Molecular Innovations toward Theranostics of Aggressive Prostate Cancer.
DOD Synergistic Idea Award W81XWH-12-1-0336 (Initiating PI: Sun; Partner PIs: Hsieh/Simanek)
Project goal: To construct biocompatible theranostic agents containing specific targeting molecules, therapeutic agents, and an imaging moiety for detection and therapy of advanced prostate cancer.
Project description: This project combines the recent advances in prostate cancer PCa research from three different labs integrated with a strong interest and dedication to develop a new molecular medicine approach towards the eventual cure of PCa. The synergistic effort and productivities of the three PIs are obvious in their recent joint publications in the field of PCa research (as well as their joint extramural grants): i) metastasis is the main cause of cancer-related deaths. While metastasis is a complex process, published data indicate that cancer cells undergo epithelium-to-mesenchymal transition (EMT), in which cells become motile and acquire invasiveness to the surrounding tissue upon the initiation of metastasis.
Recently, we have demonstrated that EMT can be reversed to prevent PCa metastasis by DAB2IP, which was firstly identified by the Hsieh lab (partnering PI) as a DOC-2/DAB2 interactive protein that is a tumor suppressor associated with several cancer types; ii) protein-protein interaction via specific function domain is critical for many cell physiologic function. For example, proline-rich (PR) domain is known to interact with an SH3 domain and both sequences appear in many proteins often involved in signal transduction. However, the specificity and affinity of PR domain is still largely unknown. In the past years, the extensive work published by the Hsieh lab has shown that the specific binding of PR domain to Grb2, Src or PI3K, results in inhibiting these proteins activities. Furthermore, peptides derived from these domains and transfected into cells exhibited a similar binding affinity and biologic activities as the native protein; iii) To increase the cell delivery efficiency of the therapeutic peptides, the Sun and Hsieh labs evaluated the uptake efficient of four different cell permeable peptides (CPP) by various PCa cell lines. Among them, a polyarginine peptide sequence appears to be the most potent CPP for several PCa cell lines and can be utilized for specific imaging of metastatic PCa; iv) the Simanek lab at Texas Christian University has pioneered the design and synthesis of triazine dendrimers.
Lead dendrimer platforms have been subjected to a barrage of assays to establish safety and have passed all to date. In the past years, the three PIs have engaged in the comprehensive evaluation of triazine dendrimers for drug delivery. Impressively, the dendrimer prodrugs with paclitaxel have shown tumor growth inhibition and/or regression as a function of dose and linker chemistry. This project was proposed to take advantage of this unique dendrimer nanoscaffold system to present the therapeutic peptides, the prostate specific molecules, and a PET imaging reporter so as to develop a novel theranostic agent system for aggressive PCa.
Significant to these studies is the advancement of a promising platform with far-reaching potential in a clinical model for either/both diagnosis and therapy. The ability to exquisitely and unambiguously control the chemistry associated with the platform is paramount to success. Specifically, the Simanek lab makes dendrimers that bear functional handles for conjugation with imaging agents (Sun) and DAP2IP-based therapeutic peptides (Hsieh). These PIs with different disciplinary from synthetic chemistry, radiochemistry and imaging, and molecular cell/tumor biology have been working side-by-side on developing the proposed theranostic agent system.