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

Turnham, Daniel J. ORCID: https://orcid.org/0000-0002-2540-7363, Mullen, Manisha S., Bullock, Nicholas P., Gilroy, Kathryn L., Richards, Anna E., Patel, Radhika, Quintela, Marcos, Meniel, Valerie S., Seaton, Gillian, Kynaston, Howard ORCID: https://orcid.org/0000-0003-1902-9930, Clarkson, Richard W. E. ORCID: https://orcid.org/0000-0001-7389-8673, Phesse, Toby J. ORCID: https://orcid.org/0000-0001-9568-4916, Nelson, Peter S., Haffner, Michael C., Staffurth, John N. ORCID: https://orcid.org/0000-0002-7834-3172 and Pearson, Helen B. ORCID: https://orcid.org/0000-0002-3284-0843 2024. Development and characterisation of a new patient-derived Xenograft model of AR-negative metastatic asctration-resistant prostate cancer. Cells 13 (8) , 673. 10.3390/cells13080673

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	MDPI
ISSN:	2073-4409
Date of First Compliant Deposit:	15 April 2024
Date of Acceptance:	10 April 2024
Last Modified:	29 Apr 2024 09:56
URI:	https://orca.cardiff.ac.uk/id/eprint/167938

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