Contribution of mouse adrenal glands to intratumor androgens and growth of castration-resistant prostate cancer xenografts.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 224-224 ◽  
Author(s):  
Elahe A. Mostaghel ◽  
Heather Biehl ◽  
Susanna Hernandez ◽  
Ailin Zhang ◽  
Jon Bartlett ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Adrenal Glands ◽  
Castration Resistant Prostate Cancer ◽  
Adrenal Androgens ◽  
Castration Resistant ◽  
Kidney Liver ◽  
The Impact ◽  
Delayed Time ◽  
Pdx Models ◽  
Rapid Regrowth

224 Background: Historical studies using radioimmunoassay did not detect adrenal androgens in serum from castrate mice, and it is widely held that rodent adrenal glands do not make adrenal androgens due to lack of CYP17A expression. This contrasts with the clinical setting in which circulating adrenal androgens are significant and inhibition of adrenal CYP17A markedly decreases tissue androgens. Methods: We evaluated CYP17A (by methylation, transcript and protein) and androgens (by mass spectrometry) in adrenal glands of CB17-NOD/SCID mice. We determined the impact of adrenalectomy (ADX) on suppressing tumor androgens and growth in two patient derived xenografts (PDX) models of castration resistant prostate cancer (CRPC). Results: CYP17A is unmethylated, and transcript and protein are present in adrenals from intact and castrate mice. In castrate mice adrenal levels of DHEA (0.75 pg/mg), androstenedione (AED; 44pg/mg), T (12.5pg/mg) and DHT (4.7 pg/mg) are detectable and nearly 2 orders of magnitude higher than in kidney, liver or muscle (p < 0.05 for all). In castrate mice bearing LuCaP35 and LuCaP96 tumors, ADX suppressed tumor steroids at 21-30 days after ADX vs castration alone (LuCaP35: AED 0.05 vs 0.02 pg/mg, p = 0.005; T 0.64 vs 0.03 pg/mg p < 0.001; DHT 2.3 vs 0.23 pg/mg, p = 0.0003; LuCaP96: AED 0.06 vs 0.02 pg/mg p = 0.08; T 0.81 vs 0.03 pg/mg, p < 0.0001; DHT 1.3 vs 0.04 pg/mg, p = 0.002), and delayed time to tumor re-growth (median survival: LuCaP35 33 vs 179 days, p = 0.006; LuCaP96 25 vs 301 days, p = 0.0012). Whereas tumor recurrence in LuCaP96 was uniformly delayed, a subset of tumors in LuCaP35 showed more rapid regrowth after ADX (66 days vs undefined, p = 0.008), with a trend toward increased levels of tumor steroids (progesterone 0.25 vs 0.02 pg/mg, p = 0.07; T 0.14 vs 0.02, p = 0.04; DHT 0.36 vs 0.21, p = 0.17). Recurrent tumors variably showed induction of full length and truncated AR variants and/or induction of steroidogenic enzymes as potential mechanisms of resistance. Conclusions: Adrenally-derived steroids are produced in mice and contribute to tumor androgen levels and growth in PDX models. Mice are an appropriate model for evaluation of steroidogenesis inhibitors in CRPC xenograft studies

scholarly journals ZRSR2 overexpression is a frequent and early event in castration-resistant prostate cancer development

2021 ◽  
Author(s):  
Haiqing He ◽  
Jun Hao ◽  
Xin Dong ◽  
Yu Wang ◽  
Hui Xue ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle Progression ◽  
Locally Advanced ◽  
Patient Treatment ◽  
Early Event ◽  
Driver Gene ◽  
Castration Resistant Prostate Cancer ◽  
Driver Genes ◽  
Castration Resistant ◽  
Pdx Models

Abstract Background Androgen deprivation therapy (ADT) remains the leading systemic therapy for locally advanced and metastatic prostate cancers (PCa). While a majority of PCa patients initially respond to ADT, the durability of response is variable and most patients will eventually develop incurable castration-resistant prostate cancer (CRPC). Our research objective is to identify potential early driver genes responsible for CRPC development. Methods We have developed a unique panel of hormone-naïve PCa (HNPC) patient-derived xenograft (PDX) models at the Living Tumor Laboratory. The PDXs provide a unique platform for driver gene discovery as they allow for the analysis of differentially expressed genes via transcriptomic profiling at various time points after mouse host castration. In the present study, we focused on genes with expression changes shortly after castration but before CRPC has fully developed. These are likely to be potential early drivers of CRPC development. Such genes were further validated for their clinical relevance using data from PCa patient databases. ZRSR2 was identified as a top gene candidate and selected for further functional studies. Results ZRSR2 is significantly upregulated in our PDX models during the early phases of CRPC development after mouse host castration and remains consistently high in fully developed CRPC PDX models. Moreover, high ZRSR2 expression is also observed in clinical CRPC samples. Importantly, elevated ZRSR2 in PCa samples is correlated with poor patient treatment outcomes. ZRSR2 knockdown reduced PCa cell proliferation and delayed cell cycle progression at least partially through inhibition of the Cyclin D1 (CCND1) pathway. Conclusion Using our unique HNPC PDX models that develop into CRPC after host castration, we identified ZRSR2 as a potential early driver of CRPC development.

scholarly journals The Impact of Special Access Programs (SAP) on Prescribing Patterns in Metastatic Castration Resistant Prostate Cancer (mCRPC)

2021 ◽  
Vol 6 (1) ◽  
pp. 33
Author(s):  
Nimira Alimohamed ◽  
Raya Leibowitz-Amit ◽  
Arnoud Templeton ◽  
Jo-An Seah ◽  
Francisco Emilio Vera-Badillo ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Prescribing Patterns ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
The Impact ◽  
Access Programs

scholarly journals Impact of Extraskeletal Metastases on Skeletal-Related Events in Metastatic Castration-Resistant Prostate Cancer with Bone Metastases

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2034
Author(s):  
Soraia Lobo-Martins ◽  
Arlindo R. Ferreira ◽  
André Mansinho ◽  
Sandra Casimiro ◽  
Kim Leitzel ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastases ◽  
Unmet Need ◽  
Bone Alkaline Phosphatase ◽  
Multicenter Clinical Trial ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Therapeutic Landscape ◽  
Skeletal Related Events ◽  
The Impact

The therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC) has substantially evolved over the last decade. Nonetheless, a better understanding of bone-targeted agents (BTAs) action in mCRPC remains an unmet need. Theuse of BTAs aims to reduce the incidence of skeletal-related events (SREs) in patients with mCRPC. Less frequent BTA schedules are currently being studied to minimize adverse events. In this study, the impact of metastatic compartment (bone and extraskeletal metastases (BESM) vs. bone-only metastases (BOM)) on bone biomarker kinetics, time to first on-study SRE, and symptomatic skeletal events (SSEs) is evaluated. This is a retrospective analysis of the prospective, randomized, multicenter clinical trial of denosumab vs. zoledronic acid in patients with mCRPC and bone metastases. A total of 1901 patients were included, 1559 (82.0%) with BOM and 342 with BESM (18.0%). Bone metastases burden was balanced between groups. Baseline levels and normalization rates of corrected urinary N-terminal telopeptide and bone alkaline phosphatase did not differ between groups. However, BESM patients had a higher risk of SREs (adjusted HR 1.21; 95% CI 1.01–1.46; p = 0.043) and SSEs (adjusted HR 1.30; 95% CI 1.06–1.61; p = 0.014). This difference was more pronounced in the first 12 months of BTA treatment.In mCRPC, strategies of BTA schedule de-escalation may take into account presence of extraskeletal metastases.

scholarly journals Contribution of Adrenal Glands to Intratumor Androgens and Growth of Castration-Resistant Prostate Cancer

2018 ◽  
Vol 25 (1) ◽  
pp. 426-439 ◽  
Author(s):  
Elahe A. Mostaghel ◽  
Ailin Zhang ◽  
Susana Hernandez ◽  
Brett T. Marck ◽  
Xiaotun Zhang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Adrenal Glands ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant

scholarly journals The impact of statin use on the efficacy of abiraterone acetate in patients with castration-resistant prostate cancer

The Prostate ◽  
2017 ◽  
Vol 77 (13) ◽  
pp. 1303-1311 ◽  
Author(s):  
Lauren C. Harshman ◽  
Lillian Werner ◽  
Abhishek Tripathi ◽  
Xiaodong Wang ◽  
Benjamin L. Maughan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Abiraterone Acetate ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
The Impact ◽  
Statin Use

A prospective randomized phase II trial evaluating maintenance GM-CSF in an intermittent chemotherapy (chemo) regimen for metastatic castration-resistant prostate cancer (mCRPC): A DoD prostate cancer clinical trials consortium trial.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 35-35
Author(s):  
Eric Jay Small ◽  
Vivian K. Weinberg ◽  
Charles J. Ryan ◽  
Celestia S. Higano ◽  
Amy Mimi Lin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Optimal Number ◽  
Castration Resistant Prostate Cancer ◽  
Time To Progression ◽  
Gm Csf ◽  
Castration Resistant ◽  
Randomized Phase Ii ◽  
Intermittent Chemotherapy ◽  
Number Of Cycles ◽  
The Impact

35 Background: The optimal number of cycles of docetaxel for patients (pts) with mCRPC is not known, and in practice, treatment breaks are common. The current study was designed to test the safety and efficacy of utilizing 6 cycles of standard docetaxel with chemo free intervals in patients who achieve and maintain a response to docetaxel. Methods: Pts with mCRPC, no prior chemo, and KPS > 60% were eligible. Pts were treated with “induction” docetaxel 75 mg/m2 q 3 weeks, and prednisone 5 mg po bid. PSAWG1 criteria were used to define response and progression. After 6 cycles, responding pts stopped chemo and were randomized to observation (Obs) or to GM-CSF, 250 mcg/m2 daily for 14 days out of every 28-day cycle. Pts were followed with monthly PSA and imaging every 2 cycles until progression, at which point docetaxel was reinitiated for another 6 cycles, followed by the same “off chemo” regimen. The primary endpoint was the time to progression while on chemo (time to chemo resistance). Results: 114 pts have been enrolled: 3 are undergoing induction, and 111 are therefore evaluable. Of these pts, 82 completed induction, (10 did not due to PD, 9 due to adverse events (AE), 10 due to pt or MD choice). Of 111 evaluable pts, 48 (43%) had a response to chemo and were eligible for randomization. 22 were randomized to Obs and 26 to GM-CSF. Of 48 randomized pts, 25 restarted chemo, all for PSA PD. (23 pts did not re-start chemo because of AE, other therapy being started, or pt choice; 1 pt is still on GM-CSF.) 6/25 (24%) pts experienced a response to the 2nd series of chemo, and 1/6 (17%) to the 3rd. The time to chemo re-initiation (n=25) was 3.1 mos in Obs pts and 4.2 mos in GM-CSF pts. Conclusions: 43% of patients met criteria for undergoing intermittent chemo. The response proportion to the 1st, 2nd, and 3rd series of docetaxel was 43%, 24% and 17%, respectively. GM-CSF may modestly delay the time to chemo re-initiation, but the sample size is small and insufficient to assess the impact of GM-CSF on time to chemo resistance.

A phase III, randomized, double-blind, placebo-controlled study of enzalutamide in men with nonmetastatic castration-resistant prostate cancer: Post-hoc analysis of PROSPER by prior therapy.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 185-185
Author(s):  
Ugo De Giorgi ◽  
Eleni Efstathiou ◽  
William R. Berry ◽  
Heather Ann Payne ◽  
Katarzyna Madziarska ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Hormonal Therapy ◽  
Phase Iii ◽  
Controlled Study ◽  
Castration Resistant Prostate Cancer ◽  
Targeting Therapy ◽  
Prior Therapy ◽  
Castration Resistant ◽  
Bone Targeting ◽  
The Impact

185 Background: Men with nonmetastatic castration-resistant prostate cancer (nmCRPC) are at high risk of developing metastatic CRPC. In the primary analysis of PROSPER, enzalutamide (ENZA) provided a statistically significant and clinically meaningful improvement in metastasis-free survival (MFS) in men with nmCRPC. Here we report the impact of prior therapy on MFS. Methods: Eligible men with nmCRPC, prostate-specific antigen (PSA) doubling time ≤ 10 months, and PSA ≥ 2 ng/mL at screening continued androgen deprivation therapy and were randomized 2:1 to ENZA 160 mg or placebo (PBO). The primary endpoint was MFS. Results: 1401 men were enrolled, with a median age of 74 y (range, 50-95 y). In all men, ENZA reduced the risk of metastasis or death by 71% (hazard ratio [HR], 0.29; 95% confidence interval [CI], 0.24-0.35; P < .0001). The treatment effect consistently favored ENZA regardless of whether men had prior bilateral orchiectomy, prior radiation, ≤1 or > 1 prior hormonal therapy, or prior bone-targeting therapy (Table). Men who received > 1 prior hormonal therapy had a shorter median MFS than those who received ≤1 line of hormonal therapy (5 months and 3 months in the ENZA and PBO groups, respectively). Conclusions: In men with nmCRPC and rapidly rising PSA, ENZA treatment resulted in a clinically meaningful reduction in the risk of developing metastases or death irrespective of prior surgery, radiation, or bone-targeting therapy. MFS was longer in men who had received ≤1 prior hormonal therapy. Clinical trial information: NCT02003924. [Table: see text]

Colina 111 PET results in a nonmetastatic castration-resistant cancer (nmCRPC) in population that is negative by conventional imaging: True incidence from real-world evidence data.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e17522-e17522
Author(s):  
Martin Pitzzu ◽  
Luciana Gennari ◽  
Norberto Olguin ◽  
Gustavo Jankilevich
Keyword(s):  
Prostate Cancer ◽  
Real World ◽  
Drop Out ◽  
Conventional Imaging ◽  
Castration Resistant Prostate Cancer ◽  
True Incidence ◽  
Castration Resistant ◽  
Real World Evidence ◽  
Metastatic Setting ◽  
The Impact

e17522 Background: Nonmetastatic Castration-Resistant Prostate Cancer (nmCRPC) is characterized by a rising prostate-specifing antigen (PSA) level, castrate testosterone levels,and no evidence of distant metastases by conventional bone scan and croos-sectional image of the chest,abdomen and pelvis. SPARTAN and PROSPER trials recently demonstrated metastasis free survival in patients with nmCPRC treated with apalutamide with androgen blockade therapy and enzalutamide respectively, Real incidence of nmCPRC in latinoamerican population is unknown. Therefore, patients with negative conventional imaging could be metastatic with PET use, fall the percentage of non metastatic setting PET Colina demonstrated improved sensitivity and specificity used for biochemically recurrent hormone – sensitive patients and staging advanced disease. Colina – PET performance in nmCPRC remain largely unknown and requires evaluation. In this study we examined the incidence of nmCPRC in an Argentinian population by conventional imaging studies and the impact of use of Colina Pet. Methods: Overall 300 patients from public and private insitutions were assessed. Real World Evidence Prostate cancer database were retrospectively screened for records of patients with nmCPRC. Results: Three hundred medical records of consecutive patients with prostate cancer were assessed. All patients were evaluated by multidisciplinary team Localized disease 214 patients and metastatic Prostate Cancer Castration Sensitive 86 patients. With a median a six years of median follow up, 43 patients developed Prostate Cancer Castration Resistant. Six patients showed nmCPRC criteria, in all of them Colina Pet was indicated. After PET colina 5 cases were positives and only one patient were negative. Conclusions: The incidence or nmCPRC is 0,02% in argentine cohort and drop out to 0,003% with PET use. Colina-PET detected loco-regional of M1 disease in nearly all patients with CPRC and no detectable metastasis by conventional imaging. Further epidemiologic with real world evidence data studies with cost-efective evaluations should be launched to put in context the rol of PET in this setting.

scholarly journals Circulating and Intratumoral Adrenal Androgens Correlate with Response to Abiraterone in Men with Castration-Resistant Prostate Cancer

2021 ◽  
Author(s):  
Elahe A. Mostaghel ◽  
Brett T. Marck ◽  
Orpheus Kolokythas ◽  
Felix Chew ◽  
Evan Y. Yu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Castration Resistant Prostate Cancer ◽  
Adrenal Androgens ◽  
Castration Resistant
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