Journal Article

Development and Characterisation of a New Patient-Derived Xenograft Model of AR-Negative Metastatic Castration-Resistant Prostate Cancer

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

2024

Overview

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.

• Publisher: MDPI AG
• Subject: androgen receptor (AR) / Androgen receptors / Androgens / Animals / Antigens / Benzamides - pharmacology / Biopsy / BRCA2 protein / Cancer therapies / Castration / castration-resistant prostate cancer (CRPC) / CD56 antigen / Chemotherapy / Clinical trials / Cryopreservation / Disease Models, Animal / double-negative prostate cancer (DNPC) / Genetic diversity / Humans / Male / Metastases / Metastasis / Mice / Mutation / Neoplasm Metastasis / neuroendocrine (NE) / Nitriles - pharmacology / p53 Protein / patient-derived xenograft (PDX) / Patients / Phenotypes / Phenylthiohydantoin - analogs & derivatives / Phenylthiohydantoin - pharmacology / Phenylthiohydantoin - therapeutic use / Phthalazines - pharmacology / Phthalazines - therapeutic use / Piperazines / Prostate cancer / Prostatic Neoplasms, Castration-Resistant - drug therapy / Prostatic Neoplasms, Castration-Resistant - genetics / Prostatic Neoplasms, Castration-Resistant - metabolism / Prostatic Neoplasms, Castration-Resistant - pathology / PTEN protein / Receptors, Androgen - genetics / Receptors, Androgen - metabolism / Research ethics / Testosterone / Tumors / Xenograft Model Antitumor Assays