RT Journal Article
T1 Computational modeling identifies multitargeted kinase inhibitors as effective therapies for metastatic, castration-resistant prostate cancer
A1 Bello, Thomas
A1 Paindelli, Claudia
A1 Díaz Gómez, Luis
A1 Gujral, Taranjit S.
K1 Kinase
K1 Prostate cancer
K1 Computational modeling
K1 Combination therapy
AB Castration-resistant prostate cancer (CRPC) is an advanced subtype of prostate cancer with limited therapeutic options. Here, we applied a systems-based modeling approach called kinome regularization (KiR) to identify multitargeted kinase inhibitors (KIs) that abrogate CRPC growth. Two predicted KIs, PP121 and SC-1, suppressed CRPC growth in two-dimensional in vitro experiments and in vivo subcutaneous xenografts. An ex vivo bone mimetic environment and in vivo tibia xenografts revealed resistance to these KIs in bone. Combining PP121 or SC-1 with docetaxel, standard-of-care chemotherapy for late-stage CRPC, significantly reduced tibia tumor growth in vivo, decreased growth factor signaling, and vastly extended overall survival, compared to either docetaxel monotherapy. These results highlight the utility of computational modeling in forming physiologically relevant predictions and provide evidence for the role of multitargeted KIs as chemosensitizers for late-stage, metastatic CRPC.
PB National Academy of Sciences
YR 2021
FD 2021-09-30
LK https://hdl.handle.net/10347/43651
UL https://hdl.handle.net/10347/43651
LA eng
NO T. Bello,C. Paindelli,L.A. Diaz-Gomez,A. Melchiorri,A.G. Mikos,P.S. Nelson,E. Dondossola, & T.S. Gujral,  Computational modeling identifies multitargeted kinase inhibitors as effective therapies for metastatic, castration-resistant prostate cancer, Proc. Natl. Acad. Sci. U.S.A. 118 (40) e2103623118, https://doi.org/10.1073/pnas.2103623118 (2021)
NO This work was supported by the NIH/National Cancer Institute (NCI) (Grants K22CA201229, P30CA015704, 3 U24 CA209923-01S1, and P50CA097186). T.B. is a recipient of the Fred Hutch Interdisciplinary Training Grant Dual Mentor Fellowship in Cancer Research (T32CA080416). T.S.G. is supported in part by the NSF under Grant No. 2047289, Research Scholar Grant 133870-RSG-19-197-01-CDD from the American Cancer Soci- ety, the Translational Adult Glioma Award from The Ben and Catherine Ivy Foundation, and a Conquer Cancer Now Award from The Concern Founda- tion. P.S.N. is supported by the Pacific Northwest Prostate Cancer Specialized Program of Research Excellence (SPORE) CA097186 and Congressionally Di- rected Medical Research Programs Award W81XWH-18-1-0347. E.D. is sup- ported by the American Association for Cancer Research-Bayer Innovation and Discovery Grant and the MD Anderson Cancer Center Prostate Cancer SPORE (P50 CA140388-09). The Genitourinary Cancers Program of the Cancer Center Support Grant shared resources at MD Anderson Cancer Center and is supported by NIH/NCI Award P30 CA016672. The Center for Engineering Complex Tissue is supported by the NIH (Grant P41 EB023833). We thank Dr. Eva Corey and Dr. Nora Navone for providing PDX samples for ex vivo assays. We thank Dr. Milka Kostic, Dr. Andrew Hsieh, and Dr. Paul Corn for helpful comments on the manuscript.
DS Minerva
RD 24 abr 2026