bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preliminary results of a two stage phase II study of 18F-DCFPyL PET-MR for enabling oligometastases ablative therapy in subclinical prostate cancer.
Authors: Glicksman Rachel , Metser Ur , Vines Doug , Chan Rosanna , Valliant John , Chung Peter W. M. , Gospodarowicz Mary K. , Bayley Andrew , Catton Charles N , Warde Padraig Richard , Helou Joelle Antoine , Lalani Nafisha , Green David E , Perlis Nathan , Fleshner Neil Eric , Hamilton Robert James , Zlotta Alexandre , Finelli Antonio , Jaffray David A. , Berlin Alejandro 
Published: March 2019

250 Background: Despite maximal local therapies (MLT) (radical prostatectomy followed by radiotherapy [RT]), 20-30% of men will have incurable progression of prostate cancer (PC). Most recurrences in this scenario are characterized by continuous PSA rises and failure of standard imaging (bone scan [BS] and computed tomography [CT]) to detect recurrence sites. We conducted a phase II trial for men with rising PSA after MLT using 18F-DCFPyL PET-MR followed by targeted ablation of PET positive foci. We report the results of our pre-defined analysis. Methods: Patients with rising PSA (0.43.0 ng/mL) after MLT, negative BS/CT and no prior salvage ADT were eligible. All patients underwent 18F-DCFPyL PET-MR followed by immediate PET-CT acquisition. Those with limited disease, where possible, underwent stereotactic ablative RT (SABR) or surgery. No ADT was used. The primary endpoint was biochemical response rate (complete [undetectable PSA] or partial [PSA decline ≥50% compared to baseline]). A Simon’s two stage study design was employed. Stage 1 included 12 response evaluable patients, requiring 1 or more responses in the absence of grade 3+ toxicities to proceed to stage 2 (additional 25 response evaluable patients). Results: After a median of 58 months (range 29-120) post MLT, 20 patients underwent PET-MR/CT to have 12 response evaluable patients. Median PSA at enrollment was 1.3 ng/mL (range 0.4-2.8). Three patients had negative PET-MR/CT, while 17 had positive scans, of which 12 (60%) were amenable to response evaluable ablation. The median number of detected lesions in those treated was 2 (range 1-5). Ten patients underwent SABR (27-30 Gy/3 fractions) and 2 had surgery. One patient (8%) had complete and 4 (33%) had partial PSA responses at a median of 3.3 months (range 2.8-6.0) after ablation, while the remaining 7 (59%) did not have biochemical response. No grade 3+ toxicities were observed. Conclusions: 18F-DCFPyL PET/MR has high detection rates in men with rising PSA after MLT. We observed favorable early results with SABR or surgery (41% RR). Trial completion will inform if this approach offers potential for cure in an early molecularly-defined PC oligometastatic state. Clinical trial information: NCT03160794.
Evaluation of circulating tumor DNA (ctDNA) with respect to germline alterations in metastatic castrate resistant prostate cancer patients.
Authors: Steinwald Peter , Chapman Lynne , Christensen Bryce Raymon , Ko Leta , Vu James , Schiff Joshua , Ranasinghe Lahiru , Moses Marcus Marie , Cotogno Patrick , Manogue Charlotte , Layton Jodi Lyn , Lewis Brian E. , Sartor A. Oliver , Ledet Elisa 
Published: March 2019

254 Background: Circulating tumor-derived DNA (ctDNA) is an accessible method for characterizing tumoral alterations. We report ctDNA screenings of mCRPC patients (pts) who have had germline testing. Methods: Guardant360 (Guardant Health, Inc.) assesses ctDNA using sequencing to identify genomic alterations in 73 cancer-related genes. Alterations were categorized by type which included amplifications, deletions, frameshift mutations, insertions, missense mutations, splice mutations, truncations, and other. A total of 186 PCa pts in various stages of therapy had both ctDNA and germline DNA tested. Results: Of the 186 pts tested for germline mutations, 26 (14%) were germline positive. The most common germline mutation was BRCA2 with 12 (46%) pts, followed by ATM with 3 (11%). Of the total gene alterations were detected on ctDNA analysis of germline positive pts, with the most common genes being TP53 (n = 14/73, 19%), NF1 (n = 6/73, 8%), PIK3CA (n = 6/73, 8%), and BRCA2 (n = 5/73, 7%). Of the total gene alteration were detected on ctDNA analysis of germline negative pts, with the most common genes being TP53 (n = 94/588, 16%), AR (n = 90/588, 15%), EGFR (n = 31/588, 5%), and BRAF (n = 29/588, 5%). Germline negative pts showed had more amplifications (p = 0.008) while germline positive patients had more frameshift mutations (p = 0.025). Other alterations (deletion, missense, insertion, other, splicing, and truncating) were not significantly different. Missense mutations were the most prevalent type of gene alteration in germline negative (n = 306/609, 44%) and germline positive (n = 45/77, 48%), followed by amplifications (n = 210/609, 25% germline negative and n = 15/45, 18% germline positive). The median percent ctDNA values for missense mutations in germline negative and positive patients were 0.5% and 0.3% respectively. Of the germline positive pts, BRCA2 mutation was associated with the highest number of genes with alterations (n = 39), followed by RECQL4 (n = 8), ATM (n = 5), and MSH2 (n = 5). Conclusions: Germline positive pts had a higher number of frameshift mutations compared to germline negative pts. Additionally, pts with BRCA2 had the highest number of genes altered in ctDNA.
Lessons learned from the metastatic castration-resistant prostate cancer phase I trial of EPI-506, a first-generation androgen receptor N-terminal domain inhibitor.
Authors: Le Moigne Ronan , Zhou Han-Jie , Obst Jon K. , Banuelos C. Adriana , Jian Kunzhong , Williams David , Virsik Peter , Andersen Raymond J , Sadar Marianne , Perabo Frank , Chi Kim N. 
Published: March 2019

257 Background: Aniten compounds bind to the N-terminal domain (NTD) of the androgen receptor (AR) and inhibit AR dependent transcription. EPI-506, the pro-drug of EPI-002, was the first AR NTD inhibitor tested in a Phase 1 study in men with metastatic castration-resistant prostate cancer (mCRPC). The drug was well-tolerated but required high doses. At doses >1280 mg, EPI-506 treatment resulted in PSA declines; however, these were minor and of short duration, reflecting EPI-506’s low potency and short half-life. To understand EPI-506’s metabolic vulnerabilities, patient plasma samples were analyzed to identify metabolites. Methods: PSA serum levels were assessed after a month of dosing. Patient plasma samples were analyzed and pharmacokinetic (PK) parameters calculated. Three plasma samples from patients (one 80 and two 3,600 mg doses), were pooled across timepoints and metabolites were analyzed. EPI-506 metabolism was assessed in in vitro ADME assays and metabolite activity was measured. Results: EPI-002 patient plasma profiles exhibited dose-proportional Cmax and AUC following once or twice-daily EPI-506 administration. PSA declines (range of 8-29%) were observed, especially at higher doses (≥ 1,280 mg). A total of 19 metabolites were identified. Metabolite M19, a glycerol-moiety oxidant, was the major drug-related component. Other metabolic pathways included O-glucuronidation, sulfation, carboxylic acid formation, and oxidative chlorine loss. The major metabolites were tested in an AR driven reporter assay and were shown to be inactive. Interestingly, in vitro ADME assays predicted glucuronidation and sulfation but not cytochrome dependent metabolism. Conclusions: EPI-506 was tested in a phase 1 trial and showed minor PSA declines. The drug was well-tolerated but was highly metabolized. Patient plasma samples identified 19 metabolites. Newer molecules have been synthesized to address EPI-002’s metabolic liabilities and demonstrate > 20-fold improved potency and higher stability. These next generation Anitens are currently being characterized for IND filing. Clinical trial information: NCT02606123.
ARV-110: An oral androgen receptor PROTAC degrader for prostate cancer.
Authors: Neklesa Taavi , Snyder Lawrence B , Willard Ryan R , Vitale Nicholas , Pizzano Jennifer , Gordon Deborah A , Bookbinder Mark , Macaluso Jennifer , Dong Hanqing , Ferraro Caterina , Wang Gan , Wang Jing , Crews Craig M , Houston John , Crew Andrew P , Taylor Ian 
Published: March 2019

259 Background: The Androgen Receptor (AR) remains the principal driver of castration-resistant prostate cancer during the transition from a localized to metastatic disease. Most patients initially respond to inhibitors of the AR pathway, but the response is often relatively short-lived. The majority of patients progressing on enzalutamide or abiraterone exhibit genetic alterations in the AR locus, either in the form of amplifications or point mutations in the AR gene. Given these mechanisms of resistance, our goal is to eliminate the AR protein using the PROteolysis TArgeting Chimera (PROTAC) technology. Methods: Here we report an orally bioavailable small molecule AR PROTAC degrader, ARV-110, that promotes ubiquitination and degradation of AR. This molecule has been characterized in in vitro degradation and functional assays, and DMPK, toxicology and preclinical efficacy studies. Results: ARV-110 robustly degrades AR in all cell lines tested, with an observed half-maximal degradation concentration (DC50) of ~1 nM. ARV-110 treatment leads to highly selective AR degradation, as demonstrated by proteomic studies. In VCaP cells, PROTAC-mediated AR degradation suppresses the expression of the AR-target gene PSA, inhibits AR-dependent cell proliferation, and induces apoptosis at low nanomolar concentrations. Further, ARV-110 degrades clinically relevant mutant AR proteins and retains activity in a high androgen environment. In mouse xenograft studies, greater than 90% AR degradation is observed at a 1 mg/kg PO QD dose. Significant inhibition of tumor growth and AR signaling has been achieved in LNCaP, VCaP and prostate cancer patient derived xenograft (PDX) models. Notably, ARV-110 demonstrates in vivo efficacy and reduction of AR-target gene expression in a long term, castrate, enzalutamide-resistant VCaP tumor model. Conclusions: In summary, we report preclinical data on an orally bioavailable AR PROTAC degrader, ARV-110, that demonstrates efficacy in multiple prostate cancer models. ARV-110 has completed IND-enabling studies and FIH studies are planned for 1Q2019.
PARP-1 regulation of DNA repair factor availability.
Authors: Schiewer Matthew Joseph , Mandigo Amy C , Gordon Nicolas , McNair Christopher , Lallas Costas D. , Trabulsi Edouard John , Leiby Benjamin , Knudsen Karen E. 
Published: March 2019

269 Background: PARP-1 holds major functions on chromatin, DNA damage repair and transcriptional regulation, both of which are relevant in the context of cancer. Previously, it was determined that PARP-1 ins involved in regulation of androgen receptor activity. Methods: Here, unbiased transcriptional profiling revealed the downstream transcriptional profile of PARP-1 enzymatic activity.Results: Further investigation of the PARP-1-regulated transcriptome and secondary strategies for assessing PARP-1 activity in patient tissues revealed that PARP-1 activity was unexpectedly enriched as a function of disease progression and was associated with poor outcome independent of DNA double-strand breaks, suggesting that enhanced PARP-1 activity may promote aggressive phenotypes. Mechanistic investigation revealed that active PARP-1 served to enhance E2F1 transcription factor activity, and specifically promoted E2F1-mediated induction of DNA repair factors involved in homologous recombination (HR). Conversely, PARP-1 inhibition reduced HR factor availability and thus acted to induce or enhance “BRCA-ness”. Conclusions: These observations bring new understanding of PARP-1 function in cancer and have significant ramifications on predicting PARP-1 inhibitor function in the clinical setting.
Ductal and acinar carcinomas of the prostate: A comparative comprehensive genomic profiling study.
Authors: Liu Nick , Kotula Leszek , Byler Timothy , Jacob Joseph , Alexander Brian Michael , Gay Laurie M. , Shapiro Oleg , Millis Sherri Z. , Elvin Julia Andrea , Chung Jon , Vergilio Jo-Anne , Ramkissoon Shakti , Severson Eric Allan , Killian Jonathan Keith , Ali Siraj Mahamed , Schrock Alexa Betzig , Miller Vincent A. , Necchi Andrea , de La Roza Gustavo , Ross Jeffrey S. 
Published: March 2019

271 Background: Prostatic ductal carcinoma (PDC) is an uncommon centrally located prostate with a characteristic tubulopapillary histology. PDC shares some biomarker features with the more common prostatic acinar carcinoma (PAC) including PSA expression. Methods: In this comparative comprehensive genomic profiling (CGP) study, FFPE samples from 61 clinically advanced PDC and 4,132 PAC were profiled for all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Results: The age, frequency of genomic alterations (GA) per tumor and TP53 GA of PDA and PAC were similar (Table). TMPRSS2:ERG fusions and AR GA were more often identified in PAC than PDC whereas PTEN GA were more common in PDC than PAC. Targetable GA were identified at similar frequencies in both groups focused on BRCA2 (PARP inhibitors), BRAF (BRAF/MEK inhibitors) and PIK3CA (MTOR inhibitors). ATM GA (PARP inhibitors) were more common in PAC than PDC. CDK12 GA potentially associated with immunotherapy (IO) benefit were similar in PDA and PAC as were the frequencies of MSI-High status, median TMB and high TMB levels. Conclusions: The pathologic features of PDC and PAC have been classically maintained as representative of 2 different tumor types with potentially contrasting histogenesis. In the current CGP-based study, PDA and PAC did not display significant differences in genomic signatures. CGP may reveal biomarkers that could direct patients to targeted (PARP, MTOR and BRAF/MEK inhibitors) or immunotherapies ( CDK12 GA, MSI-High or high TMB status) in both PDA and PAC. [Table: see text]
Sipuleucel-T to modify the B7-H3 immune checkpoint in men with castrate resistant prostate cancer.
Authors: Tan Wei Phin , Barton Gregory John , Chang Andrew , Nair Smita , Inman Brant Allen 
Published: March 2019

273 Background: B7-H3 is a T cell costimulatory molecule whose expression correlates with increased prostate cancer stage and mortality. We measured serum B7-H3 (sB7-H3) levels in men undergoing sipuleucel-T (sip-T) immunotherapy for castrate-resistant prostate cancer (CRPC) to determine if sip-T modified B7-H3 levels. Methods: We analyzed 41 banked serum specimens before and after sip-T treatment for CRPC. An ELISA test for sB7-H3 was used to measure serum sB7-H3 levels using a standard curve consisting of B7-H3 fusion protein, and a 4 parameter logistic model fit to back-calculate sB7-H3 levels. Each sample was measured in duplicate and the average of these two measurements used. Generalized additive and segmented regression models were used to model the relationship between sB7-H3 level and time to (and from) sip-T treatment. Results: We found that the sB7-H3 assay had a high degree of reproducibility with a Pearson correlation coefficient of 0.9 between the two measurement occasions. Importantly, sB7-H3 had no correlation with prostate specific antigen (PSA) level, indicating that sB7-H3 was providing incremental biological information not contained in the PSA level. Median PSA before sip-T treatment was 6.2 ng/mL [IQR 3.9-14.7] and median PSA post sip-T treatment was 23.4 ng/mL [IQR 9.8-107.4). Median serum sB7-H3 before sip-T treatment was 24.2 ng/dL [IQR 20.3-27.1] and median serum B7-H3 after sip-T treatment was 23.1 ng/mL [IQR 21.8-26.6]. Using a generalized additive model to measure the level of sB7-H3 from time to sip-T treatment, we found a statistically significant relationship between sB7-H3 levels and sip-T treatment, p=0.038. Using segmented linear regression, we found that sB7-H3 levels increased gradually as CRPC worsened prior to sip-T immunotherapy then, at a mean of 24 days after sip-T initiation, sB7-H3 levels started to fall. Conclusions: We found that sB7-H3 levels increased in men with CRPC and that sip-T treatment reversed this trend. Therefore, sip-T may have a positive immunological effect in CRPC irrespective of PSA change. These results suggest that one potential mechanism of action of sipuleucel-T is the reduction of sB7-H3 production by prostate cancer cells.
Treatment facility volume and survival in patients with advanced prostate cancer.
Authors: Joshi Shreyas , Handorf Elizabeth A. , Srivastava Abhishek , Masic Selma , Cahn David B. , Kadow Brian T. , Zibelman Matthew R. , Ghatalia Pooja , Uzzo Robert , Kutikov Alexander , Smaldone Marc C. , Greenberg Richard E. , Viterbo Rosalia , Chen David , Horwitz Eric M. , Hallman Mark A , Sobczak Mark Leslie , Geynisman Daniel M. 
Published: March 2019

274 Background: Despite improvements in the medical management of advanced prostate cancer (aPC), it continues to be the 2nd leading cause of cancer death in American men. The contemporary management of men with aPC is increasingly complex and can vary based on access to up-to-date treatments, which is often found at busier treatment centers. We thus evaluated the relationship between facility volume and survival outcomes in aPC. Methods: The National Cancer Database (NCDB) was queried from 2004-2014 for aPC, defined as T4, N+, or M+ disease. Six pre-defined patient cohorts were evaluated. Cohort A = patients with aPC (N = 64,815); cohort B = M0 patients (N = 27,155); cohort C = M0 patients undergoing active treatment (N = 21,755); cohort = all M1 patients (N = 37,660); cohort E = M0 patients undergoing active treatment (N = 30,643); and cohort F = M1 patients who underwent active treatment and who had known metastatic sites (N = 12,452). Treatment facilities were divided into quartiles based on median treatment volume: <1.8 patients/year, 1.8-3.3 patients/year, 3.4-5.6 patients/year, and >5.6 patients/year. Regression models were adjusted along a set of covariates available in the NCDB. The primary outcome was overall survival (OS). Results: OS improved with each increase in volume quartile. The top quartile (>5.6 pts/yr) demonstrated significantly greater OS compared to the bottom quartile (<1.8 pts/yr) [HR 0.82, 95% CI 0.77-0.88, p<0.001]. The improved OS in the top volume quartile remained consistent when analyzed across the six pre-defined patient cohorts. Sensitivity analyses were conducted on Cohort A, adjusting for Gleason score and facility type, which did not change the effect of volume on survival. Conclusions: In this retrospective analysis of nearly 65K men who presented with aPC, we demonstrate that management at a high-volume facility (top quartile, >5.6 pts/yr) confers a significant OS advantage when compared to management at a facility in the lowest quartile (<1.8 pts/yr). This OS advantage persisted with similar magnitudes of effect after narrowing the cohorts by disease and treatment characteristics. These findings may have implications on the optimal management of men with advanced PC.
EphB4-EphrinB2 receptor-ligand pair as a novel target in prostate cancer (PC).
Authors: Sadeghi Sarmad , Li Grace , Siddiqi Imran , Sali Akash , Liang Gangning , Gill Inderbir , Pinski Jacek K. , Quinn David I. , Gill Parkash S. 
Published: March 2019

275 Background: Studies have shown that EphB4 (B4), a receptor kinase, is upregulated in PC. The ligand for B4, EphrinB2 (B2) has not been studied in PC thus far. In our PTEN null mouse PC model, B4 and B2 are both upregulated in PC, but not in normal prostate. Furthermore, Soluble B4-albumin (sB4) decoy receptor blocks B4-B2 bidirectional signaling, inhibits PI3K/AKT signaling and is currently in phase II clinical trials in multiple tumor types. We thus studied B2 expression in human PCs and normal tissues. Methods: B2 levels were studied in 180 clinically localized human PCs and normal prostates. Tissue staining was performed with specific monoclonal antibody, using LEICA platform. B2 expressions in tumor vessel, tumor cell and stromal cells were scored by a pathologist. In addition, a CRPC patient was treated with sB4 under an IND approved by the FDA and IRB. The patient’s prostate cancer was diagnosed in 2014, Gleason’s score 4+3, treated with radical prostatectomy (pT3bN0) with subsequent metastases bone/bone marrow and progression on sipuleucel T, enzalutamide, abiraterone, docetaxel, cabazitaxel, and carboplatin. Tumor and blood samples were obtained and analyzed after informed consent. Results: B2 was not expressed in any of the 40 normal prostate gland or normal vessels in bladder, pancreas, small intestine, liver, adrenal glands, skeletal muscle, and bone marrow tissues. B2 was expressed 50% of the human prostate cancer tissues, being positive in tumor cells and negative in vascular and stromal cells. Expression was correlated with Gleason score (p = 0.003). B2 was also upregulated in PC cell lines that are characterized for genomic, and epigenomic alterations to study mechanisms of B2 induction. Metastatic tumor tissue from the CRPC patient showed high elevation of B2. After a 4-week course of sB4, PSA level declined by 45% (from 2284 to 1257). PI3K and AR levels in tumor tissue declined compared to baseline. PI3K/AKT/pS6 and AR levels in tumor tissue ex-vivo studies were also reduced with sB4 exposure. Conclusions: B2 is expressed in half of PCs and our experiments suggest a significant role for the EphB4-EphrinB2 pair through regulation of PI3K and AR signaling. Given the central role of AR in PC, sB4 may offer a novel approach to targeting AR.
3βHSD1 immunohistochemistry and HSD3B1 genotype in prostate cancer.
Authors: Zhang JJ Haijing , Nicolas Marlo , Hardaway Aimalie , Bohn Kelsey , Hettel Daniel , Klein Eric A. , Sharifi Nima 
Published: March 2019

277 Background: 3β-hydroxysteroid dehydrogenase (3βHSD1), encoded by HSD3B1, catalyzes intratumoral androgen synthesis from adrenal precursors. The HSD3B1(1245A>C) germline variant encodes a more stable enzyme that promotes increased DHT synthesis and more rapid clinical progression in men treated with androgen deprivation therapy (ADT). 3βHSD1 localization and expression in prostate tissue has not been rigorously characterized. We hypothesized that HSD3B1 homozygous variant genotype is associated with elevated 3βHSD1 immunoreactivity compared with wild-type (WT) genotype. Methods: In a pilot study, HSD3B1 genotypes were obtained from prostatectomy tissues of 30 patients with prostate cancer (10 WT, 10 heterozygous, and 10 homozygous variant). Following prostatectomy, tumor tissue with adjacent benign prostate was formalin-fixed and paraffin-embedded. Immunostaining for 3βHSD1 using a validated mouse monoclonal antibody was performed. Human placenta was used as a positive control. Immunostaining patterns and histology was qualitatively assessed by a GU pathologist. Immunoreactivity was quantitatively assessed using ImagePro7. Results: Qualitative IHC scoring localizes 3βHSD1 to epithelial cells in prostatic glands and urothelium, with faint muscle and stromal staining. 3βHSD1 was immunoreactive in 100% of prostates in both benign and malignant regions. When stratified by HSD3B1 genotype, the mean density/intensity was significantly greater for HSD3B1 homozygous variant prostate (670.10u) compared to heterozygous (174.69u) and WT (176.19u) (p=0.044). (Density/Intensity) per square micron demonstrated higher mean values for homozygous variant (35.79)> heterozygous (28.67) >WT (22.56) (p=0.52). Conclusions: These pilot data demonstrate differential tissue expression of 3βHSD1 according to HSD3B1 genotype: importantly, homozygous variant HSD3B1 (1245A>C) specimen showed the most robust 3βHSD1 expression compared to heterozygous and WT prostates. These results explore the potential for 3βHSD1 as a prostate biomarker to predict aggressive disease.