Development and characterisation of a new patient-derived xenograft model of AR-negative metastatic castration-resistant prostate cancer

Turnham, Daniel J.; Mullen, Manisha S.; Bullock, Nicholas P.; Gilroy, Kathryn L.; Richards, Anna E.; Patel, Radhika; Quintela, Marcos; Meniel, Valerie S.; Seaton, Gillian; Kynaston, Howard; Clarkson, Richard W. E.; Phesse, Toby J.; Nelson, Peter S.; Haffner, Michael C.; Staffurth, John N.; Pearson, Helen B.

Abstract

As the treatment landscape for prostate cancer gradually evolves, the frequency of treatment-induced neuroendocrine prostate cancer (NEPC) and double-negative prostate cancer (DNPC) that is deficient for androgen receptor (AR) and neuroendocrine (NE) markers has increased. These prostate cancer subtypes are typically refractory to AR-directed therapies and exhibit poor clinical outcomes. Only a small range of NEPC/DNPC models exist, limiting our molecular understanding of this disease and hindering our ability to perform preclinical trials exploring novel therapies to treat NEPC/DNPC that are urgently needed in the clinic. Here, we report the development of the CU-PC01 PDX model that represents AR-negative mCRPC with PTEN/RB/PSMA loss and CTNN1B/TP53/BRCA2 genetic variants. The CU-PC01 model lacks classic NE markers, with only focal and/or weak expression of chromogranin A, INSM1 and CD56. Collectively, these findings are most consistent with a DNPC phenotype. Ex vivo and in vivo preclinical studies revealed that CU-PC01 PDX tumours are resistant to mCRPC standard-of-care treatments enzalutamide and docetaxel, mirroring the donor patient’s treatment response. Furthermore, short-term CU-PC01 tumour explant cultures indicate this model is initially sensitive to PARP inhibition with olaparib. Thus, the CU-PC01 PDX model provides a valuable opportunity to study AR-negative mCRPC biology and to discover new treatment avenues for this hard-to-treat disease.

• Journal Article Type: Article
• Acceptance Date: Apr 10, 2024
• Online Publication Date: Apr 12, 2024
• Publication Date: Apr 24, 2024
• Deposit Date: Oct 22, 2024
• Publicly Available Date: Oct 23, 2024
• Journal: Cells
• Electronic ISSN: 2073-4409
• Publisher: MDPI
• Peer Reviewed: Peer Reviewed
• Volume: 13
• Issue: 8
• Article Number: 673
• DOI: https://doi.org/10.3390/cells13080673
• Public URL: https://uwe-repository.worktribe.com/output/13307264