drug resistance. Moreover, ectopic expression of miR-338-5p and miR-421 abrogates SPINK1-mediated oncogenesis, tumor growth, and distant metastases in murine xenograft model. Further, mechanistically we demonstrate that Polycomb group protein enhancer of zeste homolog 2 (EZH2) mediates epigenetic silencing by establishing histone H3K27me3 repressive marks and DNA methylation, 5’ methyl cytosine (5mC) marks on the promoters of miR-338-5p and miR-421 in SPINK1-positive subtype. Thus, restoring miR-338-5p and miR-421 expression using either epigenetic drugs or synthetic mimics could abrogate SPINK1-mediated oncogenesis by targeting multiple oncogenic pathways and eliciting anticancer pleiotropic effects.

Taken together, the present study for the first time unravels the molecular mechanism underlying SPINK1 overexpression and thereby opens up new avenues for the use of miR-338-5p and miR-421 replacement therapy for the treatment of SPINK1-positive malignancies.

Citation Format: Vipul Bhatia, Anjali Yadav, Ritika Tiwari, Shivansh Nigam, Apul Goel, Bushra Ateeq. Repression of microRNA-338/421 by EZH2 represents a novel mechanism for SPINK1-positive prostate cancers [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A060.
Abstract A062: Systemic oncolytic virotherapy for prostate cancer
Authors: Nguyen Tien , Barry Michael A.
Published: February 2019

Oncolytic viruses hold promise as “self-amplifying” cancer therapies wherein a virally killed cell can produce thousands of new viral “drugs” that can kill more cancer cells. Oncolytic viruses may also serve to reawaken or initiate immune responses against cancers by virtue of their abilities to lyse cells, liberate cancer antigens, and provide viral DNA and proteins as immune adjuvants. Oncolytics can also be armed with cytokine or checkpoint inhibitors to amplify antitumor immune responses. Adenoviruses (Ads) are one family of oncolytic viruses. Most human studies have used human Ad serotype 5 (Ad5). Unfortunately, most patients are already immune to Ad5, increasing the likelihood that the agent will be neutralized if used as a cancer therapy. In this work, low seroprevalence Ad6 and Ad57 oncolytic viruses were tested as intravenous therapies against distant prostate cancer sites. After prostate cell infection in vitro, Ad viruses executed these cells efficiently and generated 10,000 to 100,000 progeny infectious viruses. This genome replication also amplified transgene protein production by 100 to 1,000-fold when compared to nonreplicating Ad vectors. Ad5, Ad6, and Ad57 were injected intravenously a single time in nude mice bearing human prostate tumors, and toxicity and efficacy were assessed. Ad6 and 57 produced 30-fold lower liver damage and less toxicity than Ad5. Ad6 and Ad57 significantly repressed the growth of androgen-resistant human DU145 prostate tumors and androgen-sensitive LNCaP prostate tumors and extended survival after single intravenous injection in mice. Ad6 and Ad57 E1 protein were also modified to protect normal cells from viral oncolysis while allowing the virus to amplify and kill prostate cancer cells having perturbations in p300 and pRB pathways. These and other data suggest that targeted and untargeted low seroprevalent Ad6 and Ad57 have better efficacy and safety than the benchmark oncolytic virus Ad5 for systemic therapy of advanced prostate cancer.

Citation Format: Tien Nguyen, Michael A. Barry. Systemic oncolytic virotherapy for prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A062.
Abstract A073: Metabolism of saturated fatty acids accelerates Src-mediated prostate tumor progression
Authors: KIM SUNGJIN , Yang Xiangkun , Li Qianjin , Wu Meng , Beharry Zanna , Bartlett Michael , Bielawska Alicja , Cai Houjian
Published: February 2019

The association of dietary fatty acids (FAs) with the risk of aggressive prostate cancer is controversial. The mechanisms of supporting how dietary FAs promote cancer progression are largely unknown. The expression and/or activity of Src family kinases are frequently elevated in several cancers, including advanced prostate cancer. This study demonstrates that dietary FAs accelerated Src-mediated prostate tumorigenesis and prostate cancer cell growth in vivo. Additionally, high dietary fat compromised the ability of dasatinib to block the oncogenic signaling of Src kinase. Metabolism of exogenous FAs, in particular palmitic and myristic acids, increased biosynthesis of acyl-CoAs and altered ceramide levels, in particular C16:0 ceramide. The combination of these effects elevated levels of myristoylated Src, increased the amount of Src in detergent resistant membranes, and enhanced Src kinase mediated oncogenic signaling. Targeting myristoylation of Src kinase, which is required for its association at the cellular membrane, blocked high fat diet-accelerated tumorigenesis in vivo. These findings illustrate how the metabolism of saturated FAs can accelerate Src-driven prostate tumor progression and suggest that prostate cancer survivors may benefit from a diet low in saturated fat.

Citation Format: SUNGJIN KIM, Xiangkun Yang, Qianjin Li, Meng Wu, Zanna Beharry, Michael Bartlett, Alicja Bielawska, Houjian Cai. Metabolism of saturated fatty acids accelerates Src-mediated prostate tumor progression [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A073.
Abstract A084: Reprogramming of androgen receptor gene expression by ACK1/TNK2 mediated histone H4 Tyr88-phosphorylation promotes castration resistance
Authors: Mahajan Nupam , Mahajan Kiran , Lawrence Harshani , Lawrence Nicholas
Published: February 2019

Aberrant androgen receptor (AR) transcriptional co-activator activity underlies the onset and progression of prostate cancer (PC) to castration-resistant (CRPC) state. While anti-androgens provide immediate palliative benefits by negating AR transcriptional activity, resistance inevitably develops—either by AR gene amplification, mutation, or expression of splice variants, such as AR-V7. To achieve complete remission, ablation of AR expression appears to be the key. However, targeted inhibition of AR and AR-V7 gene expression with small-molecule inhibitors has not yet been accomplished. Recently, we uncovered a novel chromatin-regulated mechanism of AR transcriptional regulation mediated by the tyrosine kinase ACK1 (also known as TNK2). We observed that ACK1 phosphorylates histone H4 at tyrosine 88 upstream of the AR transcription start site. The WDR5/MLL2 complex is read by H4-Y88-phosphorylation and in turn deposits the transcriptionally activating H3K4-trimethyl marks, promoting AR transcription in androgen-deficient environment. Reversal of the pY88-H4 epigenetic marks by the ACK1 inhibitor (R)-9bMS sensitized naive and enzalutamide-resistant prostate cancer cells and reduced AR and AR-V7 levels to mitigate CRPC tumor growth. Interestingly, we observed that AR itself was modified by acetylation at Lys609 residue in enzalutamide-resistant PC cells, revealing an additional mechanisms underlying castration resistance. Overall, these data reveal previously undocumented epigenetic circuitry that not only sustains AR and AR-V7 expression, but also provides mechanistic insight into rapid acquisition of resistance to antiandrogens.

Citation Format: Nupam Mahajan, Kiran Mahajan, Harshani Lawrence, Nicholas Lawrence. Reprogramming of androgen receptor gene expression by ACK1/TNK2 mediated histone H4 Tyr88-phosphorylation promotes castration resistance [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A084.
Abstract A098: Whole blood assay for rapid detection of AR-v7 in metastatic castration-resistant prostate cancer: No correlation with response to androgen-axis targeting agents
Authors: To Sarah , Kwan Edmond , Fettke Heidi , Docanto Maria , Ng Nicole , Mant Andrew , Parente Phillip , Pezaro Carmel , Horvath Lisa , Graham Lisa , Todenhofer Tilman , Azad Arun
Published: February 2019

Background: The expression of AR-v7 in circulating tumor cells (CTCs) of mCRPC patients potentially confers treatment resistance to AR-axis targeting agents, though recent data from the ARMOR3-SV study as well as other publications challenge this hypothesis. Due to the potential barriers of developing a reliable CTC platform, our aim was to develop a rapid assay for AR-v7 detection in patient whole blood samples.

Method: We created and optimized a whole blood quantitative real-time polymerase chain reaction assay to correlate outcomes of patients on AR-axis targeting agents with expression of AR-v7. The expression of AR-v7 mRNA in whole blood from 47 patients with mCRPC was obtained prior to commencing therapy. Each sample was run in triplicate; positivity was defined as at least two replicates reaching cycle threshold within a standard deviation between cycles of ≤ 0.25. Gene expression was correlated with PSA response rate using Fisher’s exact test.

Results: In our cohort, 10 of 47 patients (21%) were AR-v7+. Of patients commencing abiraterone or enzalutamide (37/47 patients, 79%), we observed similar response rates in the AR-v7+ (4/7) patients, compared to the AR-v7 (20/30) patients (57% vs. 66%, P=0.63; Fisher’s exact test). In two patients, early onset of acquired resistance was associated with conversion from AR-v7 to AR-v7+. AR-v7 was not detected in any of the 13 normal male controls.

Conclusion: We developed a specific assay for AR-v7 detection in whole blood from mCRPC patients. Similar PSA response rates were seen in AR-v7+ and AR-v7 patients, inconsistent with literature characterizing AR-v7 as a predictive biomarker, but in support of ARMOR3-SV data demonstrating moderate response rates to an AR-axis targeting agent in AR-v7+ patients. Future directions will include cohort expansion, interrogation of other AR variants, and examination of other clinically meaningful endpoints.

Citation Format: Sarah To, Edmond Kwan, Heidi Fettke, Maria Docanto, Nicole Ng, Andrew Mant, Phillip Parente, Carmel Pezaro, Lisa Horvath, Lisa Graham, Tilman Todenhofer, Arun Azad. Whole blood assay for rapid detection of AR-v7 in metastatic castration-resistant prostate cancer: No correlation with response to androgen-axis targeting agents [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A098.
Abstract B006: Analysis of the interaction of human herpes virus 8 and gp130 in prostate cancer risk
Authors: Henning Jill D. , Kercher Kathrine , Bunker Clareann H. , Ferrel Robert E. , Patrick Alan L. , Jenkins Frank J.
Published: February 2019

Prostate cancer is the most common cancer among men in the United States and is second to lung cancer as a cause of cancer death. The occurrence of prostate cancer is not uniform among different races. It is more prevalent among African Americans than either Caucasians or Asians. This increased risk for prostate cancer among men of African descent is particularly strong in the Caribbean nation of Trinidad and Tobago where the prevalence of screening-detected prostate cancer was 3-fold higher among Tobago men of African descent compared to U.S. Caucasian men. In the present study we test the hypothesis that a polymorphism in the binding domain of gp130 in association with inflammation induced by HHV-8 increases the risk of prostate cancer. As a result, Tobago men with the high-risk gp130 allele whose prostates express HHV-8 proteins have an increased risk of prostate cancer (OR=3.1, 95% C.I. 1.18-8.11). In addition, studies in B cell lines derived from Tobago men with the three different genotypes showed that IL-6 causes a significant increase in cell division based on genotype with a resulting increase in STAT-3 activation via phosphorylation. These results will also aid in defining better a treatment plan for prostatic inflammation that is a result of viral infection and will provide a better understanding of disease progression.

Citation Format: Jill D. Henning, Kathrine Kercher, Clareann H. Bunker, Robert E. Ferrel, Alan L. Patrick, Frank J. Jenkins. Analysis of the interaction of human herpes virus 8 and gp130 in prostate cancer risk [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B006.
Abstract B007: Stemness features of prostate cancer cells induced by carcinoma-associated fibroblasts
Authors: Nuñez Muriel A. , Cerda-Infante Javier , Sánchez Marianela , Sotomayor Paula , Godoy Alejandro S. , Montecinos Viviana P.
Published: February 2019

Introduction: Carcinoma-associated fibroblasts (CAFs) play a key role during cancer progression through several mechanisms, including the induction of the epithelial-mesenchymal transition (EMT) program, giving cancer cells the ability to initiate metastasis. As the cells progress to the mesenchymal state they acquire properties of cancer stem cells (CSC) or mesenchymal stem cell (MSC). However, the contribution of the CAFs in the acquisition of the differential stemness is largely unknown. Here, we studied the stemness features of prostate cancer cells (PC3) during the EMT program induced by fibroblasts obtained from patients with nonmetastatic prostate cancer (CAF) and bone metastatic prostate cancer (mCAF).

Materials and Methods: PC3 cells were incubated with conditioned medium (CM) of CAF and mCAF for 7,14, and 21 days to induced EMT. The presence of putative CSCs and MSCs was determined by qPCR, immunocytochemistry and Western blot for the expression of CSCs and MSCs markers, respectively, and functionally evaluated by the ability to perform adipogenic, chondrogrenic, and osteogenic differentiation (MSCs) and in vitro spheroids formation and clonogenic assay (CSCs).

Results and Discussion: Our results demonstrate that cancer cells treated with CM-CAF undergo to a partial EMT program, exhibiting certain mesenchymal traits and enriched for cancer stem cells (CSCs). On the other hand, tumor cells exposed to CM-mCAF, exhibited a full EMT conversion with the greater abilities to migrate and invade in vitro and in vivo. This suggests that CAFs and mCAFs induce differential EMT programs in prostate cancer cells, which leads them to acquire CSCs or MSC features enhancing the metastatic capabilities. (FONDECYT 1150397.)

Citation Format: Muriel A. Nuñez, Javier Cerda-Infante, Marianela Sánchez, Paula Sotomayor, Alejandro S. Godoy, Viviana P. Montecinos. Stemness features of prostate cancer cells induced by carcinoma-associated fibroblasts [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B007.
Abstract B012: Histone demethylase JMJD1A promotes the generation of androgen receptor variant 7 (AR-V7) in prostate cancer cells
Authors: Fan Lingling , Zhang Fengbo , Fazli Ladan , Gleave Martin , Dong Xuesen , Qi Jianfei
Published: February 2019

Generation of androgen receptor (AR) splicing variant, AR-V7, has been shown to contribute to the resistance of prostate cancer to androgen deprivation therapy and development of castration-resistant prostate cancer (CRPC). We and others have reported that histone demethylase JMJD1A promotes the transcriptional activity of AR by functioning as an AR coactivator. Here, we identified a new role for JMJD1A in the generation of AR-V7 in prostate cancer cells through interaction with HNRFPF. Knockdown of JMJD1A or HNRNPF reduced the mRNA and protein level of AR-V7 but had little effect on the full-length AR (AR-FL). Mechanistically, we found that JMJD1A and HNRNPF cooperatively bound to a polyG motif adjacent to the 5′ splicing site of Exon3b of AR gene, where they promoted the assembly of splicesome. Re-expression of AR-V7 in the JMJD1A-knockdown cells partly rescued the growth defect of prostate cancer cells in vitro and in the mouse xenograft model. The staining of AR-V7 paralleled that of JMJD1A or HNRNFP in a human prostate cancer tissue microarray. Together, our data reveal that JMJD1A enhances the castration-resistant growth of prostate cancer cells through coactivation of AR-FL and generation of AR-V7.

Citation Format: Lingling Fan, Fengbo Zhang, Ladan Fazli, Martin Gleave, Xuesen Dong, Jianfei Qi. Histone demethylase JMJD1A promotes the generation of androgen receptor variant 7 (AR-V7) in prostate cancer cells [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B012.
Abstract B013: Combined molecular targeting Src and mTOR pathways to impair prostate cancer cell survival
Authors: Dai Yao , Siemann Dietmar W.
Published: February 2019

Overexpression of oncoproteins Src and mTOR has been shown to be highly associated with prostate cancer progression and poor clinical outcomes; therefore, small-molecule Src or mTOR inhibitors are being extensively evaluated in clinical trials for advanced prostate cancer. However, clinical data suggest that single treatment with any of these inhibitors only yields limited effects in patients. One possibility is that redundant signaling pathways in tumor cells exist that allow tumor cell uninterrupted upon blockade of purely one pathway. We hypothesize that Src and mTOR are two compensatory pathways that may cooperate to promote prostate cancer survival. Here we studied treatment effects of combining inhibitors targeting Src (saracatinib) and mTOR (rapamycin) on functional behaviors associated with tumor growth in prostate cancer cells with high level expression of both kinases. Combination of both inhibitors was found to inhibit cell proliferation and clonogenic survival more strongly than either single agent, as assessed by MTT and colony formation assay, respectively. Western blot analysis demonstrated that co-targeting Src and mTOR kinases leads to not only inhibition on phosphorylation of these oncoproteins but also greater blockade of multiple downstream pathways such as focal adhesion kinase (FAK), Akt, ERK, S6K, and 4E-BP1. These data indicate that combined application of small-molecule inhibitors targeting two different key pathways may cause significant impairment of phenotypes associated with prostate cancer growth and survival, suggesting that this combinative intervention modality may serve as a potential anticancer strategy that could be further tested in advanced prostate cancer models in vivo.

Citation Format: Yao Dai, Dietmar W. Siemann. Combined molecular targeting Src and mTOR pathways to impair prostate cancer cell survival [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B013.
Abstract B026: Axl may support dormancy of disseminated tumor cells by inducing cell clustering and decreasing proliferation of metastatic prostate cancer cells
Authors: Axelrod Haley D. , Valkenburg Kenneth C. , Hicks Jessica L. , DeMarzo Angelo M. , Pienta Kenneth J.
Published: February 2019

While the majority of prostate cancer (PCa) patients are cured by radical prostatectomy and/or radiation, 10-15% of these men eventually develop recurrent disease in the form of lethal metastases. The most common site for PCa metastasis is the bone marrow. The time from primary tumor removal to recurrence can range from 1-2 years to decades, and constitutes a period of minimal residual disease in which cancer cells remain in the body but are clinically undetectable. It is thought that these disseminated tumor cells (DTCs) are able to maintain a state of cellular dormancy in the bone marrow in which they are not proliferating or dying, and may be the seeds for lethal metastases. By understanding the mechanism(s) that regulate dormancy, we may be able to prevent metastasis altogether. Our group has previously found that the secreted bone marrow factor Gas6 and the expression of its receptor Axl are associated with dormant DTCs in xenograft mouse models. Thus, we hypothesize that Gas6 signaling through Axl mediates dormancy. In this study, we sought to functionally support this hypothesis both in vitro and in human PCa tissue. Overexpression of Axl in the C42B PCa cell line decreased proliferation in vitro, and this was independent of Gas6 when Axl was highly overexpressed. Axl overexpression also led to aggregation of C42B cells, suggestive of a possible role in circulating tumor cell (CTC) clustering to survive the circulation and inhabit the bone marrow. Furthermore, immunohistochemical staining of a PCa tissue microarray showed almost no Axl positivity in cancer cells, regardless of Gleason score and other clinical outcomes. Negative staining was also observed in sections from liver, lymph node, and tibial metastases. Consistent with this, Axl expression correlates with decreased incidence of biochemical recurrence and increased overall survival in the GRID and TCGA databases, respectively. These results indicate an antiproliferative role for Axl in PCa, and suggest its temporal expression during the natural history of PCa. Ongoing work includes assessing the expression of Axl on patient CTCs and DTCs, and using xenograft mouse models of metastasis to analyze the effects of Axl overexpression and knockout in PCa cell lines.

Citation Format: Haley D. Axelrod, Kenneth C. Valkenburg, Jessica L. Hicks, Angelo M. DeMarzo, Kenneth J. Pienta. Axl may support dormancy of disseminated tumor cells by inducing cell clustering and decreasing proliferation of metastatic prostate cancer cells [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B026.
Abstract B069: Drug response variability between luminal and basal prostate cancer tumors
Authors: Den Robert , Lehrer Jonathan , Takhar Mandeep , Alshalalfa Mohammed , Erho Nicholas , Davicioni Elai , Feng Felix
Published: February 2019

Introduction: Prostate cancer (PCa) is a genomically heterogeneous disease that has been subtyped into molecularly distinct subtypes. Over the past several years, multiple drugs have demonstrated improvements in overall survival in men with advanced prostate cancer, prompting further investigations of these drugs. However, characterizing drug response in the localized disease setting and in the context of PCa molecular subtypes needs further investigation. Here in a large prospective cohort of men with adverse pathology we explore the heterogeneity of patient drug response between basal, luminal, and neuroendocrine prostate cancer subtypes.

Methods: Whole-transcriptome RNA expression profiles of 9,640 radical prostatectomy (RP) samples from prospective use of the Decipher test were obtained from the GRID registry database. Patients were subtyped into basal, luminal A, luminal B, and neuroendocrine subtypes using the PAM50 and small cell gene expression signatures. Drug response scores (DRS) predicting patient sensitivity for 89 oncology drugs were determined using in vitro drug sensitivity and microarray data from the NCI-60 panel. Pearson’s chi squared test was used to determine significant differences in drug sensitivity among PCa subtypes.

Results: Applying the subtype signatures to the cohort, we classified 43% of samples as basal, 26% as luminal A, 30% as luminal B, and 2% as neuroendocrine. DRS was highly variable across the subtypes. Basal tumors showed a distinct drug response profile where basal tumors were more sensitive to kinase inhibitors (e.g., cabozantanib, dasatnib, erlotinib), mTOR inhibitors (e.g., everolimus, temsirolumus), DNA repair inhibitors (e.g., olaparib, mitoxantrone), and alkylating (e.g., cisplatin, carboplatin) chemotherapy. Luminal A and B were more sensitive to steroid inhibition (e.g., abiraterone, tamoxifen) and anti-microtuble (e.g., docetaxel, paclitaxel, vinorelbine) chemotherapy, whereas neuroendocrine had highest DRS for antiproliferative agents (e.g., mitomycin, cytabarine, carmustine, topotecan), Significant differences in average DRS scores in subtypes were observed for all 89 drugs (p<0.001).

Conclusion: Prostate cancer subtypes in the localized disease setting have distinct drug response profiles, suggesting that subtyping and DRS scores may be useful for selecting candidates for systemic therapy trials.

Citation Format: Robert Den, Jonathan Lehrer, Mandeep Takhar, Mohammed Alshalalfa, Nicholas Erho, Elai Davicioni, Felix Feng. Drug response variability between luminal and basal prostate cancer tumors [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B069.
Abstract IA15: Targeting oligometastatic disease in prostate cancer
Authors: Pienta Kenneth J.
Published: February 2019

Clinical reports of limited and treatable cancer metastases, a disease state that exists in a transitional zone between localized and widespread systemic disease, have been noted on occasion historically and termed oligometastasis (OM). The ramification of a diagnosis of oligometastasis is a change in treatment paradigm, i.e., if the primary cancer site (if still present) is controlled or resected, and the metastatic sites are ablated (surgically or with radiation), a prolonged disease-free interval, and perhaps even cure, may be possible. Contemporary imaging diagnostics are identifying more and more OM patients. For example, in prostate cancer the use of PSMA-Pyl PET imaging is leading to the diagnosis of many OM patients who have no disease on conventional clinical imaging. It is unclear if these are truly isolated sites of disease (curable) or simply a reflection of more widespread microscopic disease (incurable or at best a bridging therapy). This is especially true in the biochemical recurrence (bcr) space after primary treatment. We will present our experience with identifying and treating prostate cancer OM disease.

Citation Format: Kenneth J. Pienta. Targeting oligometastatic disease in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr IA15.