Preclinical testing is a crucial step in evaluating cancer therapeutics. We aimed to establish a significant resource of patient-derived xenografts (PDXs) of prostate cancer for rapid and systematic evaluation of candidate therapies. The PDX collection comprises 59 tumors collected from 30 patients between 2012–2020, coinciding with availability of abiraterone and enzalutamide. The PDXs represent the clinico-pathological and genomic spectrum of prostate cancer, from treatment-naïve primary tumors to castration-resistant metastases. Inter- and intra-tumor heterogeneity in adenocarcinoma and neuroendocrine phenotypes is evident from bulk and single-cell RNA sequencing data. Organoids can be cultured from PDXs, providing further capabilities for preclinical studies. Using a 1 x 1 x 1 design, we rapidly identify tumors with exceptional responses to combination treatments. To govern the distribution of PDXs, we formed the Melbourne Urological Research Alliance (MURAL). This PDX collection is a substantial resource, expanding the capacity to test and prioritize effective treatments for prospective clinical trials in prostate cancer.

Hereditary breast and ovarian cancer syndrome (HBOC) represents 5–10% of all patients with breast cancer and is associated with high-risk pathogenic alleles in BRCA1/2 genes, but only for 25% of cases. We aimed to find new pathogenic alleles in a panel of 143 cancer-predisposing genes in 300 Mexican cancer patients with suspicion of HBOC and 27 high-risk patients with a severe family history of cancer, using massive parallel sequencing. We found pathogenic variants in 23 genes, including BRCA1/2. In the group of cancer patients 15% (46/300) had a pathogenic variant; 11% (33/300) harbored variants with unknown clinical significance (VUS) and 74% (221/300) were negative. The high-risk group had 22% (6/27) of patients with pathogenic variants, 4% (1/27) had VUS and 74% (20/27) were negative. The most recurrent mutations were the Mexican founder deletion of exons 9-12 and the variant p.G228fs in BRCA1, each found in 5 of 17 patients with alterations in this gene. Rare VUS with potential impact at the protein level were found in 21 genes. Our results show for the first time in the Mexican population a higher contribution of pathogenic alleles in other susceptibility cancer genes (54%) than in BRCA1/2 (46%), highlighting the high locus heterogeneity of HBOC and the necessity of expanding genetic tests for this disease to include broader gene panels.

Purpose: Hereditary Breast and Ovarian Cancer (HBOC) syndrome is responsible for ∼5-10% of all diagnosed breast and ovarian cancers. Breast cancer is the most common malignancy and the leading cause of cancer-related mortality among women in Latin America (LA). The main objective of this study was to develop a comprehensive understanding of the genomic epidemiology of HBOC throughout the establishment Oliver et al. Latin American HBOC Study of The Latin American consortium for HBOC-LACAM, consisting of specialists from 5 countries in LA and the description of the genomic results from the first phase of the study. Methods: We have recruited 403 individuals that fulfilled the criteria for HBOC from 11 health institutions of Argentina, Colombia, Guatemala, Mexico and Peru. A pilot cohort of 222 individuals was analyzed by NGS gene panels. One hundred forty-three genes were selected on the basis of their putative role in susceptibility to different hereditary cancers. Libraries were sequenced in MiSeq (Illumina, Inc.) and PGM (Ion Torrent-Thermo Fisher Scientific) platforms. Results: The overall prevalence of pathogenic variants was 17% (38/222); the distribution spanned 14 genes and varied by country. The highest relative prevalence of pathogenic variants was found in patients from Argentina (25%, 14/57), followed by Mexico (18%, 12/68), Guatemala (16%, 3/19), and Colombia (13%, 10/78). Pathogenic variants were found in BRCA1 (20%) and BRCA2 (29%) genes. Pathogenic variants were found in other 12 genes, including high and moderate risk genes such as MSH2, MSH6, MUTYH, and PALB2. Additional pathogenic variants were found in HBOC unrelated genes such as DCLRE1C, WRN, PDE11A, and PDGFB. Conclusion: In this first phase of the project, we recruited 403 individuals and evaluated the germline genetic alterations in an initial cohort of 222 patients among 4 countries. Our data show for the first time in LA the distribution of pathogenic variants in a broad set of cancer susceptibility genes in HBOC. Even though we used extended gene panels, there was still a high proportion of patients without any detectable pathogenic variant, which emphasizes the larger, unexplored genetic nature of the disease in these populations.

Neuroendocrine prostate cancer (NEPC) represent an aggressive malignancy that results in poor patients outcomes. At a histological level, NEPC exhibits heterogeneous pathologies; nevertheless, the molecular features, drivers and therapeutic implications of this heterogeneity are poorly understood. Single cell technology enables the resolution needed to unveil the complex heterogeneity of NEPC that bulk RNA analysis could not previously detect. Therefore, we aim to characterize the molecular heterogeneity of NEPC at a single cell level to detect common phenotypes across patients and identify new therapeutic targets. We performed single cell RNA sequencing on a novel cohort of nine patient derived xenograft (PDX) models that recapitulate the pathological and clinical heterogeneity of NEPC. Downstream analysis of single cell data was first completed on individual samples to identify distinct subpopulations of cells within each tumor. Then, integration analysis was performed to identify common and unique neuroendocrine populations across the different tumors. We profiled the transcriptome of 19,361 cells captured from the eight NEPCs. On an individual sample analysis, we detected 3 to 8 different subpopulations in each tumor, where every subpopulation displayed distinct biological properties such as epithelial mesenchymal transition, quiescence and stemness. Data integration of all samples revealed 16 subpopulations of tumor cells across all patients, of which 10 populations were primarily unique to one patient. Enriched pathway analyses revealed heterogeneous expression of most cancer hallmarks and oncogenic pathways across subpopulations, although some pathways were common to several neuroendocrine subpopulations such as EMT, P53 and KRAS. The detection of heterogeneous subpopulations in NEPC provides novel insight into why finding effective treatments for these aggressive tumors is challenging. Future work should focus on further evaluation of common druggable pathways that are shared across NEPC subpopulations. Alternatively, efforts could look at combination therapies that could effectively target these heterogeneous tumors. Citation Format: Rosalia Quezada Urban, Shivakumar Keerthikumar, Ashlee K. Clark, Laura H. Porter, Mitchell G. Lawrence, Renea A. Taylor, Gail P. Risbridger, Roxanne Toivanen, David L. Goode. Single cell RNA analysis reveals heterogeneous sub populations in aggressive variants of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4076.