Develop and deploy a robust discovery platform that encompasses heterogeneity, clinical annotation, and molecular characterization and overcomes the limited availability of prostate cancer models. This initiative builds on the rich MD Anderson (MDA) prostate cancer (PCa) patient-derived xenograft (PDX) resource to complement existing publicly available databases by addressing gaps in clinically annotated models reflecting the heterogeneity of potentially lethal and lethal prostate cancer.
We performed whole-genome, targeted, and RNA sequencing in representative samples of the same tumor from 44 PDXs derived from 38 patients linked to donor tumor metadata and corresponding organoids. The cohort includes models derived from different morphologic groups, disease states, and involved organ sites (including circulating tumor cells), as well as paired samples representing heterogeneity or stages before and after therapy.
The cohort recapitulates clinically reported alterations in prostate cancer genes, providing a data resource for clinical and molecular interrogation of suitable experimental models. Paired samples displayed conserved molecular alteration profiles, suggesting the relevance of other regulatory mechanisms (e.g., epigenomic) influenced by the microenvironment and/or treatment. Transcriptomically, models were grouped on the basis of morphologic classification. DNA damage response-associated mechanisms emerged as differentially regulated between adenocarcinoma and neuroendocrine prostate cancer in a cross-interrogation of PDX/patient datasets.
We addressed the gap in clinically relevant prostate cancer models through comprehensive molecular characterization of MDA PCa PDXs, providing a discovery platform that integrates with patient data and benchmarked to therapeutically relevant consensus clinical groupings. This unique resource supports robust hypothesis generation and testing from basic, translational, and clinical perspectives.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2024 May 15 [Epub]
Nicolas Anselmino, Estefania Labanca, Peter D A Shepherd, Jiabin Dong, Jun Yang, Xiaofei Song, Subhiksha Nandakumar, Ritika Kundra, Cindy Lee, Nikolaus Schultz, Jianhua Zhang, John C Araujo, Ana M Aparicio, Sumit K Subudhi, Paul G Corn, Louis L Pisters, John F Ward, John W Davis, Elba S Vazquez, Geraldine Gueron, Christopher J Logothetis, Andrew Futreal, Patricia Troncoso, Yu Chen, Nora M Navone
Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, Texas., Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas., Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York., Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York., Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Química Biológica, Laboratorio de Inflamación y Cáncer, Buenos Aires, Argentina., Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.