The MD Anderson Prostate Cancer Patient-derived Xenograft Series (MDA PCa PDX) Captures the Molecular Landscape of Prostate Cancer and Facilitates Marker-driven Therapy Development

Abstract

Purpose: Advances in prostate cancer lag behind other tumor types partly due to the paucity of models reflecting key milestones in prostate cancer progression. Therefore, we develop clinically relevant prostate cancer models. Experimental Design: Since 1996, we have generated clinically annotated patient-derived xenografts (PDXs; the MDA PCa PDX series) linked to specific phenotypes reflecting all aspects of clinical prostate cancer. Results: We studied two cell line-derived xenografts and the first 80 PDXs derived from 47 human prostate cancer donors. Of these, 47 PDXs derived from 22 donors are working models and can be expanded either as cell lines (MDA PCa 2a and 2b) or PDXs. The histopathologic, genomic, and molecular characteristics (androgen receptor, ERG, and PTEN loss) maintain fidelity with the human tumor and correlate with published findings. PDX growth response to mouse castration and targeted therapy illustrate their clinical utility. Comparative genomic hybridization and sequencing show significant differences in oncogenic pathways in pairs of PDXs derived from different areas of the same tumor. We also identified a recurrent focal deletion in an area that includes the speckle-type POZ protein-like (SPOPL) gene in PDXs derived from seven human donors of 28 studied (25%). SPOPL is a SPOP paralog, and SPOP mutations define a molecular subclass of prostate cancer. SPOPL deletions are found in 7% of The Cancer Genome Atlas prostate cancers, which suggests that our cohort is a reliable platform for targeted drug development. Conclusions: The MDA PCa PDX series is a dynamic resource that captures the molecular landscape of prostate cancers progressing under novel treatments and enables optimization of prostate cancer-specific, marker-driven therapy.

Androgen-Driven Fusion Genes and Chimeric Transcripts in Prostate Cancer

“…While TMPRSS2-ERG activates NO-cGMP signaling in prostate cancer cells, sGC inhibitor treatment repressed tumor growth in TMPRSS2-ERG-positive VCaP xenograft models and acted in synergy with enzalutamide, the potent AR antagonist (Zhou et al, 2019 ). In the future, more of the specific marker-driven therapies are likely to be developed, especially through utilization of patient-derived 3D cultures as well as xenografts (PDXs) [recently reviewed in Kato et al ( 2020 ), Palanisamy et al ( 2020 ), and Risbridger et al ( 2020 )]. Patient-derived 3D cultures include spheroids and organoids, which are applicable in high throughput screening of e.g., drug libraries, while PDX models entail engrafting patient tissue in immunocompromised mice [reviewed in Kato et al ( 2020 ) and Risbridger et al ( 2020 )].…”

“…Although an intact immune system against the tumor is missing from the PDXs, this experimental model retains many other valuable properties of tumor tissue and in vivo environment and is thus valuable in developing new drugs and selecting appropriate treatment strategies for prostate cancer patients. In terms of prostate cancer fusion genes, the expression of ERG has been shown to be retained in the PDXs along with other molecular, histopathologic, and genomic characteristics (Palanisamy et al, 2020 ), indicating PDXs to be a valuable strategy to assess fusion-specific therapeutic options in the future.…”

Recent Discoveries in the Androgen Receptor Pathway in Castration-Resistant Prostate Cancer

“…Yet, PDXs are often more difficult to establish from prostate cancer compared to other malignancies, due to low take rates (10–40%) and long latency periods (up to 12 months) ( 123 ). Nevertheless, several groups have established collections of serially transplantable prostate cancer PDXs ( 30 , 124 – 128 ). At least 51 PDXs of CRPC have been established, primarily from patients who failed ADT, but fewer from men treated with second generation AR-directed therapies ( 125 ).…”

PDX: Moving Beyond Drug Screening to Versatile Models for Research Discovery

“…For example, the LuCAP series of 21 PDXs have genomic and phenotypic features representing human disease, including amplification of the AR, PTEN deletion, TP53 deletion and mutation, RB1 loss, TMPRSS2-ERG rearrangements, SPOP mutation, hypermutation due to MSH2/MSH6 genomic aberrations, and BRCA2 loss [ 63 , 64 ]. The MD Anderson prostate cancer PDX series (MDA PCa PDX) also captures the molecular landscape of AR alterations, ERG fusions, and PTEN loss, as well as rare or unappreciated mutations, such as a focal deletion of the SPOPL gene, providing unique models to study the significance of specific genomic alterations in prostate tumors [ 65 ]. Similar molecular data are available for the Living Tumor Laboratory series of prostate cancer PDXs, with profiling of long noncoding RNAs [ 66 , 67 ], microRNAs [ 68 ], and genes involved in cellular energetics and macromolecular biosynthesis [ 69 ], providing an expansive transcriptomic data set from these informative models.…”

“…Tumor heterogeneity in PDXs may be a challenge if they are to be used for personalized medicine, but it can also be an opportunity. By establishing different PDXs from the same tumor or the same patient, it is possible to reveal the preexisting heterogeneity in patient samples and investigate how variations in molecular features affect tumor phenotypes [ 21 , 32 , 63 , 65 ]. For example, the Living Tumor Laboratory established 5 PDXs with varying metastatic potential from a single primary tumor of high-grade prostate cancer [ 76 ].…”