bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B39: Osteosarcoma cells interact with bronchial cells in lung to drive production of prometastatic cytokines
Authors: Hinckley John , Gross Amy , Roberts Ryan
Published: February 2019

The survival rate for patients diagnosed with osteosarcoma (OS) drops from 70% to an abysmal 20% when diagnosed with lung metastasis. We have shown that metastatic colonization of lungs by OS cells depends on the production of IL6 and CXCL8 by tumor cells, which seems to increase within the metastatic niche of the lung. Identification of key tumor-host interactions that drive this phenomenon will facilitate the development of novel therapies aimed at prevention of metastases in patients diagnosed with OS. We hypothesized that OS cells interact with lung tissues in ways that establish paracrine signal amplification loops, where IL6 and CXCL8 stimulate lung-resident cells to produce secondary signaling molecules that, in turn, stimulate tumor cell production of IL6 and CXCL8 in a feed-forward mechanism. Coculture experiments identified strong interactions between OS cells and primary cultures of bronchial epithelial cells and lung smooth muscle cells. Exposure of OS cells to conditioned supernatants from the primary cell cultures and vice versa showed that these interactions result from exchange of soluble mediators secreted by each cell type. Proteomic profiling of the resultant supernatants identifies a number of interesting candidate mediators, which might also affect the growth and survival of OS cells within the microenviroment of the lung. These results suggest a mechanism for the establishment of a metastatic niche favorable to OS cells within lung tissues.

Citation Format: John Hinckley, Amy Gross, Ryan Roberts. Osteosarcoma cells interact with bronchial cells in lung to drive production of prometastatic cytokines [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 B39.
Abstract IA07: Engineering T cells for the immunotherapy for pediatric solid tumors
Authors: Gottschalk Stephen , DeRenzo Chris , Hegde Meena , Mata Melinda , Nguyen Phoung , Krenciute Giedre , Ahmed Nabil
Published: February 2019

Engineering T cells for the immunotherapy for pediatric solid tumorsImmunotherapy with genetically modified T cells holds the promise to improve outcome for pediatric cancer patients who currently cannot be cured. In addition, T-cell therapy has the potential to reduce treatment-related complication for all patients. Cell therapy with T cells, genetically modified to express chimeric antigen receptors (CARs), had dramatic success for pediatric patients with recurrent/refractory CD19-positive acute lymphoblastic leukemia (ALL), resulting in the recent FDA approval of CD19-CAR T cells for recurrent/refractory ALL. In contrast, CAR T-cell therapies thus far have been less successful for pediatric solid tumors. In my talk, I will review current challenges of CAR T-cell therapies for solid tumors, highlighting our clinical studies targeting HER2 (Ahmed et al., JCO 2015 and JAMA Oncol 2017). In addition, I will review genetic engineering approaches that are being developed to improve the efficacy of CAR T cells for pediatric solid tumors.

Citation Format: Stephen Gottschalk, Chris DeRenzo, Meena Hegde, Melinda Mata, Phoung Nguyen, Giedre Krenciute, Nabil Ahmed. Engineering T cells for the immunotherapy for pediatric solid 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 IA07.
Abstract IA19: MYC activation through enhancer hijacking or focal enhancer amplification drives a subset of high-risk pediatric neuroblastoma
Authors: Zimmerman Mark W. , Liu Yu , He Shuning , Durbin Adam D. , Abraham Brian J. , Easton John , Shao Ying , Xu Beisi , Zhu Shizhen , Zhang Xiaoling , Weichert-Leahey Nina , Young Richard A. , Zhang Jinghui , Look A. Thomas
Published: February 2019

The amplified MYCN gene serves as an oncogenic driver in approximately 20% of high-risk pediatric neuroblastomas. Here we show that MYC itself is a potent transforming gene in a separate subset of high-risk neuroblastoma cases (~10%), based on (i) its upregulation by focal enhancer amplification or genomic rearrangements leading to enhancer hijacking, and (ii) its ability to transform neuroblastoma precursor cells in a transgenic animal model. The aberrant regulatory elements associated with oncogenic MYC activation include focally amplified distal enhancers or translocation of highly active enhancers from other genes to within topologically associating domains containing the MYC gene locus. The clinical outcome for patients with high levels of MYC expression is virtually identical to that of patients with amplification of the MYCN gene, a known high-risk feature of this disease. Together, these findings establish MYC as a bona fide oncogene in a clinically significant group of high-risk childhood neuroblastomas.

Citation Format: Mark W. Zimmerman, Yu Liu, Shuning He, Adam D. Durbin, Brian J. Abraham, John Easton, Ying Shao, Beisi Xu, Shizhen Zhu, Xiaoling Zhang, Nina Weichert-Leahey, Richard A. Young, Jinghui Zhang, A. Thomas Look. MYC activation through enhancer hijacking or focal enhancer amplification drives a subset of high-risk pediatric 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 IA19.
Abstract IA25: Functional proteomics and site-specific genomic rearrangements of pediatric cancers
Authors: Kentsis Alex
Published: February 2019

Despite intense efforts, the cure rates of childhood leukemias and solid tumors are not satisfactory. Resistance to intensive chemotherapy is common, and targets for molecular therapies are largely undefined. In this presentation, I will describe my laboratory’s recent efforts to apply functional proteomic and genomic technologies to identify causal mechanisms of childhood cancer pathogenesis and therapy resistance. I will present functional proteomic studies of pediatric acute myeloid leukemias, identifying kinase-dependent dysregulation of transcription factor control as a determinant of therapy response in AML. I will also present studies of site-specific genomic rearrangements in childhood solid tumors, identifying the PGBD5 DNA transposase as their oncogenic mutator. Lastly, I will present synthetic lethal approaches to leverage functional dependencies of transcription factor control and PGBD5-dependent DNA damage signaling to induce specific antitumor effects while sparing normal cells, including therapeutic strategies suitable for immediate translation to clinical trials.

Citation Format: Alex Kentsis. Functional proteomics and site-specific genomic rearrangements of pediatric cancers [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 IA25.
Abstract A011: Hypoxia-inducible PIM kinase expression promotes resistance to antiangiogenic agents in prostate cancer
Authors: Casillas Andrea , Toth Rachel , Sainz Alva , Kraft Andrew S. , Warfel Noel A.
Published: February 2019

Angiogenesis is known to play an important role in prostate cancer pathogenesis. Although the addition of VEGF-targeting agents (i.e., bevacizumab) to docetaxel improved response rates in mCRPC patients, it failed to improve overall survival. Patients can develop resistance to antiangiogenic drugs due to changes in the tumor microenvironment, including hypoxia. PIM kinases are prosurvival kinases whose expression is increased in hypoxia and advanced prostate cancer. The goal of this study was to determine whether targeting hypoxia-induced PIM kinase expression is effective in combination with VEGF-targeting agents. The rationale for this therapeutic approach is based on the fact that antiangiogenic drugs can make tumors hypoxic, and thus more sensitive to PIM inhibitors.

We establish PIM kinase expression as a novel mechanism of resistance to antiangiogenic agents. Xenograft and orthotopic models of prostate cancer were used to assess the effect of PIM activation on the efficacy of VEGF-targeting agents. We show that PIM is upregulated following treatment with anti-VEGF therapies, and PIM expression reduces the ability of these drugs to effectively disrupt tumor vasculature. Combinatorial inhibition of PIM and VEGF produces a synergistic antitumor response that is characterized by enhanced cell death, growth arrest, decreased angiogenesis, and reduced metastasis. Mechanistically, small-molecule PIM inhibitors reduce HIF-1 activity, opposing a shift to the proangiogenic gene signature associated with hypoxia. Our data provide justification for combining PIM and VEGF inhibitors to treat advanced prostate cancer.

Citation Format: Andrea Casillas, Rachel Toth, Alva Sainz, Andrew S. Kraft, Noel A. Warfel. Hypoxia-inducible PIM kinase expression promotes resistance to antiangiogenic agents 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 A011.
Abstract A036: Blocking DNA and RNA synthesis by targeting glutamine metabolism in prostate cancer
Authors: Wang Qian (Kevin) , Geldermalsen Michelle van , Pang Angel , Zhang Blake , Holst Jeff
Published: February 2019

Cancer cells greatly increase their uptake of nutrients (glucose, amino acids, and lipids), and metabolize them to provide the necessary building blocks for new cancer cells. It was recently shown that extracellular amino acids make up by far the majority of the carbon sources used by cancer cells for cell division, highlighting amino acid uptake as a viable therapeutic target. In addition, amino acids such as glutamine are critical in providing nitrogen for purine and pyrimidine metabolism. We have previously shown that glutamine uptake is mediated predominantly by ASCT2 in prostate cancer, with ASCT2 knockdown blocking cell growth in vitro and in vivo. Using the TCGA dataset, we have discovered increased expression of downstream glutamine metabolism enzymes in approximately 25% of prostate cancer patients. One of these enzymes, guanine monophosphate synthase (GMPS), is a glutamine amidotransferase involved in de novo purine biosynthesis and is responsible for the last step in the synthesis of the guanine nucleotide. Expression of GMPS correlates with increasing Gleason score in prostate cancer patient samples. Furthermore, patients with high GMPS expression had significantly reduced disease-free survival in the TCGA dataset. Immunofluorescent staining shows that GMPS is localized in both the cytoplasm and nucleus of LNCaP and PC-3 cells—consistent with a secondary role for GMPS in p53 stabilization. Inhibition of GMPS using decoyinine significantly decreased cell growth of both LNCaP and PC-3 cells. Knockdown of GMPS by shRNA significantly decreased cell growth, which could be rescued by addition of extracellular guanosine to the media, suggesting a direct effect on nucleotide synthesis. These results show the importance of downstream glutamine metabolism in prostate cancer, and suggest that GMPS is a potential therapeutic target in “glutamine-addicted” prostate cancers.

Citation Format: Qian (Kevin) Wang, Michelle van Geldermalsen, Angel Pang, Blake Zhang, Jeff Holst. Blocking DNA and RNA synthesis by targeting glutamine metabolism 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 A036.
Abstract A048: Bone remodeling in relation to androgen receptor activity in prostate cancer bone metastases
Authors: Ylitalo Erik Bovinder , Nordstrand Annika , Thysell Elin , Jernberg Emma , Crnalic Sead , Widmark Anders , Bergh Anders , Lerner Ulf H. , Wikström Pernilla
Published: February 2019

Prostate cancer often metastasizes to bone and the metastases are generally classified as osteoblastic, although a mixed osteoblastic/osteolytic bone response may exist. The present study aimed to characterize the bone remodeling activity in clinical bone metastasis samples, with the overall hypothesis that diversities exist that may be of importance for clinical response to current therapies. Specifically, we aimed to study bone remodeling activity in relation to tumor cell androgen receptor (AR) activity. Metastasis tissue obtained from treatment-naïve (n=11) and castration-resistant (n=28) patients during surgery for spinal cord compression was characterized using whole-genome expression analysis followed by multivariate modeling and functional enrichment analysis as well as by histologic evaluation. By analyzing expression levels of a predefined set of markers representing osteoclasts (ACP5, CTSK, MMP9), osteoblasts (ALPL, BGLAP, RUNX2), and osteocytes (SOST), we found high osteoblast activity to be coupled to high osteoclast activity. Immunohistochemistry verified a significant correlation between RUNX2-positive osteoblasts and TRAP (ACP5)-positive osteoclasts lining metastatic bone surfaces in close contact to tumor cells. No difference in bone remodeling activity was seen between treatment-naïve and castration-resistant patients, while the bone remodeling activity was inversely correlated to AR activity in metastasis tissue (measured as expression of the AR, FOXA1, HOXB13, KLK2, KLK3, NKX3-1, STEAP2, and TMPRSS2) and to patient serum PSA levels. Ontology analysis suggested enriched BMP signaling in metastases with high bone remodeling activity and, accordingly, BMP4 mRNA expression was significantly higher in bone metastases with than without ongoing bone formation, as determined from histologic evaluation of van Gieson-stained sections. In conclusion, we have observed diversities in bone remodeling activity among clinical samples of prostate cancer bone metastases that may be of importance when selecting therapy for patients with bone metastatic cancer, especially when bone-targeting therapies are considered. The importance of the BMP signaling system for the development of sclerotic metastasis lesion deserves further exploration.

Citation Format: Erik Bovinder Ylitalo, Annika Nordstrand, Elin Thysell, Emma Jernberg, Sead Crnalic, Anders Widmark, Anders Bergh, Ulf H. Lerner, Pernilla Wikström. Bone remodeling in relation to androgen receptor activity in prostate cancer bone metastases [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 A048.
Abstract A054: Loss of an androgen-inactivating and isoform-specific HSD17B4 splice form enables emergence of castration-resistant prostate cancer
Authors: Ko Hyun-Kyung , Berk Michael , Chung Yoon-Mi , Willard Belinda , Bareja Rohan , Rubin Mark , Sboner Andrea , Sharifi Nima
Published: February 2019

The development of castration-resistant prostate cancer (CRPC) requires tumors to engage metabolic mechanisms that allow sustained concentrations of testosterone and/or dihydrotestosterone, which stimulate tumor progression despite castration. 17βHSD4, encoded by HSD17B4, is an enzyme that is thought to inactive testosterone and dihydrotestosterone by way of conversion to their respective inert 17-keto steroids. Counterintuitively, HSD17B4 expression is known to increase in CRPC and predict for poor prognosis. Here, we show that of 5 alternative splice forms of HSD17B4, only isoform 2 encodes an enzyme capable of testosterone and dihydrotestosterone inactivation. In contrast to other transcripts, functional expression of isoform 2 is specifically suppressed in development of CRPC in patients. Genetically silencing isoform 2 shifts the metabolic balance toward 17β-OH androgens (testosterone and dihydrotestosterone), stimulates PSA expression, and spurs the development of CRPC in xenograft models. Together, our studies specifically implicate HSD17B4 isoform 2 loss in the development of lethal prostate cancer.

Citation Format: Hyun-Kyung Ko, Michael Berk, Yoon-Mi Chung, Belinda Willard, Rohan Bareja, Mark Rubin, Andrea Sboner, Nima Sharifi. Loss of an androgen-inactivating and isoform-specific HSD17B4 splice form enables emergence of castration-resistant 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 A054.
Abstract A064: Mass spectrometry-based proteomics study makes apolipoprotein E a potential risk factor for prostate cancer
Authors: Bizzotto Juan , Vickers Sofia Lage , Paez Alejandra , Scorticati Carlos , Cotignola Javier , Valacco Pia , Mazza Osvaldo , Vazquez Elba , Gueron Geraldine
Published: February 2019

Proteomics represents an important tool for the identification of new molecular targets for prostate cancer (PCa) tailored therapy. Innovative high-throughput proteomic platforms are now identifying and quantifying new specific and sensitive biomarkers for PCa detection, stratification, and treatment. Formalin-fixed and paraffin-embedded (FF-PE) sections mounted on microscope slides are hard to achieve given the low peptide yield obtained from the slides. Here we performed an innovative protocol for an in-depth quantitative mass spectrometry-based proteomics analysis of FF-PE PCa and benign prostate hyperplasia (BPH) sections, using phase-transfer surfactant-aided extraction/tryptic digestion of FF-PE proteins. Results yielded a list of 50 differential proteins only expressed in PCa samples. Of note, apolipoprotein E (APOE) was highly present in carcinoma samples. Furthermore, to evaluate the clinical significance of APOE in PCa we performed a bioinformatics analysis using the Oncomine database. We identified 16 publicly available gene expression microarray datasets comparing prostate adenocarcinoma versus normal prostate, which met our eligibility criteria. We carried out meta-analysis combining the data from the independent datasets. APOE was ranked by its P-value for every analysis scoring a gene rank and then we obtained a median rank (median P-value rank across datasets). APOE showed a significant upregulation (fold change >1.5, P<0.05) comparing prostate adenocarcinoma vs. normal prostate gland. Accordingly, when extending the bioinformatics analysis to evaluate whole-exome and RNA-seq data using cBioportal, the most frequent genetic alteration found for APOE was amplification. RNA-seq data also confirmed a significant upregulation for APOE (P<0.05). We thus identify APOE as a key target in PCa, ascertaining it as a potential risk factor for this disease.

Citation Format: Juan Bizzotto, Sofia Lage Vickers, Alejandra Paez, Carlos Scorticati, Javier Cotignola, Pia Valacco, Osvaldo Mazza, Elba Vazquez, Geraldine Gueron. Mass spectrometry-based proteomics study makes apolipoprotein E a potential risk factor 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 A064.
Abstract A081: Activation of sphingosine kinase 1 by lipopolysaccharide promotes prostate cancer cell invasion via matriptase
Authors: Lee Cheng-Fan , Chen Benjamin , Hsieh Jer-Tsong , Lee Ming-Shyue
Published: February 2019

A 15-year cohort study indicates that bacterial-induced prostatitis is correlated to prostate cancer (PCa) incidence. Several gram-negative bacteria have been identified in PCa patient specimens and inflammatory cytokines derived from bacterial infection have been involved in PCa tumorigenesis. However, the direct effect of lipopolysaccharide (LPS), a potent inflammatory substance from gram-negative bacteria, on PCa development is not well studied. In this study, we examine the effect of LPS on the growth (MTT assay) and invasion (Transwell assay) of several PCa cells lines including LNCaP, PC3, and DU145. Although LPS does not change the cell growth, our results reveal that LPS can enhance the PCa cell invasiveness and increase pericellular proteolytic activities. Using protease inhibitor screening and proteolytic analyses, we have identified that matriptase (MTX), a member of the membrane-anchored serine protease family, plays a key role in LPS-induced PCa cell invasiveness. The activated levels of MTX can be detected in the cells and the conditioned medium (CM) from LPS-treated cells. Indeed, the elevation of MTX expression is associated with high-grade PCa in archival specimens. Knowing LPS as a ligand for toll-like receptor 4 (TLR4), specific antagonists and shRNA knockdown methodology were used to delineate the mechanism by which TLR4/sphingosine kinase 1 (SphK1) signaling cascade plays a role in LPS-induced PCa cell invasion. The results show that SphK1 was important for MTX activation and PCa cell invasion. Moreover, we found that LPS could induce the activation of SphK1 based on an elevated phosphorylation level and SphK1 translocation to plasma membrane for the production of sphingosine 1-phosphate (S1P). S1P can subsequently induce MTX activation and PCa cell invasion through S1P receptor 4 (S1PR4) in a paracrine or autocrine manner. S1PR4 is further identified as an important receptor for S1P to mediate MAPK signaling. Furthermore, there is a significant correlation between the elevated expression of SphK1 and the Gleason scores of PCa specimens. The phenomenon was further corroborated by the fact that LPS could induce SphK1 activation in patient-derived explant model (PDeX). Taken together, we have unveiled a novel LPS-elicited pathway leading to PCa cell invasion. Our results provide not only the potential impact of bacterial infection on PCa progression but also several therapeutic target(s) against PCa metastasis.

Citation Format: Cheng-Fan Lee, Benjamin Chen, Jer-Tsong Hsieh, Ming-Shyue Lee. Activation of sphingosine kinase 1 by lipopolysaccharide promotes prostate cancer cell invasion via matriptase [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 A081.
Abstract A089: Challenging the free hormone hypothesis for vitamin D in the prostate has implications for the prostate cancer disparity in African American men
Authors: Richards Zachary , Nonn Larisa
Published: February 2019

African American (AA) men are disproportionately at risk for both prostate cancer (PCa) and vitamin D (vitD) deficiency compared to European American (EA) men. Based on the numerous chemopreventative properties of vitD and its status with PCa aggressiveness and mortality, vitD deficiency has been hypothesized as a biologic contributor to the PCa disparity in AA men. We recently reported that despite having deficient levels of vitD in the serum, AAs have higher levels of vitD in their prostate tissue compared to EAs. This suggests a mechanism of active vitD transport across the membrane and challenges the longstanding free hormone hypothesis, which asserts that the activity of a hormone is due to the bioavailable fraction and its passive diffusion across the membrane. The majority of VitD circulates bound to D binding protein (DBP) and is sequestered in the serum, rendering it unavailable for passive diffusion. A mechanism of active DBP-vitD endocytosis has been well characterized in the kidney by the extracellular receptor megalin. We hypothesized that megalin is functional in prostate epithelium and facilitates adequate prostatic vitD levels in AAs with vitD deficiency. Here, we report megalin protein expression in prostate tissue, LNCaP, and primary human prostate cells. Megalin function was further assessed in primary human-derived organoids treated with 25D in the presence or absence of DBP. Surprisingly, vitD import and metabolism occurred faster in +DBP conditions and suggests that DBP-vitD active transport is more efficient than passive diffusion of vitD alone. VDR activation was diminished in a dose-responsive manner by addition of a megalin antagonist. Additionally, megalin protein levels in PCa were significantly lower compared to benign (p<0.05) on a tissue microarray quantified by immunofluorescent staining. In summary, our data support a model of megalin-mediated active transport for vitD in the prostate and demonstrate ancestry-related and PCa differences in megalin regulation. These findings challenge the free hormone hypothesis and postulate that vitD deficiency is more complex than previously thought.

Citation Format: Zachary Richards, Larisa Nonn. Challenging the free hormone hypothesis for vitamin D in the prostate has implications for the prostate cancer disparity in African American men [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 A089.
Abstract B004: A combination of two chemically distinct inhibitors of class I HDACs is highly effective to suppress AR signaling and in vivo growth of prostate cancer xenograft
Authors: Tian Guimei , Mahmud Iqbal , Stowe Ryan , Zhang Yushan , Purayil Hamsa Thayek , Roush William , Daaka Yehia , Liao Daiqing
Published: February 2019

Class I HDACs 1-3 are critical for the AR-mediated transcriptional program. Thus, targeting class I HDACs is a promising strategy for treating prostate cancer. However, several FDA-approved HDAC inhibitors (HDACi) broadly inhibiting different HDACs have been shown to be ineffective and overtly toxic for treating castration-resistant prostate cancer in clinical trials. These observations suggest that HDACi selective for class I HDACs may be more effective but less toxic for treating prostate cancer than pan HDACi. Notably, we and others have shown that HDACi of different chemical classes individually exhibit nonoverlapping but limited effects on the acetylome in cancer cells. We hypothesize that a combination treatment strategy with class I HDAC-selective HDACi of different chemical classes is more effective to block AR signaling and prostate tumor growth than such HDACi individually. We have recently discovered the novel benzoylhydrazide chemo-type of class I HDAC-selective HDACi with a unique pharmacologic profile. Medicinal chemistry effort led to an optimized analog, SR-4370, with 6 nM potency to HDAC3. In support of our hypothesis, SR-4370 in combination with the clinical class I HDACi entinostat markedly suppressed AR signaling, prostate cancer cell proliferation in vitro, and tumor growth in vivo, and the tumor-suppressive effects by the HDACi combination were more pronounced than by SR-4370 and entinostat individually. Gene expression profiling experiments revealed that the SR-4370/entinostat combination profoundly downregulated AR, AR-V7, and AR target genes, while activating immune and cell death signaling pathways. In a C4-2 xenograft model using athymic nude mice, the SR-4370/entinostat combination was highly effective in suppressing tumor growth. Importantly, these HDACi alone or in combination did not cause observable adverse effects judged by body weight and blood chemistry tests of treated mice. Overall, our data suggest that the SR-4370/entinostat combination may be a translatable treatment for castration-resistant prostate cancer.

Citation Format: Guimei Tian, Iqbal Mahmud, Ryan Stowe, Yushan Zhang, Hamsa Thayek Purayil, William Roush, Yehia Daaka, Daiqing Liao. A combination of two chemically distinct inhibitors of class I HDACs is highly effective to suppress AR signaling and in vivo growth of prostate cancer xenograft [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 B004.
Abstract B005: Ginger consumption inhibits β-arrestin-2 expression and functions in melanoma and prostate cancer cells
Authors: Mowart Tonelia A. , Adekoya Timothy , Smith Nikia , Lane Tonya S. , Richardson Ricardo M.
Published: February 2019

Ginger active components are widely known for being a potent antioxidant and recently as a potential anticancer agent. [6]-Gingerol, the most abundant and pungent bioactive component of ginger, was shown to inhibit angiogenesis and tumorigenesis in xenograph models of both prostate cancer (PCa) and melanoma. To date, the precise mechanism(s) for the antitumor effect of ginger is not well understood. The adaptor proteins, β-arrestins, have been shown to modulate tumor development and metastasis in both PCa and melanoma. In this study, we sought to determine the role of [6]-gingerol in β-arrestin (βarr) 1 and 2-mediated PCa and melanoma development, progression, and metastasis. To that end, the PCa cells PC-3 and the melanoma B16-F10 cells were treated with different concentrations of [6]-gingerol for 48 hours. Cell lysates were assayed by Western blot analysis for βarr-1 and βarr-2, CXCR1, and CXCR2 expression, as well as MAP kinase and transcription factors activation. The data demonstrated that pretreatment with [6]-gingerol caused a dose-dependent inhibition of βarr-2, but not βarr-1, in both cell lines, which correlated with significant decrease in Akt and NF-κB activation. [6]-Gingerol pretreatment decreased CXCR1 and CXCR2 expression, CXCL-8-induced intracellular calcium mobilization; and delayed wound closure. [6]-Gingerol exposure also decreased PC-3 and B16 metastasis in zebrafish. Altogether the data indicated that the protective effect of [6]-gingerol in tumorigenesis is likely mediated via a βarr-2-dependent mechanism.

Citation Format: Tonelia A. Mowart, Timothy Adekoya, Nikia Smith, Tonya S. Lane, Ricardo M. Richardson. Ginger consumption inhibits β-arrestin-2 expression and functions in melanoma and 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 B005.
Abstract B014: Simulating prostate cancer stem cell dynamics to predict patient-specific sensitivity or resistance to intermittent androgen-deprivation therapy
Authors: Brady Renee , Nagy John , Nagy John , Enderling Heiko
Published: February 2019

Intermittent androgen suppression is an attractive treatment approach for biochemically recurrent locally advanced prostate cancer to delay evolution of treatment resistance (PMID: 16783817). We developed a mathematical model of prostate cancer stem cell dynamics during therapy as a plausible mechanism of resistance evolution. We simulate division dynamics of cancer stem cells, non-stem cancer cells, and PSA concentration and generate highly accurate model fits to the longitudinal data of 55 patients undergoing 2-4 cycles of intermittent androgen suppression. We analyze model dynamics to identify cancer stem cell proliferation patterns that correlate with patient outcomes, and score model predictive power to accurately forecast evolution of resistance in individual patients. The presented framework may contribute to identifying patients who do and do not develop resistance to intermittent androgen suppression. The obtained predictive power on a retrospective data set warrants prospective evaluation in a clinical setting.

Citation Format: Renee Brady, John Nagy, John Nagy, Heiko Enderling. Simulating prostate cancer stem cell dynamics to predict patient-specific sensitivity or resistance to intermittent androgen-deprivation therapy [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 B014.
Abstract B024: Family history of prostate cancer and the incidence of ERG- and PTEN-defined prostate cancer
Authors: Hashim Dana , Gonzalez-Feliciano Amparo G. , Ahearn Thomas U. , Pettersson Andreas , Barber Lauren , Pernar Claire H. , Ebot Ericka M. , Finn Stephen , Giovannucci Edward L. , Lis Rosina T. , Loda Massimo , Parmigiani Giovanni , Penney Kathryn L. , Lotan Tamara , Kantoff Philip W. , Mucci Lorelei A. , Graff Rebecca E.
Published: February 2019

Introduction: Family history is among the strongest known risk factors for prostate cancer. Emerging data suggest unique molecular subtypes of disease, including common somatic genetic aberrations: fusions of androgen-regulated promoters with ERG and, separately, PTEN loss. We examined associations between family history and incidence of these subtypes under the hypothesis that family history could be differentially associated with their occurrence.

Methods: We studied 47,115 men in the prospective Health Professionals Follow-up Study from 1986 to 2009. ERG and PTEN status were assessed with immunohistochemistry. Multivariable competing risk models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations between self-reported family history of prostate cancer and disease defined by molecular subtypes.

Results: During a median follow-up of 22.3 years, 5,606 prostate cancer cases were diagnosed. Among them, 889 and 711 were assayed for ERG status (48% ERG+) and PTEN loss (14% PTEN null), respectively. Prostate cancer family history was positively associated with both ERG+ (HR=1.85; 95% CI: 1.47-2.33) and ERG- (HR=2.20; 95% CI: 1.78-2.72) disease (P-heterogeneity=0.29). High-grade ERG+ disease suggested a pronounced association (HR=2.58; 95% CI: 1.85-3.61; P-heterogeneity versus high-grade ERG-: 0.08). Family history was also positively associated with PTEN null (HR=2.39; 95% CI: 1.53-3.71) and PTEN intact (HR=1.88; 95% CI: 1.54-2.28) prostate cancer (P-heterogeneity=0.34).

Conclusion: Prostate cancer family history is positively associated with prostate cancer defined by ERG and PTEN, suggesting a similar role of genetic susceptibility for these subtypes. It is possible that high-grade ERG+ disease could be uniquely associated with positive family history.

Citation Format: Dana Hashim, Amparo G. Gonzalez-Feliciano, Thomas U. Ahearn, Andreas Pettersson, Lauren Barber, Claire H. Pernar, Ericka M. Ebot, Stephen Finn, Edward L. Giovannucci, Rosina T. Lis, Massimo Loda, Giovanni Parmigiani, Kathryn L. Penney, Tamara Lotan, Philip W. Kantoff, Lorelei A. Mucci, Rebecca E. Graff. Family history of prostate cancer and the incidence of ERG- and PTEN-defined 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 B024.
Abstract B032: Inappropriate AR reactivation-induced redox stress as a novel therapeutic target in castration-resistant prostate cancer
Authors: Samaranayake Govindi J. , Troccoli Clara I. , Huynh Mai Q. , Lyles Rolando D.Z. , Kwon Deukwoo , Ban Yuguang , Chen Steven Xi , Jorda Merce , Burnstein Kerry , Rai Priyamvada
Published: February 2019

Androgen deprivation therapy (ADT) initially suppresses prostate cancer (PC) progression. However, castration-resistant PC (CRPC) cells inevitably emerge, resulting in incurable disease. We recently demonstrated that AD produces a form of cellular senescence leading to outgrowth of CRPC subpopulations from the AD-sensitive parental cells. Gene expression profiling studies comparing the parental LNCaP line to the senescence-resistant, early CRPC variant, LNCaP SB5, revealed an enrichment of redox-protective proteins in the latter under AD conditions. This finding suggests that redox stress due to hyperactivated mitogenic/survival signaling or metabolic stresses may be an important and understudied Achilles heel in the progression to CRPC. Here we present the effects of inhibiting thioredoxin-1 (TRX1), a redox-protective protein that was identified as being elevated in our early CRPC LNCaP SB5 model as well as in human CRPC vs. AD-responsive PC datasets. Suppression of TRX1 expression via shRNA led to profound growth suppression of CRPC cells, relative to their AD-sensitive counterparts, and significantly reduced CRPC xenograft tumor growth. Furthermore, under AD, TRX1 suppression promoted p53-induced cell death, which was accompanied by increased reactive oxygen species (ROS). Curiously, TRX1 inhibition led to increased AR and Sp1 expression under AD, and the oxidative stress effects associated with TRX1 inhibition could be mitigated by depleting AR expression. These in vitro and in vivo results were recapitulated using PX-12 a phase I-approved pharmacologic TRX1 inhibitor. Thus our results point to TRX1 as a critical requirement for protecting against redox stress evoked by the inappropriate reactivation of AR in a low-androgen environment in CRPC. Our work provides a rationale for using TRX1 inhibitors in conjunction with ADT to limit CRPC.

Citation Format: Govindi J. Samaranayake, Clara I. Troccoli, Mai Q. Huynh, Rolando D.Z. Lyles, Deukwoo Kwon, Yuguang Ban, Steven Xi Chen, Merce Jorda, Kerry Burnstein, Priyamvada Rai. Inappropriate AR reactivation-induced redox stress as a novel therapeutic target in castration-resistant 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 B032.
Abstract B034: Time to treatment and overall survival among men with localized prostate cancer
Authors: Pierre-Victor Dudith , Pinsky Paul , Martin Iman K. , McCaskill-Stevens Worta
Published: February 2019

Background: Prostate cancer is the second most common cancer diagnosed among men in the United States. Delays from the time of confirmed diagnosis to primary treatment are more common for prostate compared to other malignancies. The objective of this study was to investigate factors associated with time to treatment and the effect of time to treatment on overall survival among men with early-stage prostate cancer.

Methods: From the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, men diagnosed with localized prostate cancer who received treatment within a year of diagnosis were selected for analysis (N=6,349). Selected men had date of diagnosis, treatment date, and mortality status as of 2012. We investigated sociodemographic and clinical factors associated with time to treatment using Cox regression. We also used Cox regression to examine the effect of time to treatment on overall survival. Covariates included Gleason score, PSA level, age at diagnosis, employment status, education level, race, marital status, and comorbidity burden.

Results: The median time to treatment was 73 (IQR: 44-120) days. Demographic factors associated with longer time to treatment included being Black (adjusted hazard ratio (aHR)= 0.85, 95%CI: 0.76-0.95), having some college education (aHR= 0.91, 95%CI: 0.85-0.97), and having a baccalaureate degree or a post-baccalaureate degree (aHR= 0.89, 95% CI: 0.84-0.95). Clinical factors associated with longer time to treatment were being diagnosed at an older age (aHR= 0.86, 95%CI:0.80-0.93 for age of 70-74 years and aHR= 0.80, 95%CI: 0.74-0.87 for 75 year and older) and having an elevated PSA level (HR=0.89, 95%CI: 0.81-0.94 for third PSA quartile (6.11-9.0) and HR=0.87, 95%CI: 0.81-0.94 for fourth PSA quartile (9.0 and above). Gleason score and comorbidity burden were not associated with time to treatment. Being married (aHR=1.11, 95%CI: 1.03-1.19) and being retired (aHR=1.09, 95%CI:1.034-1.16) were associated with shorter time to treatment. After adjusting for sociodemographic and clinical characteristics, time to treatment did not have a significant effect on overall survival.

Conclusions: College education, being Black, older age at diagnosis, and higher PSA levels were associated with longer time to treatment. Being married and being retired were associated with shorter time to treatment. Longer time to treatment was not associated with overall mortality among PLCO men with localized prostate cancer.

Citation Format: Dudith Pierre-Victor, Paul Pinsky, Iman K. Martin, Worta McCaskill-Stevens. Time to treatment and overall survival among men with localized 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 B034.
Abstract B038: Convergent hormone therapy resistance mediated by stress/dormancy-like pathways in prostate cancer
Authors: Ware Kathryn E. , Gupta Santosh , Eng Jared , Foo Wen-Chi , Crawford Lorin , Austin Garland , Puviindran Bhairavy , Freedman Jennifer , Patierno Steven R. , Zhang Tian , Corcoran David , Pierobon Mariaelena , Petricoin Emanuel , Somarelli Jason A. , Armstong Andrew J.
Published: February 2019

Background: Novel agents that inhibit the androgen receptor (AR), including abiraterone acetate and enzalutamide, have significantly prolonged life in many men with metastatic castration-resistant prostate cancer (mCRPC). However, after 1-2 years of therapy acquired resistance to these drugs is nearly universal. Therefore, identifying mechanisms of resistance and innovative therapies to treat enzalutamide-resistant disease represents a major unmet clinical need.

Methods: In this study, we developed four enzalutamide-resistant cell lines and analyzed each cell line by RNA-seq and phospho-proteomics to identify common pathways deregulated during disease progression to enzalutamide resistance. We manipulated p38 levels and activity in order to determine its mechanistic relationship to resistance. We measured p38 activity in metastatic biopsies from men with both hormone-sensitive and metastatic prostate cancer.

Results: At the nexus of acquired enzalutamide resistance in four independently derived prostate cancer model systems, we identified a convergent mechanism of resistance through activation of the p38 stress response/dormancy pathway. Enzalutamide-resistant cells are sensitized to p38 inhibition, and enzalutamide- sensitive cells developed resistance to enzalutamide with constitutive activation of p38 signaling. Enzalutamide-resistant cells have sustained AR activity, which is blocked with genetic or small-molecule p38 inhibition, indicating that p38 promotes AR activity in the absence of ligand binding. Finally, we found common activation of p38 in lymph node, visceral, and bone metastases from men with mCRPC.

Conclusions: We have identified the stress response/dormancy p38-signaling pathway as a common mechanism driving enzalutamide resistance. Most importantly, p38 is a targetable pathway activated in tumors from men with mCRPC, suggesting that novel therapeutic strategies could be applied to prolong the lives of men with metastatic, drug-resistant prostate cancer.

Citation Format: Kathryn E. Ware, Santosh Gupta, Jared Eng, Wen-Chi Foo, Lorin Crawford, Garland Austin, Bhairavy Puviindran, Jennifer Freedman, Steven R. Patierno, Tian Zhang, David Corcoran, Mariaelena Pierobon, Emanuel Petricoin, Jason A. Somarelli, Andrew J. Armstong. Convergent hormone therapy resistance mediated by stress/dormancy-like pathways 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 B038.
Abstract B061: Alternative RNA splicing and prostate cancer aggressiveness
Authors: Abo Muthana Al , Patierno Steven R. , Freedman Jennifer A.
Published: February 2019

Prostate cancer (PCa) is the most common cancer in men in the United States. Aggressive pathology, metastasis, and drug resistance of cancer cells are the most important prognostic factors for patients with PCa. African Americans (AAs) suffer disproportionately from PCa, with higher aggressiveness, progression, and mortality. A recently published analysis involving our laboratory reported more than 2,500 alternatively RNA spliced (ARS) genes between AA and white PCa biopsy tissue specimens. Subsequent analysis revealed that, among the race-related ARS genes in PCa tissue, 19 are also ARS in breast, lung, and liver cancer. Several of the genes that are ARS across multiple tumor types are important for cancer aggressiveness, including CD44, FN1, and LMO7. We designed PCR primers to further explore the expression of LMO7 variants in preclinical models of white and AA PCa, and found that a LMO7 variant that skips exons 10, 11, and 12 is predominantly expressed in VCaP (white) and MDA PCA 2b (AA) PCa cell lines. In addition, we detected a unique race-related LMO7 splicing event that excludes exons 10 and 11, but preserves exon 12. This event is detected in MDA PCA 2b cells, but not in VCaP cells. Importantly, both of these LMO7 splicing events are in-frame and are not frameshifts leading to truncated or extended C-terminal proteins. These LMO7 variants translate to proteins of 1297 amino acids (missing 344 amino acids coded by skipped exons 10, 11, and 12) and 1287 amino acids (missing 334 amino acids coded by skipped exons 10 and 11), which differ from the full-length LMO7 variant that translates to a protein of 1631 amino acids. Interestingly, the enrichment of these variants in cancer cells suggests an important regulatory role for the amino acids encoded by the skipped exons. Further work to study the impact of LMO7 variants as well as other candidate RNA splice variants on PCa aggressiveness is ongoing, using gene overexpression, gene depletion, and splicing manipulation by siRNA or CRISPR-cas, followed by assessment of resulting alterations in growth, migration, invasion, and drug sensitivity. In summary, we have identified genes that undergo race-related ARS in multiple tumor types and novel ARS events that may functionally contribute to increased tumor aggressiveness, including that of PCa in AA men.

Citation Format: Muthana Al Abo, Steven R. Patierno, Jennifer A. Freedman. Alternative RNA splicing and prostate cancer aggressiveness [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 B061.