Translational Cancer Research

We are targeting HER2+ve breast cancers and also prostate cancers. The research involves several Stanford scientists with expertise in prodrug therapies, bioimaging, oncology, breast cancer surgery, prostate cancer, blood-brain barrier characterization, biostatistics, a local industry, and (at SRI) pharmacologists, who will participate in eventual clinical trials. The research is part of a nationwide NIH NCATS consortium. We are using exosomes to deliver therapy specifically to breast tumors and metastasis to the brain. Exosomes/microvesilces, the body's " natural antigen delivery system " are vesicles secreted by most cells in the body. They have an abundant surface protein (Lamp2b) that can be conjugated to ligands such as those that specifically target overexpressed HER2 marker (breast cancer) and PSMA (prostate cancer); C1C2 domains of lactadherin can also be used for this purpose. Our industrial collaborators have developed XPack and XStamp technologies that permit, respectively, insertion of proteins of interest into the exosomes, and display of desired targeting ligands on exosome surface. We have used chemical, Ab (ScFv; larger antibodies), and aptamer ligands and have already achieved a degree of specific targeting; these are now being improving. More recently we have thoroughly investigated the nature of exosomes and other extracellular vesicles and their differential capacity to deliver biomolecules (see the PNAS early edition article, accessible via the Publication link). Three types of therapies are being developed. One is our newly discovered CNOB prodrug (a harmless compound) which has the advantage that its activated toxic product (MCHB) can be visualized non-invasively in living mice. This makes an 'observational approach' possible, and minimizes the need for mouse sacrifice and the use of more involved tests (e.g., LS/MS/MS) in preclinical work. We also discovered the CNOB activating enzyme and have improved it markedly using cutting edge technology. Follow these links to access relevant publications, as well as the article published in PNAS early edition (via the Publication link): The capacity to deliver the activating enzyme is conferred on the exosomes by mRNA DNA/protein loading. The second therapy is concerned with delivering microRNAs via targeting exosomes. By using bioinformatics we have identified several promising anti-cancer candidates and their specific delivery is being developed for both cancers. The third therapy uses specific single-chain fragment variable (ScFv) antibodies or full-length (FL) antibodies on their surface not only for specific targeting of exosomes but also as a therapeutic measure. Since exosomes can cross the blood-brain barrier, this will, if successful, overcomes …