Phosphoprotein-based biomarkers as predictors for cancer therapy

Angela M. Carter, Chunfeng Tan, Karine Pozo, Rahul Telange, Roberto Molinaro, Ailan Guo, Enrica De Rosa, Jonathan O. Martinez, Shanrong Zhang, Nilesh Kumar, Masaya Takahashi, Thorsten Wiederhold, Hans K. Ghayee, Sarah C. Oltmann, Karel Pacak, Eugene A. Woltering, Kimmo J. Hatanpaa, Fiemu E. Nwariaku, Elizabeth G. Grubbs, Anthony J. GillBruce Robinson, Frank Gillardon, Sushanth Reddy, Renata Jaskula-Sztul, James A. Mobley, M. Shahid Mukhtar, Ennio Tasciotti, Herbert Chen, James A. Bibb

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)18401-18411
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number31
DOIs
StatePublished - Aug 4 2020

Keywords

  • Cyclin-dependent kinase 5
  • Neuroendocrine tumors
  • Predictive biomarkers

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Phosphoprotein-based biomarkers as predictors for cancer therapy'. Together they form a unique fingerprint.

Cite this