TY - JOUR
T1 - The MD Anderson Prostate Cancer Patient-derived Xenograft Series (MDA PCa PDX) Captures the Molecular Landscape of Prostate Cancer and Facilitates Marker-driven Therapy Development
AU - Palanisamy, Nallasivam
AU - Yang, Jun
AU - Shepherd, Peter D.A.
AU - Li-Ning-Tapia, Elsa M.
AU - Labanca, Estefania
AU - Manyam, Ganiraju C.
AU - Ravoori, Murali K.
AU - Kundra, Vikas
AU - Araujo, John C.
AU - Efstathiou, Eleni
AU - Pisters, Louis L.
AU - Wan, Xinhai
AU - Wang, Xuemei
AU - Vazquez, Elba S.
AU - Aparicio, Ana M.
AU - Carskadon, Shannon L.
AU - Tomlins, Scott A.
AU - Kunju, Lakshmi P.
AU - Chinnaiyan, Arul M.
AU - Broom, Bradley M.
AU - Logothetis, Christopher J.
AU - Troncoso, Patricia
AU - Navone, Nora M.
N1 - Funding Information:
E. Efstathiou reports grants, personal fees, and non-financial support from Sanofi, Janssen, Astellas, Tolmar, and Bayer outside the submitted work. S.A. Tomlins reports grants, and personal fees from Astellas/Medivation [consultant for (with honoraria) and sponsored research agreement), personal fees from Janssen, and personal fees from Strata Oncology (co-founder of, equity holder in, prior consultant for, and current employee) outside the submitted work, and reports that the University of Michigan has been issued patents on ETS gene fusions in prostate cancer, on which S.A. Tomlins is a co-inventor and included in the royalty streams issued, licensed, and with royalties paid (The diagnostic field of use was licensed to Hologic/Gen-Probe Inc., which has sublicensed rights to Roche/Ventana Medical Systems). B.M. Broom reports grants from NIH during the conduct of the study. N.M. Navone reports grants from Prostate Cancer Foundation, The University of Texas MD Anderson Moon Shot Program, NCI Cancer Center Support Grant (P30CA16672), Cancer Center Prostate Cancer SPORE (NIH/NCI P50 CA140388-08), David H. Koch Center for Applied Research in Genitourinary Cancers at MD Anderson (Houston, TX), Janssen
Funding Information:
We thank Sarah E. Townsend for editing the article. We thank Agilent Technologies for the ?Agilent University Relations Grant Award to N. Palanisamy.? This work was supported by the Prostate Cancer Foundation, The University of Texas MD Anderson Moon Shot Program, NCI Cancer Center Support Grant (P30CA16672), Cancer Center Prostate Cancer SPORE (NIH/NCI P50 CA140388), David H. Koch Center for Applied Research in Genitourinary Cancers at MD Anderson (Houston, TX), Janssen Research and Development, and NIH/NCI U01 CA224044.
Funding Information:
We thank Sarah E. Townsend for editing the article. We thank Agilent Technologies for the “Agilent University Relations Grant Award to N. Palanisamy.” This work was supported by the Prostate Cancer Foundation, The University of Texas MD Anderson Moon Shot Program, NCI Cancer Center Support Grant (P30CA16672), Cancer Center Prostate Cancer SPORE (NIH/NCI P50 CA140388), David H. Koch Center for Applied Research in Genitourinary Cancers at MD Anderson (Houston, TX), Janssen Research and Development, and NIH/NCI U01 CA224044.
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/9/15
Y1 - 2020/9/15
N2 - Purpose: Advances in prostate cancer lag behind other tumor types partly due to the paucity of models reflecting key milestones in prostate cancer progression. Therefore, we develop clinically relevant prostate cancer models. Experimental Design: Since 1996, we have generated clinically annotated patient-derived xenografts (PDXs; the MDA PCa PDX series) linked to specific phenotypes reflecting all aspects of clinical prostate cancer. Results: We studied two cell line–derived xenografts and the first 80 PDXs derived from 47 human prostate cancer donors. Of these, 47 PDXs derived from 22 donors are working models and can be expanded either as cell lines (MDA PCa 2a and 2b) or PDXs. The histopathologic, genomic, and molecular characteristics (androgen receptor, ERG, and PTEN loss) maintain fidelity with the human tumor and correlate with published findings. PDX growth response to mouse castration and targeted therapy illustrate their clinical utility. Comparative genomic hybridization and sequencing show significant differences in oncogenic pathways in pairs of PDXs derived from different areas of the same tumor. We also identified a recurrent focal deletion in an area that includes the speckle-type POZ protein-like (SPOPL) gene in PDXs derived from seven human donors of 28 studied (25%). SPOPL is a SPOP paralog, and SPOP mutations define a molecular subclass of prostate cancer. SPOPL deletions are found in 7% of The Cancer Genome Atlas prostate cancers, which suggests that our cohort is a reliable platform for targeted drug development. Conclusions: The MDA PCa PDX series is a dynamic resource that captures the molecular landscape of prostate cancers progressing under novel treatments and enables optimization of prostate cancer–specific, marker-driven therapy.
AB - Purpose: Advances in prostate cancer lag behind other tumor types partly due to the paucity of models reflecting key milestones in prostate cancer progression. Therefore, we develop clinically relevant prostate cancer models. Experimental Design: Since 1996, we have generated clinically annotated patient-derived xenografts (PDXs; the MDA PCa PDX series) linked to specific phenotypes reflecting all aspects of clinical prostate cancer. Results: We studied two cell line–derived xenografts and the first 80 PDXs derived from 47 human prostate cancer donors. Of these, 47 PDXs derived from 22 donors are working models and can be expanded either as cell lines (MDA PCa 2a and 2b) or PDXs. The histopathologic, genomic, and molecular characteristics (androgen receptor, ERG, and PTEN loss) maintain fidelity with the human tumor and correlate with published findings. PDX growth response to mouse castration and targeted therapy illustrate their clinical utility. Comparative genomic hybridization and sequencing show significant differences in oncogenic pathways in pairs of PDXs derived from different areas of the same tumor. We also identified a recurrent focal deletion in an area that includes the speckle-type POZ protein-like (SPOPL) gene in PDXs derived from seven human donors of 28 studied (25%). SPOPL is a SPOP paralog, and SPOP mutations define a molecular subclass of prostate cancer. SPOPL deletions are found in 7% of The Cancer Genome Atlas prostate cancers, which suggests that our cohort is a reliable platform for targeted drug development. Conclusions: The MDA PCa PDX series is a dynamic resource that captures the molecular landscape of prostate cancers progressing under novel treatments and enables optimization of prostate cancer–specific, marker-driven therapy.
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U2 - 10.1158/1078-0432.CCR-20-0479
DO - 10.1158/1078-0432.CCR-20-0479
M3 - Article
C2 - 32576626
AN - SCOPUS:85094095815
SN - 1078-0432
VL - 26
SP - 4933
EP - 4946
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 18
ER -