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Background Metastatic prostate cancer is a common and lethal disease for which there are no therapies that produce cures or long-term durable remissions. Clinically relevant preclinical models are needed to increase our understanding of the biology of this malignancy and to evaluate new agents that might provide effective treatment. Our objective was to establish and characterize patient-derived xenografts (PDXs) from advanced prostate cancer (PC) to investigation of biology and evaluation of new treatment modalities. Methods Samples of advanced PC obtained from surgery or from metastases collected at time of death were implanted into immunocompromised mice to establish PDXs. Established LuCaP PDXs were propagated in vivo. Genomic, transcriptomic and STR profiles were generated. Responses to androgen deprivation and docetaxel in vivo were characterized. Results We established multiple PDXs (LuCaP series), which represent the major genomic and phenotypic features of the disease in humans, including amplification of androgen receptor, PTEN deletion, TP53 deletion and mutation, RB1 loss, and TMPRSS2-ERG rearrangements, SPOP mutation, hypermutation due to MSH2/MSH6 genomic aberrations, and BRCA2 loss. The PDX models also exhibited variation in intra-tumoral androgen levels. Our in vivo results show heterogeneity of response to androgen deprivation and docetaxel, standard therapies for advanced PC, similar to the responses of patients to these treatments. Conclusions The LuCaP PDX series reflects the diverse molecular composition of human castration-resistant PC and allows for hypothesis-driven cause-and-effect studies of mechanisms underlying treatment response and resistance.

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Preclinical data highlight AZD1390 as a potentially powerful new therapy to enhance brain tumor patient responses to radiotherapy.

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Purpose The neuroendocrine (NE) phenotype is associated with the development of metastatic castration-resistant prostate cancer (CRPC). Our objective was to characterize the molecular features of the NE phenotype in CRPC. Experimental Design Expression of chromogranin A (CHGA), synaptophysin (SYP), androgen receptor (AR), and prostate-specific antigen (PSA) was analyzed by immunohistochemistry (IHC) in 155 CRPC metastases from 50 patients and in 24 LuCaP prostate cancer patient-derived xenografts (PDX). Seventy-one of 155 metastases and the 24 LuCaP xenograft lines were analyzed by whole genome microarrays. REST splicing was verified by PCR. Results Co-expression of CHGA and SYP in >30% of cells was observed in 22 of 155 metastases (9 patients); 11 of the 22 metastases were AR+/PSA+ (6 patients), 11/22 were AR−/PSA− (4 patients), and 4/24 LuCaP PDXs were AR−/PSA−. By IHC, of the 71 metastases analyzed by whole genome microarrays, 5 metastases were CHGA+/SYP+/AR− and 5 were CHGA+/SYP+/AR+. Only CHGA+/SYP+ metastases had a NE transcript signature. The neuronal transcriptional regulator SRRM4 transcript was associated with the NE signature in CHGA+/SYP+ metastases and all CHGA+/SYP+ LuCaP xenografts. Additionally, expression of SRRM4 in LuCaP NE xenografts correlated with a splice variant of REST that lacks the transcriptional repressor domain. Conclusions (a) metastatic NE status can be heterogeneous in the same patient, (b) the CRPC NE molecular phenotype can be defined by CHGA+/SYP+ dual positivity, (c) the NE phenotype is not necessarily associated with the loss of AR activity, and (d) the splicing of REST by SRRM4 could promote the NE phenotype in CRPC.

Metastatic prostate cancer (mPC) comprises a spectrum of diverse phenotypes. However, the extent of inter- and intra-tumor heterogeneity is not established. Here we use digital spatial profiling (DSP) technology to quantitate transcript and protein abundance in spatially-distinct regions of mPCs. By assessing multiple discrete areas across multiple metastases, we find a high level of intra-patient homogeneity with respect to tumor phenotype. However, there are notable exceptions including tumors comprised of regions with high and low androgen receptor (AR) and neuroendocrine activity. While the vast majority of metastases examined are devoid of significant inflammatory infiltrates and lack PD1, PD-L1 and CTLA4, the B7-H3/CD276 immune checkpoint protein is highly expressed, particularly in mPCs with high AR activity. Our results demonstrate the utility of DSP for accurately classifying tumor phenotype, assessing tumor heterogeneity, and identifying aspects of tumor biology involving the immunological composition of metastases.

These animal models can be used to study biological interactions, pathways, and potential therapeutic targets, and also to evaluate new agents for treatment and prevention of CaP bone metastasis.