TY - JOUR
T1 - Phosphoprotein-based biomarkers as predictors for cancer therapy
AU - Carter, Angela M.
AU - Tan, Chunfeng
AU - Pozo, Karine
AU - Telange, Rahul
AU - Molinaro, Roberto
AU - Guo, Ailan
AU - Rosa, Enrica De
AU - Martinez, Jonathan O.
AU - Zhang, Shanrong
AU - Kumar, Nilesh
AU - Takahashi, Masaya
AU - Wiederhold, Thorsten
AU - Ghayee, Hans K.
AU - Oltmann, Sarah C.
AU - Pacak, Karel
AU - Woltering, Eugene A.
AU - Hatanpaa, Kimmo J.
AU - Nwariaku, Fiemu E.
AU - Grubbs, Elizabeth G.
AU - Gill, Anthony J.
AU - Robinson, Bruce
AU - Gillardon, Frank
AU - Reddy, Sushanth
AU - Jaskula-Sztul, Renata
AU - Mobley, James A.
AU - Mukhtar, M. Shahid
AU - Tasciotti, Ennio
AU - Chen, Herbert
AU - Bibb, James A.
N1 - Funding Information:
for help with SEM, Kelly Hartman for assistance with leukosome preparation, John Totenhagen and Samuria Thomas and the University of Alabama at Birmingham (UAB) Small Animal Imaging Facility for additional MRI, and HMRI Intravital Microscopy Core for IVM. We thank Champions Oncology for PDX tissue and preclinical testing in PDX models, and Pfizer for CP681301. We thank Peter Kipp for collegial advice and support. We thank Eckard Wimmer for his contribution to this work. This work was supported by an American Cancer Society Postdoctoral Fellowship (A.M.C.) and the Sackler Foundation (A.M.C. and J.A.B.); a North American Neuroendocrine Tumor Society fellowship (K. Pozo); NIH award S10OD023552-01 (M.T.); an American Thyroid Association Research Grant and the Dedman Family Scholar in Clinical Care Award (S.C.O.); an American Cancer Society Institutional Research Grant Junior Faculty Development Award (S.R.) and the SDHB Pheo/Para Coalition (S.R. and J.A.B.); a North American Neuroendocrine Tumor Society/Neuroendocrine Tumor Research Foundation Basic/Translational Science Investigator Award (R.J.-S.); the William Randolph Heart Foundation, the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation, Cancer Prevention & Research Institute of Texas Award ID RP170466, and National Cancer Institute (NCI) and the Office of Research on Women’s Health Grant 1R56CA213859 (E.T.); an American Cancer Society Research Scholars Award, and NIH awards DA033485-01, MH083711-01, NS073855-01, and R56MH116896 (J.A.B.); and NCI awards 5P30CA142543 (UTSW Simmons Comprehensive Cancer Center) and P30CA013148 (UAB O’Neal Comprehensive Cancer Center).
Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.
PY - 2020/8/4
Y1 - 2020/8/4
N2 - Disparities in cancer patient responses have prompted widespread searches to identify differences in sensitive vs. nonsensitive populations and form the basis of personalized medicine. This customized approach is dependent upon the development of pathway-specific therapeutics in conjunction with biomarkers that predict patient responses. Here, we show that Cdk5 drives growth in subgroups of patients with multiple types of neuroendocrine neoplasms. Phosphoproteomics and high throughput screening identified phosphorylation sites downstream of Cdk5. These phosphorylation events serve as biomarkers and effectively pinpoint Cdk5-driven tumors. Toward achieving targeted therapy, we demonstrate that mousemodels of neuroendocrine cancer are responsive to selective Cdk5 inhibitors and biomimetic nanoparticles are effective vehicles for enhanced tumor targeting and reduction of drug toxicity. Finally, we show that biomarkers of Cdk5-dependent tumors effectively predict response to anti-Cdk5 therapy in patient-derived xenografts. Thus, a phosphoprotein-based diagnostic assay combined with Cdk5-targeted therapy is a rational treatment approach for neuroendocrine malignancies.
AB - Disparities in cancer patient responses have prompted widespread searches to identify differences in sensitive vs. nonsensitive populations and form the basis of personalized medicine. This customized approach is dependent upon the development of pathway-specific therapeutics in conjunction with biomarkers that predict patient responses. Here, we show that Cdk5 drives growth in subgroups of patients with multiple types of neuroendocrine neoplasms. Phosphoproteomics and high throughput screening identified phosphorylation sites downstream of Cdk5. These phosphorylation events serve as biomarkers and effectively pinpoint Cdk5-driven tumors. Toward achieving targeted therapy, we demonstrate that mousemodels of neuroendocrine cancer are responsive to selective Cdk5 inhibitors and biomimetic nanoparticles are effective vehicles for enhanced tumor targeting and reduction of drug toxicity. Finally, we show that biomarkers of Cdk5-dependent tumors effectively predict response to anti-Cdk5 therapy in patient-derived xenografts. Thus, a phosphoprotein-based diagnostic assay combined with Cdk5-targeted therapy is a rational treatment approach for neuroendocrine malignancies.
KW - Cyclin-dependent kinase 5
KW - Neuroendocrine tumors
KW - Predictive biomarkers
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U2 - 10.1073/pnas.2010103117
DO - 10.1073/pnas.2010103117
M3 - Article
C2 - 32690709
AN - SCOPUS:85089161523
SN - 0027-8424
VL - 117
SP - 18401
EP - 18411
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 31
ER -