Introduction: Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer with a mean survival of less than 12 months after diagnosis. The poor prognosis of NEPC is partly due to its intrinsic resistance to androgen deprivation therapy. Thus, novel therapeutic strategies are urgently needed. While our understanding of the mechanisms regulating NEPC development is expanding, the translation of biological findings into clinical practice has been hampered by a lack of preclinical models that reflect the heterogeneity of this disease.
Objective: To address the shortage of preclinical models for NEPC, our goal was to establish a collection of patient-derived xenografts (PDXs) using tissues collected from men with prostate cancer.
Methods and results: Our laboratory has successfully derived 26 serially transplantable neuroendocrine PDXs from 12 patients across the clinical trajectory of prostate cancer. NEPC PDXs were histologically characterised by a pathologist and defined as positive immunohistochemical staining for one or more of the three neuroendocrine biomarkers: chromogranin A, synaptophysin, and CD56. Overall, we detected 6 of the 8 known histological variants of NEPC in this cohort, including small cell NEPC, large cell NEPC and amphicrine tumours. Interestingly, none of the three biomarkers were universally expressed in neuroendocrine PDXs. Next, by comparing NE biomarker expression to matched patient specimens, we confirmed that PDXs faithfully recapitulated the histopathology of original specimens despite years of serial transplantation. Finally, we attempted to broaden the preclinical capabilities of this collection by culturing organoids from 12 neuroendocrine PDXs. Overall, 10/12 lines were successfully grown as organoids; 4 of these lines achieved long-term, active growth in vitro and are suitable for preclinical testing.
Significance: In summary, we report a collection of 26 NEPC PDXs recapitulating the diverse histopathology of neuroendocrine tumours in contemporary patients and, therefore, is a valuable resource for examining the efficacy of novel compounds.