Abstract A05: Developing patient derived xenograft (PDX) models for metastatic castration resistant prostate cancer (CRPC) during CYP17 inhibitor therapy

2016 ◽  
Author(s):  
Fang Xie ◽  
Manish Kohli ◽  
Yin Ping ◽  
Rafael E. Jimenez ◽  
Richard M. Weinshilboum ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Inhibitor Therapy ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Patient Derived Xenograft ◽  
Pdx Models

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.

Posttherapeutic Critical Organ Dosimetry of Extensive 177Lu-PSMA Inhibitor Therapy With Metastatic Castration-Resistant Prostate Cancer

2020 ◽  
Vol 45 (4) ◽  
pp. 288-291
Author(s):  
Ahu Özkan ◽  
Burcu Uçar ◽  
Hülya Seymen ◽  
Yasemin Yildiz Yarar ◽  
Fikri Okan Falay ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Inhibitor Therapy ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Critical Organ ◽  
Psma Inhibitor

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

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