Patient-Derived Xenografts and Organoids Recapitulate Castration-Resistant Prostate Cancer with Sustained Androgen Receptor Signaling

Castration-resistant prostate cancer (CRPC) remains an incurable and lethal malignancy. The development of new CRPC treatment strategies is strongly impeded by the scarcity of representative, scalable and transferable preclinical models of advanced, androgen receptor (AR)-driven CRPC. Here, we present contemporary patient-derived xenografts (PDXs) and matching PDX-derived organoids (PDXOs) from CRPC patients who had undergone multiple lines of treatment. These models were comprehensively profiled at the morphologic, genomic ( n = 8) and transcriptomic levels ( n = 81). All are high-grade adenocarcinomas that exhibit copy number alterations and transcriptomic features representative of CRPC patient cohorts. We identified losses of PTEN and RB1, MYC amplifications, as well as genomic alterations in TP53 and in members of clinically actionable pathways such as AR, PI3K and DNA repair pathways. Importantly, the clinically observed continued reliance of CRPC tumors on AR signaling is preserved across the entire set of models, with AR amplification identified in four PDXs. We demonstrate that PDXs and PDXOs faithfully reflect donor tumors and mimic matching patient drug responses. In particular, our models predicted patient responses to subsequent treatments and captured sensitivities to previously received therapies. Collectively, these PDX-PDXO pairs constitute a reliable new resource for in-depth studies of treatment-induced, AR-driven resistance mechanisms. Moreover, PDXOs can be leveraged for large-scale tumor-specific drug response profiling critical for accelerating therapeutic advances in CRPC. </p

Modeling prostate cancer treatment responses in the organoid era: 3D environment impacts drug testing

Organoid-based studies have revolutionized in vitro preclinical research and hold great promise for the cancer research field, including prostate cancer (PCa). However, experimental var-iability in organoid drug testing complicates reproducibility. For example, we observed PCa organ-oids to be less affected by cabazitaxel, abiraterone and enzalutamide as compared to corresponding single cells prior to organoid assembly. We hypothesized that three-dimensional (3D) organoid organization and the use of various 3D scaffolds impact treatment efficacy. Live-cell imaging of an-drogen-induced androgen receptor (AR) nuclear translocation and taxane-induced tubulin stabilization was used to investigate the impact of 3D scaffolds, spatial organoid distribution and organ-oid size on treatment effect. Scaffolds delayed AR translocation and tubulin stabilization, with Mat-rigel causing a more pronounced delay than synthetic hydrogel as well as incomplete tubulin sta-bilization. Drug effect was further attenuated the more centrally organoids were located in the scaffold dome. Moreover, cells in the organoid core revealed a delayed treatment effect compared to cells in the organoid periphery, underscoring the impact of organoid size. These findings indicate that analysis of organoid drug responses needs careful interpretation and requires dedicated read-outs with consideration of underlying technical aspects

Childhood and Nation in World Cinema: borders and encounters

The child has existed in cinema since the Lumière Brothers filmed their babies having messy meals in Lyons, but it is only quite recently that scholars have paid serious attention to her/his presence on screen. Scholarly discussion is now of the highest quality and of interest to anyone concerned not only with the extent to which adult cultural conversations invoke the figure of the child, but also to those interested in exploring how film cultures can shift questions of agency and experience in relation to subjectivity. Childhood and Nation in World Cinema recognizes that the range of films and scholarship is now sufficiently extensive to invoke the world cinema mantra of pluri-vocal and pluri-central attention and interpretation. At the same time, the importance of the child in figuring ideas of nationhood is an undiminished tic in adult cultural and social consciousness. Either the child on film provokes claims on the nation or the nation claims the child. Given the waning star of national film studies, and the widely held and serious concerns over the status of the nation as a meaningful cultural unit, the point here is not to assume some extraordinary pre-social geopolitical empathy of child and political entity. Rather, the present collection observes how and why and whether the cinematic child is indeed aligned to concepts of modern nationhood, to concerns of the State, and to geo-political organizational themes and precepts. - See more at: http://www.bloomsbury.com/us/childhood-and-nation-in-contemporary-world-cinema-9781501318597/#sthash.shs7kQfm.dpu

Darolutamide added to docetaxel augments antitumor effect in models of prostate cancer through cell cycle arrest at the G1-S transition

Resistance to taxane chemotherapy is frequently observed in metastatic prostate cancer. The androgen receptor (AR) is a major driver of prostate cancer and a key regulator of the G1-S cell cycle checkpoint, promoting cancer cell proliferation by irreversible passage to the S-phase. We hypothesized that AR signaling inhibitor (ARSi) darolutamide in combination with docetaxel could augment antitumor effect by impeding the proliferation of taxane-resistant cancer cells. We monitored cell viability in organoids, tumor volume and PSA secretion in patient-derived xenografts (PDXs) and analyzed cell cycle and signaling pathway alterations. Combination treatment increased anti-tumor effect in androgen-sensitive, AR-positive prostate cancer organoids and PDXs. Equally beneficial effects of darolutamide added to docetaxel were observed in a castration-resistant model, progressive on docetaxel, enzalutamide and cabazitaxel. In vitro studies showed that docetaxel treatment with simultaneous darolutamide resulted in a reduction of cells entering the S-phase in contrast to only docetaxel. Molecular analysis in the prostate cancer cell line LNCaP revealed an upregulation of Cyclin Dependent Kinase inhibitor p21, supporting blockade of S-phase entry and cell proliferation. Our results provide a preclinical support for combining taxanes and darolutamide as a multimodal treatment strategy in metastatic prostate cancer patients progressive on ARSi and taxane chemotherapy.</p