Symposium



Noninvasive measurement of PI3K pathway signaling in GBM and prostate models


Presenting Author Senior Author
Name: Charles Truillet Name: Michael Evans
Email: charles.truillet@ucsf.edu Email: michael.evans@ucsf.edu
Presenting Author’s RIG/SRG: Prostate Cancer  
Presenting Author's Lab Location: China Basin   

Abstract Information
Imaging Modality: PET/SPECT
Disease Application: Brain Cancer Prostate Cancer
Complete author list: Charles Truillet, Sergio Wong, John T. Cunningham, Davide Ruggero, Jason S. Lewis, Michael J. Evans
Abstract highlights: We are evaluating the use of 89Zr-Tf as a biomarker of PI3K pathway activation, and as a marker of response to PI3K-directed therapies. The long-term goal of this research is to incorporate 89Zr-Tf alongside other non-invasive technologies to improve the future evaluation of experimental therapies.
 
Introduction
Over the past decade, molecular profiling programs have identified subclasses of tumors bearing distinct genetic signatures. Among these, a defining molecular event in GBM and prostate cancer is the inactivation of the tumor suppressor PTEN—occurring in ~60% of patients—with upregulation of downstream signaling through the PI3K/Akt/mTOR axis. These insights have stimulated interest in developing highly potent PI3K pathway inhibitors, several of which have already shown encouraging preclinical activity. Nevertheless, it is currently difficult to predict patient response a priori with genetic markers, and a non-invasive technology that measures PI3K pathway output during therapy could substantially enhance our understanding of experimental therapies upon translation to the clinic.
 
Methods
To address the unmet need for a biomarker of this pathway, we have developed 89Zr-labeled transferrin (89Zr-Tf), a novel positron-emitting radiotracer. 89Zr-Tf is a radiotracer that binds the transferrin receptor, a molecule that is regulated by the PI3K/Akt/mTOR signaling axis. The preclinical characterization of this radiotracer shows specific uptake in PTEN null models.
 
Results
We showed that 89Zr-Tf can measure aberrant PI3K signaling in GBM and prostate models. Since loss of PTEN is the most common genetic event promoting aberrant PI3K signaling in GBM patients and prostate, we studied a collection a cell lines annotated for PTEN status. Specifically, we examine the effects of PTEN loss on 89Zr-Tf uptake with (i) isogenic pairs of human GBM and prostate cancer cell lines differing only in PTEN status. The goal of our second aim is to demonstrate that 89Zr-Tf is a biomarker of response to PI3K pathway inhibitors. We’ve applied one representative drug from two classes of PI3K pathway inhibitors, namely RAD001 an mTOR kinase inhibitor, and BEZ235, a dual PI3K/mTOR inhibitor. We will apply these drugs as single agent therapies at bioactive doses in vitro and in vivo to PC3 and U87MG, two human cell lines, the first a prostate cancer and the second a glioma model that are PTEN null and dependent on PI3K signaling. In vivo, animals was imaged with 89Zr-Tf at multiple time points post therapy to assess changes in tumor biology, prior to onset of tumor regression.
 
Conclusions
89Zr-Tf is a radiopharmaceutical with high avidity for the transferrin receptor (TFRC), a molecule that is regulated by the PI3K/Akt/mTOR signaling axis. 89Zr-labeled transferrin (89Zr-Tf) clearly can detect genetically-driven modulations in PI3K signaling in preclinical models of Glioblastoma Multiforme and Prostate Cancer models.