LuCaP Prostate Cancer Patient-Derived Xenografts Reflect the Molecular Heterogeneity of Advanced Disease an­­d Serve as Models for Evaluating Cancer Therapeutics

Abstract

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.

Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer

“…Finally, to assess whether BROMO-10 is able to predict responsiveness of PC to bromodomain inhibitors, we used RNA-seq profiles of panels of PC cell lines and expression array profiles of patient-derived xenografts (PDXs) (Nguyen et al, 2017) to generate BROMO-10 scores (Figure 7 D and E). We then correlated these scores with publicly available IC50 data for JQ1 (Asangani et al, 2016) (Figure 7F), ZEN-3694 (Attwell et al, 2016) (Figure 7G), I-BET762 (Figure 7H), and responsiveness to I-BET762 treatment measured as a significant reduction in tumor volume (Wyce et al, 2013) (Figure 7I).…”

Establishing a cryopreservation protocol for patient‐derived xenografts of prostate cancer

“…This is evident by the low numbers of prostate cancer PDXs in international consortia, including the EurOPDX consortium, JAX Laboratories and BioMedical Research PDX encyclopedia, where prostate cancer PDXs constitute only 1% of the collection in some cases . To address this problem, academic groups developed a repertoire of serially transplantable PDX of prostate cancer, resulting in over 100 authenticated PDXs, including those from the Living Tumor Laboratory, the LuCaP series, the MD Anderson (MDA PCa) series, the Johns Hopkins University cohort, our recently published collection from the Melbourne Urological Research Alliance (MURAL), and others . The take rates for establishing these serially transplantable PDX were 10% to 40% and they often had long latency times of up to 12 months after initial grafting .…”

“…As the number of prostate cancer PDXs increases, the process of maintaining them becomes more laborious and time consuming. PDXs are often maintained by continually repassaging them into new host mice, which can be as often as every few weeks for fast growing tumors . Therefore, the ability to store PDXs through cryopreservation would decrease the workload of maintaining them.…”

The what, when, and why of human prostate cancer xenografts

“…In addition to insufficient suppression of the host's adaptive and innate immune systems, this limited success rate could be due to the fact that the previous attempts used either small biopsy samples from metastatic sites or localized prostate cancers from radical prostatectomy specimens which did not allow validation of their aggressive nature (ie, lethality). To allow a more diverse sampling of different lethal metastatic sites, including bone metastases, and to allow a more optimally standardized tissue yield and viability protocol, Robert L. Vessella and Paul H. Lange at the University of Washington, Seattle initiated a rapid autopsy program in the early 90's to harvest lethal prostate cancer tissue from a variety of metastatic sites from each patient . During the period from 1991 to 2005, the University of Washington group collected 261 prostate cancer samples from 156 patients and implanted them subcutaneously into immune deficient intact male mice without Matrigel.…”

“…This group later switched to using the more immune deficient scid intact male mice, but again did not use Matrigel co‐inoculation. Eva Corey now leads this program and has reported that 26 xenografts have been successfully propagated beyond three passages …”