Neuroendocrine Carcinoma Of Prostate Research Articles

AKAP2-anchored protein phosphatase 1 controls prostatic neuroendocrine carcinoma cell migration and invasion

Prostate cancer (PC) is the second leading cause of cancer-related death in men. The growth of primary prostate cancer cells relies on circulating androgens and thus the standard therapy for the treatment of localized and advanced PC is the androgen deprivation therapy. Prostatic neuroendocrine carcinoma (PNEC) is an aggressive and highly metastatic subtype of prostate cancer, which displays poor prognosis and high lethality. Most of PNECs develop from prostate adenocarcinoma in response to androgen deprivation therapy, however the mechanisms involved in this transition and in the elevated biological aggressiveness of PNECs are poorly defined. Our current findings indicate that AKAP2 expression is dramatically upregulated in PNECs as compared to non-cancerous prostate tissues. Using a PNEC cell model, we could show that AKAP2 is localized both intracellularly and at the cell periphery where it colocalizes with F-actin. AKAP2 and F-actin interact directly through a newly identified actin-binding domain located on AKAP2. RNAi-mediated silencing of AKAP2 promotes the phosphorylation and deactivation of cofilin, a protein involved in actin turnover. This effect correlates with a significant reduction in cell migration and invasion. Co-immunoprecipitation experiments and proximity ligation assays revealed that AKAP2 forms a complex with the catalytic subunit of protein phosphatase 1 (PP1) in PNECs. Importantly, AKAP2-mediated anchoring of PP1 to the actin cytoskeleton regulates cofilin dephosphorylation and activation, which, in turn, enhances F-actin dynamics and favors migration and invasion. In conclusion, this study identified AKAP2 as an anchoring protein overexpressed in PNECs that controls cancer cell invasive properties by regulating cofilin phosphorylation.

Genomic Evolution and Transcriptional Changes in the Evolution of Prostate Cancer into Neuroendocrine and Ductal Carcinoma Types.

Prostate cancer is typically of acinar adenocarcinoma type but can occasionally present as neuroendocrine and/or ductal type carcinoma. These are associated with clinically aggressive disease, and the former often arises on a background of androgen deprivation therapy, although it can also arise de novo. Two prostate cancer cases were sequenced by exome capture from archival tissue. Case 1 was de novo small cell neuroendocrine carcinoma and ductal adenocarcinoma with three longitudinal samples over 5 years. Case 2 was a single time point after the development of treatment-related neuroendocrine prostate carcinoma. Case 1 showed whole genome doubling in all samples and focal amplification of AR in all samples except the first time point. Phylogenetic analysis revealed a common ancestry for ductal and small cell carcinoma. Case 2 showed 13q loss (involving RB1) in both adenocarcinoma and small cell carcinoma regions, and 3p gain, 4p loss, and 17p loss (involving TP53) in the latter. By using highly curated samples, we demonstrate for the first time that small-cell neuroendocrine and ductal prostatic carcinoma can have a common ancestry. We highlight whole genome doubling in a patient with prostate cancer relapse, reinforcing its poor prognostic nature.

Spatial Gene Expression Analysis Reveals Characteristic Gene Expression Patterns of De Novo Neuroendocrine Prostate Cancer Coexisting with Androgen Receptor Pathway Prostate Cancer.

Neuroendocrine prostate carcinoma (NEPC) accounts for less than 1% of prostate neoplasms and has extremely poorer prognosis than the typical androgen receptor pathway-positive adenocarcinoma of the prostate (ARPC). However, very few cases in which de novo NEPC and APRC are diagnosed simultaneously in the same tissue have been reported. We report herein a 78-year-old man of de novo metastatic NEPC coexisting with ARPC treated at Ehime University Hospital. Visium CytAssist Spatial Gene Expression analysis (10× genetics) was performed using formalin-fixed, paraffin-embedded (FFPE) samples. The neuroendocrine signatures were upregulated in NEPC sites, and androgen receptor signatures were upregulated in ARPC sites. TP53, RB1, or PTEN and upregulation of the homologous recombination repair genes at NEPC sites were not downregulated. Urothelial carcinoma markers were not elevated. Meanwhile, Rbfox3 and SFRTM2 levels were downregulated while the levels of the fibrosis markers HGF, HMOX1, ELN, and GREM1 were upregulated in the tumor microenvironment of NEPC. In conclusion, the findings of spatial gene expression analysis in a patient with coexisting ARPC and de novo NEPC are reported. The accumulation of cases and basic data will help with the development of novel treatments for NEPC and improve the prognosis of patients with castration-resistant prostate cancer.

KEYNOTE-365 cohort I: Phase 1b/2 study of pembrolizumab combined with platinum-containing chemotherapy and chemotherapy alone for treatment-emergent neuroendocrine prostate carcinoma (t-NE).

TPS218 Background: In previously treated adenocarcinoma metastatic castration-resistant prostate cancer (mCRPC), approximately 20% of patients develop t-NE PC, which is aggressive with short overall survival (OS). t-NE PC treatment includes platinum-containing chemotherapy because of t-NE’s histologic, biologic, and clinical similarity to small cell/NE lung cancer. In the open-label, multicohort, phase 1b/2 KEYNOTE-365 study (NCT02861573), pembrolizumab, when combined with several agents for treatment of adenocarcinoma mCRPC, showed clinical activity and acceptable safety. To identify new treatment options for t-NE mCRPC, cohort I will help to evaluate platinum-containing chemotherapy alone or combined with pembrolizumab for patients with t-NE. Methods: Cohort I of the KEYNOTE-365 study will enroll patients with t-NE (≥1% neuroendocrine cells in a recent biopsy specimen confirmed by central histology review) and prior docetaxel treatment for mCRPC. Prior treatment with ≤2 next-generation hormonal agents (NHAs) for metastatic hormone-sensitive prostate cancer (mHSPC) or mCRPC and 1 other chemotherapy for mCRPC is permitted. Additionally, enrollment in cohort I requires previous prostate cancer progression within 6 months of starting an NHA (mHSPC or mCRPC) and within < 6 cycles of docetaxel for mCRPC. Each arm will enroll 40-100 patients with Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1. Eligible patients will be randomly assigned 1:1 to receive pembrolizumab 200 mg IV on day 1 of each cycle every 3 weeks + carboplatin AUC of 5 IV on day 1 + etoposide 100 mg/m2 IV on days 1, 2, and 3 of each 21-day cycle for 4 cycles (arm 1) or the same chemotherapy regimen without pembrolizumab (arm 2). Pembrolizumab treatment will continue for up to 2 years until disease progression, unacceptable toxicity, or withdrawal of consent. Patients will be stratified by ECOG PS score (0 vs 1). Primary end points are safety and tolerability, prostate-specific antigen (PSA) response rate, and objective response rate (ORR) per RECIST v1.1 by blinded independent central review (BICR). Secondary end points include time to PSA progression; duration of response (DOR) and disease control rate (DCR) per RECIST v1.1 by BICR; ORR, DOR, DCR, and radiographic progression-free survival per Prostate Cancer Working Group 3–modified RECIST v1.1 by BICR; and OS. End points will be summarized for each arm without formal hypothesis testing. This cohort of KEYNOTE-365 is enrolling in Australia, Germany, New Zealand, Spain, and the United States. Clinical trial information: NCT02861573.

639TiP KEYNOTE-365 cohort I: Phase Ib/II study of platinum containing chemotherapy in combination with pembrolizumab and chemotherapy alone for treatment-emergent neuroendocrine prostate carcinoma (t-NE)

Neuroendocrine prostate cancer is an aggressive disease that can occur de novo or from previously treated metastatic castration-resistant prostate cancer (mCRPC). Based on histologic similarity to small cell lung cancer, the treatment for t-NE often includes platinum-containing chemotherapy, but there is no standard of care. The PD-1 inhibitor pembrolizumab has shown promising efficacy with acceptable safety in combination with olaparib, docetaxel, or enzalutamide for treatment of mCRPC in the multicohort phase Ib/II KEYNOTE-365 study (NCT02861573).

Large-cell neuroendocrine tumor of the prostate: a\xa0case report and review of the literature

BackgroundPrimitive neuroendocrine prostate neoplasms are rarely reported. This entity comprises carcinoïd tumors and poorly differentiated neuroendocrine tumors, mainly those of the small-cell type. Large-cell-type primitive tumors are exceptional, and only nine cases are reported in the literature. Similar to neuroendocrine tumors of the prostate, large-cell-type primitive tumors may be observed in the context of conventional adenocarcinoma during androgen deprivation therapy or as prostatic metastasis of a distant neuroendocrine tumor, mainly pulmonary neoplasms.Case presentationWe report a Caucasian case of a mixed prostatic carcinoma, with the largest component being the large-cell neuroendocine carcinoma, in a patient who underwent a total prostatectomy for a localized cancer. Diagnostic, histological, therapeutic and evolutive aspects are reported and discussed.ConclusionsLarge-cell primitive prostate neuroendocrine carcinoma is a rare but aggressive histological entity, which can be associated or not with an adenocarcinomatous component. Mixed forms have a better outcome, mainly when diagnosed at an early stage.

Large-Cell Neuroendocrine Carcinoma of the Prostate

Primary large-cell neuroendocrine carcinoma of the prostate is very rare. The tumor genomic alterations have not been reported. We report a case of a 78-year-old man with a recurrent large-cell prostatic neuroendocrine carcinoma with distinctive pathological features and genetic changes including ATM frameshift duplication, TP53 missense mutation, and a chromosomal translocation leading to STAG2-BTD gene fusion.

Telomere lengths differ significantly between small-cell neuroendocrine prostate carcinoma and adenocarcinoma of the prostate

Small-cell neuroendocrine carcinoma (SCNC) of the prostate is an aggressive subtype with frequent TP53 mutation and RB1 inactivation; however, the molecular phenotype remains an area of investigation. Here, we compared telomere lengths in prostatic SCNC and usual-type prostatic adenocarcinoma (AdCa). We studied 32 cases of prostatic SCNC (including 11 cases with concurrent AdCa) and 347 cases of usual-type AdCa on tissue microarrays. Telomere lengths in tumor cells were qualitatively compared with those in normal cells using a telomere-specific fluorescence in situ hybridization assay. ERG, PTEN, and TP53 status were assessed in a proportion of cases using genetically validated immunohistochemistry protocols. Clinicopathological and molecular characteristics of cases were compared between the telomere groups using the chi-square test.A significantly higher proportion of prostatic SCNC cases (50%, 16/32) showed normal/long telomeres compared with AdCa cases (11%, 39/347; P<0.0001). In 82% (9/11) of cases with concurrent SCNC and AdCa, the paired components were concordant for telomere length status. Among AdCa cases, the proportion of cases with normal/long telomeres significantly increased with increasing tumor grade group (P=0.01) and pathologic stage (P=0.02). Cases with normal/long telomeres were more likely to be ERG positive (P=0.04) and to have TP53 missense mutation (P=0.01) than cases with short telomeres.Normal or long telomere lengths are significantly more common in prostatic SCNC than in AdCa and are similar between concurrent SCNC and AdCa tumors, supporting a common origin. Among AdCa cases, longer telomere lengths are significantly associated with high-risk pathologic and molecular features.

Paraneoplastic Dermatomyositis Presenting as Atopic Blepharitis

A 61-year-old man with a history of severe seasonal allergies presented with violaceous erythema of the eyelids (Fig A). Complete physical examination disclosed reddish macules of interphalangeal/metacarpophalangeal joints (Fig A, Gottron’s sign) and proximal muscle weakness. Serum creatine phosphokinase was elevated (485 U/l, normal 31-288) and muscle biopsy revealed endomysial inflammatory cell infiltration, consistent with the diagnosis of dermatomyositis (Fig B). Magnetic resonance imaging subsequently documented a prostate tumor (Fig C, red arrow), histologically identified as large-cell neuroendocrine prostate carcinoma (Fig D, positive immunohistochemical staining for chromogranin A). Dermatomyositis is an idiopathic inflammatory myopathy carrying a sustained increased risk of cancer, up to 30% of patients. (Magnified version of Fig A-D is available online at www.aaojournal.org).

Abstract 2962: Targeting BCL2 as a therapeutic strategy in neuroendocrine prostate cancer

Abstract Small-cell neuroendocrine prostate carcinoma (SC/NEPC) is an aggressive subtype of prostate cancer (PC) with poor response to conventional therapies and no approved targeted therapies. The molecular mechanisms that drive the growth and survival of these tumors are poorly understood due to disease rarity and a lack of model systems for the subtype. SC/NEPC shares defining characteristics with other aggressive small-cell neuroendocrine tumors, such as “small-blue round cell” morphology and expression of chromogranin A. In this study, we compare whole transcriptome RNA-sequencing data from metastatic PCs and two additional SC/NE tumor types, small cell lung cancer (SCLC) and Merkel Cell carcinoma (MCC). By differential expression analysis of each neuroendocrine tumor type to Androgen Receptor-responsive Prostate Cancer (AR-PC), we identify 4,300 genes exhibiting shared expression patterns in multiple neuroendocrine tumor types. Among these “pan-neuroendocrine” genes are known and proposed drivers of the neuroendocrine transcriptional program including MYCN (p=8.7E-07, upregulated in SC/NEPC over AR-PC) and potential novel drivers of the neuroendocrine phenotype in PC such as MYCL (p=3.5E-05, upregulated in SC/NEPC over AR-PC). We also identify conserved expression patterns of druggable targets including BCL2 which has previously been reported as highly expressed in subsets of SCLC and MCC, but not SC/NEPC (p=1.24E-05, upregulated in SC/NEPC over AR-PC). We then analyzed a panel of cell lines and novel PDX models, which further confirm that the BCL2 protein is highly expressed specifically in the SC/NEPC phenotype. We determined that SC/NEPC cell lines and PDX models are sensitive to BCL2 family member inhibitors targeting BCL2, BCLXL, BCLW, including, ABT263, ABT199 and ABT737, at sub-micromolar concentrations, whereas models of ARPC were resistant. These inhibitors lead to apoptotic cell death in SC/NEPC. Collectively, our data suggests that BCL2 inhibition may present a novel targeted approach for SC/NEPC that warrants further evaluation. Citation Format: Alexandra N. Corella, Jared M. Lucas, Arja Kaipainen, Ilsa M. Coleman, Colm Morrissey, Eva Corey, Paul Nghiem, David MacPherson, Peter S. Nelson. Targeting BCL2 as a therapeutic strategy in neuroendocrine prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2962.

Multi-Omics Analyses Detail Metabolic Reprogramming in Lipids, Carnitines, and Use of Glycolytic Intermediates between Prostate Small Cell Neuroendocrine Carcinoma and Prostate Adenocarcinoma.

As the most common cancer in men, prostate cancer is molecularly heterogeneous. Contributing to this heterogeneity are the poorly understood metabolic adaptations of the two main types of prostate cancer, i.e., adenocarcinoma and small cell neuroendocrine carcinoma (SCNC), the latter being more aggressive and lethal. Using transcriptomics, untargeted metabolomics and lipidomics profiling on LASCPC-01 (prostate SCNC) and LNCAP (prostate adenocarcinoma) cell lines, we found significant differences in the cellular phenotypes of the two cell lines. Gene set enrichment analysis on the transcriptomics data showed 62 gene sets were upregulated in LASCPC-01, while 112 gene sets were upregulated in LNCAP. ChemRICH analysis on metabolomics and lipidomics data revealed a total of 25 metabolite clusters were significantly different. LASCPC-01 exhibited a higher glycolytic activity and lower levels of triglycerides, while the LNCAP cell line showed increases in one-carbon metabolism as an exit route of glycolytic intermediates and a decrease in carnitine, a mitochondrial lipid transporter. Our findings pinpoint differences in prostate neuroendocrine carcinoma versus prostate adenocarcinoma that could lead to new therapeutic targets in each type.

Insulinoma-associated protein 1 is a novel sensitive and specific marker for small cell carcinoma of the prostate

The correct diagnosis of small cell carcinoma (SCC) of the prostate is critical because of its aggressive behavior and poor prognosis. The histopathologic diagnosis could be challenging without neuroendocrine markers, which currently has limitations. Insulinoma-associated protein 1 (INSM1), a zinc-finger transcription factor, is considered to play an important role in the development of several neuroendocrine precursor cells. Its diagnosis value has only recently been evaluated. In this study, we analyzed the expression of INSM in three high-throughput RNA sequencing data sets and performed INSM1 immunohistochemistry on a large series of prostatic SCCs and non-neuroendocrine prostate tissues. To validate its possible utility as a diagnostic marker, the performance of chromogranin and synaptophysin was used for comparison. We found INSM1 mRNA is up-regulated in neuroendocrine prostate carcinoma samples from the published data sets. The results were verified by the immunohistochemistry performance. INSM1 was positive in 92.3% of prostatic SCCs, compared with 53.8% positive for chromogranin, and 84.6% positive for synaptophysin. INSM1 was also stained all of the mixed SCC-acinar adenocarcinomas and metastatic SCCs progression from acinar adenocarcinoma. Only 3.4% of benign prostate tissues and 4.0% of prostate adenocarcinomas were INSM1 positive. Our data suggest that INSM1 is a novel sensitive and specific marker for detection of SCC of the prostate. Application of INSM1 in clinical pathologic diagnosis will be valuable.

Severe Cushing's syndrome due to small cell prostate carcinoma: a case and review of literature.

Cushing’s syndrome (CS) due to ectopic adrenocorticotrophic hormone (ACTH) is associated with a variety of tumours most of which arise in the thorax or abdomen. Prostate carcinoma is a rare but important cause of rapidly progressive CS. To report a case of severe CS due to ACTH production from prostate neuroendocrine carcinoma and summarise previous published cases. A 71-year-old male presented with profound hypokalaemia, oedema and new onset hypertension. The patient reported two weeks of weight gain, muscle weakness, labile mood and insomnia. CS due to ectopic ACTH production was confirmed with failure to suppress cortisol levels following low- and high-dose dexamethasone suppression tests in the presence of a markedly elevated ACTH and a normal pituitary MRI. Computed tomography demonstrated an enlarged prostate with features of malignancy, confirmed by MRI. Subsequent prostatic biopsy confirmed neuroendocrine carcinoma of small cell type and conventional adenocarcinoma of the prostate. Adrenal steroidogenesis blockade was commenced using ketoconazole and metyrapone. Complete biochemical control of CS and evidence of disease regression on imaging occurred after four cycles of chemotherapy with carboplatin and etoposide. By the sixth cycle, the patient demonstrated radiological progression followed by recurrence of CS and died nine months after initial presentation. Prostate neuroendocrine carcinoma is a rare cause of CS that can be rapidly fatal, and early aggressive treatment of the CS is important. In CS where the cause of EAS is unable to be identified, a pelvic source should be considered and imaging of the pelvis carefully reviewed.

Large Cell Neuroendocrine Carcinoma of Prostate: A Rare Interesting Case and Literature Review

: Prostate cancer (PC) is one of the most common forms of malignancies and the second cause of cancer death all around the world and the eight causes in Iran. The main portion of PC is adenocarcinoma, in some cases neuroendocrine differentiation occurs. Neuroendocrine prostate cancers (NePCs) incidence varies from 0.5% to 2% of all prostate cancers. Large cell neuroendocrine differentiation is very rare. In this study we presented a 71-year-old man with large cell neuroendocrine carcinoma of the prostate.

Prise en charge des carcinomes neuroendocrines de prostate : revue de la littérature

Neuroendocrine prostate carcinoma is a rare entity causing both diagnostic and therapeutic issues. There are basically four histological forms (adenocarcinoma with neuroendocrine differentiation, carcinoid tumors, small cell neuroendocrine carcinomas, large cell neuroendocrine carcinomas), which can be pure or mixed associated with prostatic carcinoma. There is no consensus on the management or the prognosis of these various tumor subtypes. We conducted a literature review aiming to determine the potential therapeutic implications.

Persistence of AR signaling in small cell neuroendocrine prostate cancer (SCNC) and intermediate atypical carcinoma (IAC): Results from the SU2C/PCF/AACR West Coast Prostate Cancer Dream Team (WCDT).

5045Background: De novo small cell neuroendocrine prostate carcinoma (SCNC) is an AR-null subtype observed in ~ 1% of patients (pts). We have observed a higher frequency of SCNC in castration-resis...

2,3,7,8-Tetrachlorodibenzo-p-dioxin has both pro-carcinogenic and anti-carcinogenic effects on neuroendocrine prostate carcinoma formation in TRAMP mice

It is well established that the prototypical aryl hydrocarbon receptor (AHR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can both cause and protect against carcinogenesis in non-transgenic rodents. But because these animals almost never develop prostate cancer with old age or after carcinogen exposure, whether AHR activation can affect cancer of the prostate remained unknown. We used animals designed to develop this disease, Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice, to investigate the potential role of AHR signaling in prostate cancer development. We previously reported that AHR itself has prostate tumor suppressive functions in TRAMP mice; i.e., TRAMP mice in which Ahr was knocked out developed neuroendocrine prostate carcinomas (NEPC) with much greater frequency than did those with both Ahr alleles. In the present study we investigated effects of AHR activation by three different xenobiotics. In utero and lactational TCDD exposure significantly increased NEPC tumor incidence in TRAMP males, while chronic TCDD treatment in adulthood had the opposite effect, a significant reduction in NEPC incidence. Chronic treatment of adult TRAMP mice with the low-toxicity selective AHR modulators indole-3-carbinol or 3,3′-diindolylmethane did not significantly protect against these tumors. Thus, we demonstrate, for the first time, that ligand-dependent activation of the AHR can alter prostate cancer incidence. The nature of the responses depended on the timing of AHR activation and ligand structures.

Targeting neuroendocrine prostate cancer: molecular and clinical perspectives.

Neuroendocrine prostate carcinoma, either co-present with the local adenocarcinoma disease or as a result of transdifferentiation later in time, was described as one major process of emerging resistance to androgen deprivation therapies, and at the clinical level it is consistent with the development of rapidly progressive visceral disease, often in the absence of elevated serum prostate-specific antigen level. Until present, platinum-based chemotherapy has been the only treatment modality, able to produce a fair amount of responses but of short duration. Recently, several efforts for molecular characterization of this lethal phenotype have resulted in identification of novel signaling factors involved in microenvironment interactions, mitosis, and neural reprograming as potential therapeutic targets. Ongoing clinical testing of specific inhibitors of these targets, for example, Aurora kinase A inhibitors, in carefully selected patients and exploitation of expression changes of the target before and after manipulation is anticipated to increase the existing data and facilitate therapeutic decision making at this late stage of the disease when hormonal manipulations, even with the newest androgen-directed therapies are no longer feasible.

Abstract 4952: Germline variation modulates susceptibility to aggressive disease development in a mouse model of prostate tumorigenesis

Abstract Although prostate cancer is common, with over 238,000 new cases being diagnosed in the US in 2012, it typically runs an indolent course with most men succumbing to unrelated disease processes. This is reflected in the low prostate cancer-specific mortality, with approximately 29,000 men succumbing in the same period. It is of critical importance to identify modifiers that increase susceptibility to aggressive disease to allow physicians to more accurately identify men at risk of fatal disease forms. The goal of this work is to map prostate tumor progression and metastasis modifier loci mapping using the C57BL/6-Tg(TRAMP)8247Ng/J (TRAMP) mouse model of aggressive neuroendocrine prostate carcinoma. We hypothesize that germline variation influences tumor progression and metastasis in prostate cancer. The effect of germline variation in TRAMP mice was investigated by crossing it to Collaborative Cross progenitor strains and quantifying tumor progression and metastasis in transgene-positive F1 males. Those strains with the greatest phenotypic variation from the wildtype TRAMP C57BL6/J mice were chosen for modifier mapping using an F2 intercross approach. F2 mice were genotyped using a linkage panel consisting of 1,449 SNPs and modifier loci analyzed using j/qtl. The greatest number of loci achieving genomewide significance were observed in the TRAMPxNOD/ShiLtJ F2 cross (n=232). Modifier loci associated with primary tumor growth were observed on chromosomes 4, 7 and 8. Additionally, loci associated with metastasis were observed on chromosomes 1, 11, 13 and 17. We have therefore identified multiple loci associated with aggressive disease development in a mouse model of prostate cancer. Candidate gene identification is ongoing, and focuses upon characterizing cis-eQTLs in TRAMPxNOD/ShiLtJ F2 primary tumors. Additionally, we are performing high resolution modifier mapping in TRAMPxJ:DO F1 mice. Our eventual aim is to confirm the relevance of candidate genes identified in the TRAMP mouse in human association cohorts. Citation Format: Kendra A. Williams, Sujata Bupp, Shashank Patel, Jonathan Andreas, Suiyuan Zhang, Alfredo Molinolo, Silvio Gutkind, Nigel Crawford. Germline variation modulates susceptibility to aggressive disease development in a mouse model of prostate tumorigenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4952. doi:10.1158/1538-7445.AM2014-4952

A Fluorescence-Coupled Assay for Gamma Aminobutyric Acid (GABA) Reveals Metabolic Stress-Induced Modulation of GABA Content in Neuroendocrine Cancer

Pathways involved in the synthesis of the neurotransmitter gamma-aminobutyric acid (GABA) have been implicated in the pathogenesis of high grade neuroendocrine (NE) neoplasms as well as neoplasms from a non-NE lineage. Using The Cancer Genome Atlas, overexpression of the GABA synthetic enzyme, glutamate decarboxylase 1 (GAD1), was found to be associated with decreased disease free-survival in prostate adenocarcinoma and decreased overall survival in clear cell renal cell carcinomas. Furthermore, GAD1 was found to be expressed in castrate-resistant prostate cancer cell lines, but not androgen-responsive cell lines. Using a novel fluorescence-coupled enzymatic microplate assay for GABA mediated through reduction of resazurin in a prostate neuroendocrine carcinoma (PNEC) cell line, acid microenvironment-induced stress increased GABA levels while alkaline microenvironment-induced stress decreased GABA through modulation of GAD1 and glutamine synthetase (GLUL) activities. Moreover, glutamine but not glucose deprivation decreased GABA through modulation of GLUL. Consistent with evidence in prokaryotic and eukaryotic organisms that GABA synthesis mediated through GAD1 may play a crucial role in surviving stress, GABA may be an important mediator of stress survival in neoplasms. These findings identify GABA synthesis and metabolism as a potentially important pathway for regulating cancer cell stress response as well as a potential target for therapeutic strategies.