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At least 271 records · Page 15
All sourcesNASA NTRSDOE OSTI
DOE OSTI2016

Image Guided Hypofractionated Postprostatectomy Intensity Modulated Radiation Therapy for Prostate Cancer

Purpose: Hypofractionated radiation therapy (RT) has promising long-term biochemical relapse-free survival (bRFS) with comparable toxicity for definitive treatment of prostate cancer. However, data reporting outcomes after adjuvant and salvage postprostatectomy hypofractionated RT are sparse. Therefore, we report the toxicity and clinical outcomes after postprostatectomy hypofractionated RT. Methods and Materials: From a prospectively maintained database, men receiving image guided hypofractionated intensity modulated RT (HIMRT) with 2.5-Gy fractions constituted our study population. Androgen deprivation therapy was used at the discretion of the radiation oncologist. Acute toxicities were graded according to the Common Terminology Criteria for Adverse Events version 4.0. Late toxicities were scored using the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer scale. Biochemical recurrence was defined as an increase of 0.1 in prostate-specific antigen (PSA) from posttreatment nadir or an increase in PSA despite treatment. The Kaplan-Meier method was used for the time-to-event outcomes. Results: Between April 2008 and April 2012, 56 men received postoperative HIMRT. The median follow-up time was 48 months (range, 21-67 months). Thirty percent had pre-RT PSA <0.1; the median pre-RT detectable PSA was 0.32 ng/mL. The median RT dose was 65 Gy (range, 57.5-65 Gy). Ten patients received neoadjuvant and concurrent hormone therapy. Posttreatment acute urinary toxicity was limited. There was no acute grade 3 toxicity. Late genitourinary (GU) toxicity of any grade was noted in 52% of patients, 40% of whom had pre-RT urinary incontinence. The 4-year actuarial rate of late grade 3 GU toxicity (exclusively gross hematuria) was 28% (95% confidence interval [CI], 16%-41%). Most grade 3 GU toxicity resolved; only 7% had persistent grade ≥3 toxicity at the last follow-up visit. Fourteen patients experienced biochemical recurrence at a median of 20 months after radiation. The 4-year bPFS rate was 75% (95% CI, 63%-87%). Conclusions: The biochemical control in this series appears promising, although relatively short follow-up may lead to overestimation. Late grade 3 GU toxicity was higher than anticipated with hypofractionated radiation of 65 Gy to the prostate bed, although most resolved.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2016

Association Between Treatment at a High-Volume Facility and Improved Survival for Radiation-Treated Men With High-Risk Prostate Cancer

Purpose: Although the association between higher hospital volume and improved outcomes has been well-documented in surgery, there is little data about whether this effect exists for radiation-treated patients. We investigated whether treatment at a radiation facility that treats a high volume of prostate cancer patients is associated with improved survival for men with high-risk prostate cancer. Methods and Materials: We used the National Cancer Database (NCDB) to identity patients diagnosed with prostate cancer from 2004 to 2006. The radiation case volume (RCV) of each hospital was based on its number of radiation-treated prostate cancer patients. We used propensity-score based analysis to compare the overall survival (OS) of high-risk prostate cancer patients in high versus low RCV hospitals. Primary endpoint is overall survival. Covariates adjusted for were tumor characteristics, sociodemographic factors, radiation type, and use of androgen deprivation therapy (ADT). Results: A total of 19,565 radiation-treated high-risk patients were identified. Median follow-up was 81.0 months (range: 1-108 months). When RCV was coded as a continuous variable, each increment of 100 radiation-managed patients was associated with improved OS (adjusted hazard ratio [AHR]: 0.97; 95% confidence interval [CI]: 0.95-0.98; P<.0001) after adjusting for known confounders. For illustrative purposes, when RCV was dichotomized at the 80th percentile (43 patients/year), high RCV was associated with improved OS (7-year overall survival 76% vs 74%, log-rank test P=.0005; AHR: 0.91, 95% CI: 0.86-0.96, P=.0005). This association remained significant when RCV was dichotomized at 75th (37 patients/year), 90th (60 patients/year), and 95th (84 patients/year) percentiles but not the 50th (19 patients/year). Conclusions: Our results suggest that treatment at centers with higher prostate cancer radiation case volume is associated with improved OS for radiation-treated men with high-risk prostate cancer.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2016

Proton Therapy as Salvage Treatment for Local Relapse of Prostate Cancer Following Cryosurgery or High-Intensity Focused Ultrasound

Purpose: Local recurrence of prostate cancer after cryosurgery (CS) and high-intensity focused ultrasound (HIFU) is an emerging problem for which optimal management is unknown. Proton therapy (PT) may offer advantages over other local therapeutic options. This article reviews a single institution's experience using PT for salvage of local recurrent disease after HIFU or CS. Methods and Materials: We reviewed the medical records of 21 consecutive patients treated with salvage PT following a local recurrence of prostate cancer after CS (n=12) or HIFU (n=9) between January 2007 and July 2014. Patients were treated to a median dose of 74 Gy(relative biological effectiveness [RBE]; range: 74-82 Gy[RBE]) and 8 patients received androgen deprivation therapy with radiation therapy. Patients were evaluated for quality of life (QOL) by using the Expanded Prostate Index Composite questionnaire and toxicity by using Common Terminology Criteria for Adverse Events, version 3.0, weekly during treatment, every 6 months for 2 years after treatment, and then annually. Results: Median follow-up was 37 months (range: 6-95 months). The 3-year biochemical progression-free survival (bPFS) rate was 77%. The 3-year grade 3 toxicity rate was 17%; however, 2 of these patients had pre-existing grade 3 GU toxicities from their HIFU/CRYO prior to PT. At 1 year, bowel summary, urinary incontinence, and urinary obstructive QOL scores declined, but only the bowel QOL score at 12 months met the minimally important difference threshold. Conclusions: PT achieved a high rate of bPFS with acceptable toxicity and minimal changes in QOL scores compared with baseline pre-PT functions. Although most patients have done fairly well, the study size is small, follow-up is short, and early results suggest that outcomes with PT for salvage after HIFU or CS failure are inferior to outcomes with PT given in the de novo setting with respect to disease control, toxicity, and QOL.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2016

Five-Year Biochemical Results, Toxicity, and Patient-Reported Quality of Life After Delivery of Dose-Escalated Image Guided Proton Therapy for Prostate Cancer

Purpose: To report clinical outcomes in patients treated with image guided proton therapy (PT) for localized prostate cancer. Methods and Materials: The medical records of 1327 men were reviewed. Each man was enrolled on an outcomes tracking study. Dual enrollment on a prospective clinical trial was allowed. Each patient was treated for localized prostate cancer with PT at our institution between 2006 and 2010. Ninety-eight percent of patients received 78 Gy (radiobiological equivalent [RBE]) or higher; 18% received androgen deprivation therapy (ADT). The 5-year freedom from biochemical progression (FFBP), distant metastasis-free survival, and cause-specific survival rates are reported for each risk group. Data on patient-reported quality of life and high-grade toxicities were prospectively collected and reported. A multivariate analysis was performed to identify clinical predictors of biochemical failure and urologic toxicity. Results: The median follow-up time was 5.5 years. The 5-year FFBP rates were 99%, 94%, and 74% in low-risk, intermediate-risk, and high-risk patients, respectively. The actuarial 5-year rates of late grade 3+ Common Terminology Criteria for Adverse Events, version 4.0, gastrointestinal (GI) and genitourinary (GU) toxicity were 0.6% and 2.9%, respectively. Multivariate analysis showed a significant correlation between grade 3+ GU toxicity and pretreatment prostate reductive procedures (P<.0001), prostate volume (P=.0085), pretreatment α-blockers (P=.0067), diabetes (P=.0195), and dose–volume histogram parameters (P=.0208). The median International Prostate Symptom Scores pretreatment scores and scores at 5 years after treatment were 7 and 7, respectively. The mean Expanded Prostate Cancer Index Composite (EPIC) scores significantly declined for sexual summary for patients not receiving ADT (from 67 to 53) between baseline and 5 years. Conclusions: Image guided PT provided excellent biochemical control rates for patients with localized prostate cancer. The actuarial rates of high-grade toxicity were low after PT. From pretreatment to 5 years of follow-up, a significant decline was found only in mean EPIC sexual summary scores. Prospective clinical studies are needed to determine the comparative effectiveness of PT and other radiation treatment strategies.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2016

Survival After Conservative Management Versus External Beam Radiation Therapy in Elderly Patients With Localized Prostate Cancer

Purpose: To compare survival in elderly men with clinically localized prostate cancer (PCa) according to treatment type, defined as radiation therapy (RT) with or without androgen deprivation therapy (ADT) versus conservative management (observation). Methods and Materials: In the Surveillance, Epidemiology, and End Results (SEER)–Medicare linked database, we identified 23,790 patients aged 80 years or more with clinically localized PCa treated with either RT or observation between 1991 and 2009. Competing risks analyses focused on cancer-specific mortality and other-cause mortality, after accounting for confounders. All analyses were repeated after stratification according to grade (well-differentiated vs moderately differentiated vs poorly differentiated disease), race, and United States region, in patients with no comorbidities and in patients with at least 1 comorbidity. Analyses were repeated within most contemporary patients, namely those treated between 2001 and 2009. Results: Radiation therapy was associated with more favorable cancer-specific mortality rates than observation in patients with moderately differentiated disease (hazard ratio [HR] 0.79; 95% confidence interval [CI] 0.66-0.94; P=.009) and in patients with poorly differentiated disease (HR 0.58; 95% CI 0.49-0.69; P<.001). Conversely, the benefit of RT was not observed in well-differentiated disease. The benefit of RT was confirmed in black men (HR 0.54; 95% CI 0.35-0.83; P=.004), across all United States regions (all P≤.004), in the subgroups of the healthiest patients (HR 0.67; 95% CI 0.57-0.78; P<.001), in patients with at least 1 comorbidity (HR 0.69; 95% CI 0.56-0.83; P<.001), and in most contemporary patients (HR 0.55; 95% CI 0.46-0.66; P<.001). Conclusions: Radiation therapy seems to be associated with a reduction in the risk of death from PCa relative to observation in elderly patients with clinically localized PCa, except for those with well-differentiated disease.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2016

Macroscopic Hematuria After Conventional or Hypofractionated Radiation Therapy: Results From a Prospective Phase 3 Study

Purpose: To assess the macroscopic hematuria rates within a single-institution randomized phase 3 trial comparing dose-escalated, conventionally fractionated radiation therapy (CFRT) and moderately hypofractionated radiation therapy (MHRT) for localized prostate cancer. Methods and Materials: Patients with intermediate- to high-risk localized prostate cancer were treated with conformal RT and short-course androgen deprivation. Both the prostate and the entire seminal vesicles were treated to 80 Gy in 40 fractions over 8 weeks (CFRT) or 62 Gy in 20 fractions over 5 weeks (MHRT). The endpoint of the present study was the development of any episode or grade of macroscopic hematuria. The median follow-up period was 93 months (range 6-143). Results: Macroscopic hematuria was reported by 25 of 168 patients (14.9%). The actuarial estimate of hematuria at 8 years was 17.0% (95% confidence interval [CI] 10.7%-23.3%). The number of patients with hematuria was 6 and 19 in the CFRT and MHRT arms, respectively, for an actuarial 8-year estimate of 9.7% and 24.3%, respectively (hazard ratio 3.468, 95% CI 1.385-8.684; P=.008). Overall, 8 of 25 patients were found to have biopsy-proven urothelial carcinoma (3 in the CFRT arm and 5 in the MHRT arm; P=.27). Thus, the 8-year actuarial incidence of macroscopic hematuria (after censoring urothelial cancer–related episodes) was 4.1% and 18.2% after CFRT and MHRT, respectively (hazard ratio 4.961, 95% CI 1.426-17.263; P=.012). The results were confirmed by multivariate analysis after accounting for several patient-, treatment-, and tumor-related covariates. Conclusions: MHRT was associated with a statistically significant increased risk of macroscopic hematuria compared with CFRT.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2016

Reirradiation of Prostate Cancer Local Failures After Previous Curative Radiation Therapy: Long-Term Outcome and Tolerance

Purpose: To evaluate the safety, feasibility, side-effect profile, and proof of concept of external beam radiation therapy (EBRT) with or without a brachytherapy (BT) boost for salvage of exclusive local failure after primary EBRT for prostate cancer. Methods and Materials: Fourteen patients with presumed exclusive local recurrence after primary EBRT with or without BT were considered eligible for reirradiation. The median normalized total dose in 2-Gy fractions (NTD{sub 2Gy}, α/β ratio = 1.5 Gy) was 74 Gy (range, 66-98.4 Gy) at first irradiation. Median time between the first irradiation and the reirradiation was 6.1 years (range, 4.7-10.2 years). Results: Between 2003 and 2008 salvage treatment was delivered with a median NTD{sub 2Gy} of 85.1 Gy (range, 70-93.4) to the prostate with EBRT with (n=10) or without (n=4) BT. Androgen deprivation was given to 12 patients (median time of 12 months). No grade ≥3 toxicity was observed during and within 6 weeks after RT. After a median follow-up of 94 months (range, 48-172 months) after salvage RT, 5-year grade ≥3 genitourinary and gastrointestinal toxicity-free survival figures were 77.9% ± 11.3% and 57.1% ± 13.2%, respectively. Four patients presented with combined grade 4 genitourinary/gastrointestinal toxicity. The 5-year biochemical relapse-free, local relapse-free, distant metastasis-free, and cancer-specific survival rates were 35.7% ± 12.8%, 50.0% ± 13.4%, 85.7% ± 9.4%, and 100%, respectively. Conclusion: Salvage whole-gland reirradiation for patients with a suspicion of exclusive local recurrence after initial RT may be associated with a high rate of severe radiation-induced side effects and poor long-term biochemical and local control.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2016

Salvage Radiation Therapy Dose Response for Biochemical Failure of Prostate Cancer After Prostatectomy—A Multi-Institutional Observational Study

Purpose: To determine whether a dose-response relationship exists for salvage radiation therapy (RT) of biochemical failure after prostatectomy for prostate cancer. Methods and Materials: Individual data from 1108 patients who underwent salvage RT at 10 academic centers were pooled. The cohort was enriched for selection criteria more likely associated with tumor recurrence in the prostate bed (margin positive and pre-RT prostate-specific antigen [PSA] level of ≤2.0 ng/mL) and without the confounding of planned androgen suppression. The cumulative incidence of biochemical failure and distant metastasis over time was computed, and competing risks hazard regression models were used to investigate the association between potential predictors and these outcomes. The association of radiation dose with outcomes was the primary focus. Results: With a 65.2-month follow-up duration, the 5- and 10-year estimates of freedom from post-RT biochemical failure (PSA level >0.2 ng/mL and rising) was 63.5% and 49.8%, respectively, and the cumulative incidence of distant metastasis was 12.4% by 10 years. A Gleason score of ≥7, higher pre-RT PSA level, extraprostatic tumor extension, and seminal vesicle invasion were associated with worse biochemical failure and distant metastasis outcomes. A salvage radiation dose of ≥66.0 Gy was associated with a reduced cumulative incidence of biochemical failure, but not of distant metastasis. Conclusions: The use of salvage radiation doses of ≥66.0 Gy are supported by evidence presented in the present multicenter pooled analysis of individual patient data. The observational reporting method, limited sample size, few distant metastasis events, modest follow-up duration, and elective use of salvage therapy might have diminished the opportunity to identify an association between the radiation dose and this endpoint.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2017

Sentinel Lymph Node Dissection to Select Clinically Node-negative Prostate Cancer Patients for Pelvic Radiation Therapy: Effect on Biochemical Recurrence and Systemic Progression

Purpose: To assess the efficacy of robotic-assisted laparoscopic sentinel lymph node (SLN) dissection (SLND) to select those patients with prostate cancer (PCa) who would benefit from additional pelvic external beam radiation therapy and long-term androgen deprivation therapy (ADT). Methods and Materials: Radioisotope-guided SLND was performed in 224 clinically node-negative patients scheduled to undergo external beam radiation therapy. Patients with histologically positive SLNs (pN1) were also offered radiation therapy to the pelvic lymph nodes, combined with 3 years of ADT. Biochemical recurrence (BCR), overall survival, and metastasis-free (including pelvic and nonregional lymph nodes) survival (MFS) rates were retrospectively calculated. The Briganti and Kattan nomogram predictions were compared with the observed pN status and BCR. Results: The median prostate-specific antigen (PSA) value was 15.4 ng/mL (interquartile range [IQR] 8-29). A total number of 834 SLNs (median 3 per patient; IQR 2-5) were removed. Nodal metastases were diagnosed in 42% of the patients, with 150 SLNs affected (median 1; IQR 1-2). The 5-year BCR-free and MFS rates for pN0 patients were 67.9% and 87.8%, respectively. The corresponding values for pN1 patients were 43% and 66.6%. The PSA level and number of removed SLNs were independent predictors of BCR and MFS, and pN status was an additional independent predictor of BCR. The 5-year overall survival rate was 97.6% and correlated only with pN status. The predictive accuracy of the Briganti nomogram was 0.665. Patients in the higher quartiles of Kattan nomogram prediction of BCR had better than expected outcomes. The complication rate from SLND was 8.9%. Conclusions: For radioisotope-guided SLND, the high staging accuracy is accompanied by low morbidity. The better than expected outcomes observed in the lower quartiles of BCR prediction suggest a role for SLN biopsy as a potential selection tool for the addition of pelvic radiation therapy and ADT intensification in pN1 patients.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2017

Effect of Prostate Magnetic Resonance Imaging/Ultrasound Fusion-guided Biopsy on Radiation Treatment Recommendations

Purpose: Targeted magnetic resonance imaging (MRI)/ultrasound fusion prostate biopsy (MRI-Bx) has recently been compared with the standard of care extended sextant ultrasound-guided prostate biopsy (SOC-Bx), with the former associated with an increased rate of detection of clinically significant prostate cancer. The present study sought to determine the influence of MRI-Bx on radiation therapy and androgen deprivation therapy (ADT) recommendations. Methods and Materials: All patients who had received radiation treatment and had undergone SOC-Bx and MRI-Bx at our institution were included. Using the clinical T stage, pretreatment prostate-specific antigen, and Gleason score, patients were categorized into National Comprehensive Cancer Network risk groups and radiation treatment or ADT recommendations assigned. Intensification of the recommended treatment after multiparametric MRI, SOC-Bx, and MRI-Bx was evaluated. Results: From January 2008 to January 2016, 73 patients received radiation therapy at our institution after undergoing a simultaneous SOC-Bx and MRI-Bx (n=47 with previous SOC-Bx). Repeat SOC-Bx and MRI-Bx resulted in frequent upgrading compared with previous SOC-Bx (Gleason score 7, 6.7% vs 44.6%; P<.001; Gleason score 8-10, 2.1% vs 38%; P<.001). MRI-Bx increased the proportion of patients classified as very high risk from 24.7% to 41.1% (P=.027). Compared with SOC-Bx alone, including the MRI-Bx findings resulted in a greater percentage of pathologically positive cores (mean 37% vs 44%). Incorporation of multiparametric MRI and MRI-Bx results increased the recommended use and duration of ADT (duration increased in 28 of 73 patients and ADT was added for 8 of 73 patients). Conclusions: In patients referred for radiation treatment, MRI-Bx resulted in an increase in the percentage of positive cores, Gleason score, and risk grouping. The benefit of treatment intensification in accordance with the MRI-Bx findings is unknown.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2017

Pan-Cancer Analysis of Genomic Sequencing Among the Elderly

Purpose: We hypothesized that elderly patients might have age-specific genetic abnormalities yet be underrepresented in currently available sequencing repositories, which could limit the effect of sequencing efforts for this population. Methods and Materials: Leveraging The Cancer Genome Atlas (TCGA) data portal, 9 tumor types were analyzed. The frequency distribution of cancer by age was determined and compared with Surveillance, Epidemiology, and End Results data. Using the estimated median somatic mutational frequency of each tumor type, the samples needed beyond TCGA to detect a 10% mutational frequency were calculated. Microarray data from a separate prospective cohort were obtained from primary prostatectomy samples to determine whether elderly-specific transcriptomic alterations could be identified. Results: Of the 5236 TCGA samples, 73% were from patients aged <70 years. Comparing the distribution of TCGA samples by age to the Surveillance, Epidemiology, and End Results data, patients <70 years were well represented across most tumor types, but patients aged 80 to 99 years were underrepresented in all cancers (median TCGA underrepresentation of 167%). All cancers (except for colorectal) contained enough samples to detect a 10% mutational frequency in patients aged <60 years. In contrast, no cancer type had enough samples for which a 10% mutational frequency could be detected in patients aged ≥80 years. To further interrogate whether elderly patients with cancer were likely to harbor age-specific molecular abnormalities, we accessed transcriptomic data from a separate, larger database of >2000 prostate cancer samples. That analysis revealed significant differences in the expression of 10 genes in patients aged ≥70 years compared with those <70 years, of which 7 are involved in androgen signaling and/or DNA repair. Conclusions: Elderly patients have been underrepresented in genomic sequencing studies. Our data suggest the presence of elderly-specific molecular alterations. Further dedicated efforts to understand the biology of cancer among the elderly will be important moving forward.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2017

Exosomes and Exosomal MicroRNAs in Prostate Cancer Radiation Therapy

Despite current risk stratification systems using traditional clinicopathologic factors, many localized and locally advanced prostate cancers fail radical treatment (ie, radical prostatectomy, radiation therapy with or without androgen deprivation therapy). Therefore, a pressing need exists for enhanced methods of disease stratification through novel prognostic and predictive tools that can reliably be applied in clinical practice. Exosomes are 50- to 150-nm small vesicles released by cancer cells that reflect the genetic and nongenetic materials of parent cancer cells. Cancer cells can contain distinct sets of microRNA profiles, the expression of which can change owing to stress such as radiation therapy. These alterations or distinctions in contents allow exosomes to be used as prognostic and/or predictive biomarkers and to monitor the treatment response. Additionally, microRNAs have been shown to influence multiple processes in prostate tumorigenesis, including cell proliferation, induction of apoptosis, migration, oncogene inhibition, and radioresistance. Thus, comparative exosomal microRNA profiling at different levels could help portray tumor aggressiveness and response to radiation therapy. Although technical challenges persist in exosome isolation and characterization, recent improvements in microRNA profiling have evolved toward in-depth analyses of the exosomal cargo and its functions. We have reviewed the role of exosomes and exosomal microRNAs in biologic processes of prostate cancer progression and radiation therapy response, with a particular focus on the development of clinical assays for treatment personalization.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2017

Long-Term Quality of Life in Prostate Cancer Patients Treated With Cesium-131

Purpose: To evaluate long-term patient-reported quality of life (QOL) scores in men with prostate cancer treated at our institution with {sup 131}Cs prostate brachytherapy. Methods and Materials: Patients treated more than 4 years ago with {sup 131}Cs (n=290) were asked to fill out an Expanded Prostate Cancer Index Composite (EPIC) QOL questionnaire and American Urological Association Symptom Score (AUASS) survey, before treatment and at each follow-up appointment. We compared patients' EPIC and AUA scores at baseline with scores at a last follow-up of at least 4 years after treatment using the Wilcoxon signed-rank test. Results: At a median last follow-up of 5.5 years after treatment with {sup 131}Cs prostate brachytherapy there were no clinically significant changes in the EPIC or AUA scores from baseline. There was statistical worsening in the EPIC urinary incontinence subscore. Subset analyses revealed improved QOL outcomes in patients who received external beam radiation therapy or α-blocker therapy, whereas androgen deprivation therapy was not associated with differences in QOL change. Conclusions: Our results demonstrate minimal long-term changes in urinary or bowel patient-reported QOL with {sup 131}Cs prostate brachytherapy. These findings suggest that patients treated with this isotope are able to recover and then maintain their baseline QOL in the long term.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2023

Human cytochrome P450 17A1 structures with metabolites of prostate cancer drug abiraterone reveal substrate-binding plasticity and a second binding site

Abiraterone acetate is a first-line therapy for castration-resistant prostate cancer. This prodrug is deacetylated in vivo to abiraterone, which is a potent and specific inhibitor of cytochrome P450 17A1 (CYP17A1). CYP17A1 performs two sequential steps that are required for the biosynthesis of androgens that drive prostate cancer proliferation, analogous to estrogens in breast cancer. Abiraterone can be further metabolized in vivo on the steroid A ring to multiple metabolites that also inhibit CYP17A1. Despite its design as an active-site-directed substrate analog, abiraterone and its metabolites demonstrate mixed competitive/noncompetitive inhibition. To understand their binding, we solved the X-ray structures of CYP17A1 with three primary abiraterone metabolites. Despite different conformations of the steroid A ring and substituents, all three bound in the CYP17A1 active site with the steroid core packed against the I helix and the A ring C3 keto or hydroxyl oxygen forming a hydrogen bond with N202 similar to abiraterone itself. The structure of CYP17A1 with 3-keto, 5α-abiraterone was solved to 2.0 Å, the highest resolution to date for a CYP17A1 complex. This structure had additional electron density near the F/G loop, which is likely a second molecule of the inhibitor and which may explain the noncompetitive inhibition. Mutation of the adjacent Asn52 to Tyr positions its side chain in this space, maintains enzyme activity, and prevents binding of the peripheral ligand. Collectively, our findings provide further insight into abiraterone metabolite binding and CYP17A1 function.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2013

Developmental programming: Impact of prenatal exposure to bisphenol-A and methoxychlor on steroid feedbacks in sheep

Bisphenol-A (BPA), a polymer used in plastics manufacturing, and methoxychlor (MXC), a pesticide, are endocrine disrupting compounds with estrogenic and anti-androgenic properties. Prenatal BPA or MXC treatment induces reproductive defects in sheep with BPA causing prepubertal luteinizing hormone (LH) hypersecretion and dampening of periovulatory LH surges and MXC lengthening follicular phase and delaying the LH surge. In this study, we addressed the underlying neuroendocrine defects by testing the following hypotheses: 1) prenatal BPA, but not MXC reduces sensitivity to estradiol and progesterone negative feedback, 2) prenatal BPA, but not MXC increases pituitary responsiveness to gonadotropin releasing hormone (GnRH), and 3) prenatal BPA dampens LH surge response to estradiol positive feedback challenge while prenatal MXC delays the timing of the LH surge. Pregnant sheep were treated with either 1) 5 mg/kg/day BPA (produces approximately twice the level found in human circulation, n = 8), 2) 5 mg/kg/day MXC (the lowest observed effect level stated in the EPA National Toxicology Program's Report; n = 6), or 3) vehicle (cotton seed oil: C: n = 6) from days 30 to 90 of gestation. Female offspring of these ewes were ovariectomized at 21 months of age and tested for progesterone negative, estradiol negative, estradiol positive feedback sensitivities and pituitary responsiveness to GnRH. Results revealed that sensitivity to all 3 feedbacks as well as pituitary responsiveness to GnRH were not altered by either of the prenatal treatments. These findings suggest that the postpubertal reproductive defects seen in these animals may have stemmed from ovarian defects and the steroidal signals emanating from them. - Highlights: ► Prenatal BPA/MXC does not affect reproductive neuroendocrine steroid feedbacks. ► Prenatal BPA or MXC treatment failed to alter pituitary sensitivity to GnRH. ► LH excess in BPA-treated sheep may be due to reduced ovarian feedback signals.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

An in vitro investigation of endocrine disrupting effects of the mycotoxin alternariol

Alternariol (AOH) is a mycotoxin commonly produced by Alternaria alternata on a wide range of foods. Few studies to date have been performed to evaluate the effects of AOH on endocrine activity. The present study makes use of in vitro mammalian cellular based assays and gene expression to investigate the ability of AOH to act as an endocrine disruptor by various modes of action. Reporter gene assays (RGAs), incorporating natural steroid hormone receptors for oestrogens, androgens, progestagens and glucocorticoids were used to identify endocrine disruption at the level of nuclear receptor transcriptional activity, and the H295R steroidogenesis assay was used to assess endocrine disruption at the level of gene expression and steroid hormone production. AOH exhibited a weak oestrogenic response when tested in the oestrogen responsive RGA and binding of progesterone to the progestagen receptor was shown to be synergistically increased in the presence of AOH. H295R cells when exposed to 0.1–1000 ng/ml AOH, did not cause a significant change in testosterone and cortisol hormones but exposure to 1000 ng/ml (3.87 μM) AOH resulted in a significant increase in estradiol and progesterone production. In the gene expression study following exposure to 1000 ng/ml (3.87 μM) AOH, only one gene NR0B1 was down-regulated, whereas expression of mRNA for CYP1A1, MC2R, HSD3B2, CYP17, CYP21, CYP11B2 and CYP19 was up-regulated. Expression of the other genes investigated did not change significantly. In conclusion AOH is a weak oestrogenic mycotoxin that also has the ability to interfere with the steroidogenesis pathway. - Highlights: • Alternariol was investigated for endocrine disrupting activity. • Reporter gene assays and the H295R steroidogenesis assay have been used. • An oestrogenic effect of alternariol was observed. • This can lead to an increase in expression of the progesterone receptor. • Alternariol is capable of modulating hormone production and gene expression.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

HBCDD-induced sustained reduction in mitochondrial membrane potential, ATP and steroidogenesis in peripubertal rat Leydig cells

Hexabromocyclododecane (HBCDD), a brominated flame retardant added to various consumer products, is a ubiquitous environmental contaminant. We have previously shown that 6-hour exposure to HBCDD disturbs basal and human chorionic gonadotropin (hCG)-induced steroidogenesis in rat Leydig cells. Reduction in mitochondrial membrane potential (ΔΨm) and cAMP production was also observed. Here, we further expanded research on the effect of HBCDD on Leydig cells by using a prolonged exposure scenario. Cells were incubated in the presence of HBCDD during 24 h and then treated with HBCDD + hCG for additional 2 h. Results showed that HBCDD caused a sustained reduction in ATP level after 24 h of exposure, which persisted after additional 2-hour treatment with HBCDD + hCG. cAMP and androgen accumulations measured after 2 h of HBCDD + hCG treatment were also inhibited. Real-time PCR analysis showed significant inhibition in the expression of genes for steroidogenic enzymes, luteinizing hormone receptor, regulatory and transport proteins, and several transcription factors under both treatment conditions. Western blot analysis revealed a decreased level of 30 kDa steroidogenic acute regulatory protein (StAR) after HBCDD + hCG treatment. In addition, HBCDD decreased the conversion of 22-OH cholesterol to pregnenolone and androstenedione to testosterone, indicating loss of the activity of cytochrome P450C11A1 (CYP11A1) and 17β-hydroxysteroid dehydrogenase (HSD17β). Cell survival was not affected, as confirmed by cytotoxicity and trypan blue tests or DNA fragmentation analysis. In summary, our data showed that HBCDD inhibits ATP supply, most likely through a decrease in ΔΨm, and targets multiple sites in the steroidogenic pathway in Leydig cells. - Highlights: • HBCDD causes a sustained reduction in ΔΨm and ATP level in Leydig cells. • Prolonged HBCDD exposure decreases hCG-supported steroidogenesis in Leydig cells. • HBCDD targets StAR, HSD17β and CYP11A1 in Leydig cells.

60 APPLIED LIFE SCIENCES↗