EAU 2017: Systems pharmacology and quantitative proteomics for developing targeted triple therapy

London, England (UroToday.com) Pathway specific inhibitors which block signaling pathways activated for solid tumor growth are being used to reduce tumor load. Despite this approach being successful, it is still challenging to predict which drug combinations will be the most potent. This study describes a novel approach combining systems pharmacology with targeted and quantitative proteomics for obtaining a list of candidate genes for subsequent short listing of triple target therapy.

The study was performed on metastatic prostate cancer model LNCaP. After generating a protein list of interest in prostate cancer (PLIPCa), tools for targeted proteomics approach were established and proteomic assays were developed. Later on, systems pharmacology and quantified perturbed proteomes using both triple quadruple and high mass accuracy mass spectrometers were used.

A systematic perturbation of androgen receptor and PI3K-AKT-mTOR signaling cascade with single and double combinations quantifying PLIPCa, using targeted proteomics, was performed. Proteomics results showed there were less potent drug combinations such as dasatinib and docetaxel. Most potent with the largest fold changes and highest statistical significance were dual pathway drug combinations such as enzalutamide and the AKT inhibitor MK2206. Results also showed that there were several proteins strongly regulated as a function of perturbation. The investigators hypothesized that a subgroup of these proteins were a common response of LNCaP cells to escape from treatment. This hypothesis was tested by inhibiting key proteins and found synergistic effects in the quantified proteome upon targeted triple treatment.

In conclusion, the investigators demonstrated a method that delivers rapidly testable working hypothesis for triple targeted combination therapy. In early metastatic prostate cancer cell line LNCaP, synergistic proteome changes upon triple targeted treatment were found. The extension of PLIPCa by proteins with large fold change and statistical significance is a potential interest for monitoring targeted therapy in prostate cancer.

Speaker: Dr. Ebhardt H.A., Root A., Beizaei A., Liu Y., Gauthier N., Sander C., Aebersold R.

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto

at the #EAU17 - March 24-28, 2017- London, England