Standardized and reproducible preclinical models that recapitulate the dynamics of prostate cancer are urgently needed. We established a bank of transplantable patient-derived prostate cancer xenografts that capture the biologic and molecular heterogeneity currently confounding prognostication and therapy development. Xenografts preserved the histopathology, genome architecture, and global gene expression of donor tumors. Moreover, their aggressiveness matched patient observations, and their response to androgen withdrawal correlated with tumor subtype. The panel includes the first xenografts generated from needle biopsy tissue obtained at diagnosis. This advance was exploited to generate independent xenografts from different sites of a primary site, enabling functional dissection of tumor heterogeneity. Prolonged exposure of adenocarcinoma xenografts to androgen withdrawal led to castration-resistant prostate cancer, including the first-in-field model of complete transdifferentiation into lethal neuroendocrine prostate cancer. Further analysis of this model supports the hypothesis that neuroendocrine prostate cancer can evolve directly from adenocarcinoma via an adaptive response and yielded a set of genes potentially involved in neuroendocrine transdifferentiation. We predict that these next-generation models will be transformative for advancing mechanistic understanding of disease progression, response to therapy, and personalized oncology. Cancer Res; 74(4); 1272-83. Ó2013 AACR.

Importance The molecular landscape underpinning response to the androgen receptor (AR) antagonist enzalutamide in metastatic castration-resistant prostate cancer (mCRPC) patients is undefined. Consequently, there is an urgent need for practical biomarkers to guide therapy selection and understand resistance. Although tissue biopsies are impractical to perform routinely in the majority of mCRPC patients, the analysis of plasma cell-free DNA (cfDNA) has recently emerged as a minimally-invasive method to explore tumor characteristics. Objective To reveal genomic characteristics from cfDNA associated with clinical outcomes on enzalutamide. Design We collected temporal plasma samples (baseline, 12-week, end-of-treatment) for circulating cfDNA and performed aCGH copy number profiling and deep AR gene sequencing. Samples collected at end-of-treatment were also subjected to targeted sequencing of 19 prostate cancer associated genes. Setting Plasma samples were obtained from August 2013 to July 2015 at a single academic institution (British Columbia Cancer Agency). Participants 65 mCRPC patients. Exposure for Observational Studies Enzalutamide, 160 mg daily orally. Main Outcome Measures PSA response rate (decline ≥ 50% from baseline confirmed ≥ 3 weeks later). Radiographic (as per Prostate Cancer Working Group 2 Criteria) and/or clinical progression (defined as worsening disease-related symptoms necessitating a change in anti-cancer therapy and/or deterioration in ECOG performance status ≥ 2 levels). Results cfDNA was isolated from 122/125 plasma samples, and targeted sequencing was successful in 119/122. AR mutations and/or copy number alterations were robustly detected in 46% and 66% of baseline and progression samples respectively. Detection of AR amplification was associated with primary resistance, as was heavily mutated AR (≥2 mutations), and RB1 loss. AR mutations exhibited clonal selection during treatment, including an increase in glucocorticoid-sensitive AR-L702H and promiscuous AR-T878A in patients with prior exposure to abiraterone. At the time of progression cfDNA sequencing revealed mutations or copy number changes in all patients tested, including clinically-actionable alterations in DNA damage repair genes and PI3K pathway genes, and a high frequency of activating CTNNB1 mutations. Conclusions and Relevance These data demonstrate that clinically-informative genomic profiling of cfDNA is feasible in nearly all mCRPC patients and provides important insights into enzalutamide response and resistance.

Hereditary sensory neuropathy type I (HSN1) is the most common hereditary disorder of peripheral sensory neurons. HSN1 is an autosomal dominant progressive degeneration of dorsal root ganglia and motor neurons with onset in the second or third decades. Initial symptoms are sensory loss in the feet followed by distal muscle wasting and weakness. Loss of pain sensation leads to chronic skin ulcers and distal amputations. The HSN1 locus has been mapped to chromosome 9q22.1-22.3 (refs. 3,4). Here we map the gene SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, to this locus. Mutation screening revealed 3 different missense mutations resulting in changes to 2 amino acids in all affected members of 11 HSN1 families. We found two mutations to be located in exon 5 (C133Y and C133W) and one mutation to be located in exon 6 of SPTLC1 (V144D). All families showing definite or probable linkage to chromosome 9 had mutations in these two exons. These mutations are associated with increased de novo glucosyl ceramide synthesis in lymphoblast cell lines in affected individuals. Increased de novo ceramide synthesis triggers apoptosis and is associated with massive cell death during neural tube closure, raising the possibility that neural degeneration in HSN1 is due to ceramide-induced apoptotic cell death.