The overall objective of the proposed project is to harness a newly discovered, active transendothelial transport pathway, the caveolae pumping system, to provide an effective solution to the delivery and toxicity problem of chemotherapeutics in metastatic breast cancer treatment. We propose to develop novel antibody- drug conjugates (ADCs) that exploit our newly discovered endothelial cell (EC) caveolae targeting system in order to improve the delivery and targeting of modern chemotherapeutics. We have established that EC caveolae in preclinical models can rapidly and specifically pump Annexin A1 (AnnA1) antibodies and attached cargo across the vascular endothelial barrier directly into solid tumors. Based on this discovery, we propose to design novel EC caveolae-targeted ADCs that may revolutionize treatments for metastatic breast cancer. We have created a robust delivery platform by arming hAnnA1 with amatoxins, a class of ultra-potent toxins that can effectively kill both rapidly dividing and dormant tumor cells. These include ?-Amanitin, a toxin derived from the ?death cap? mushroom and Chaetocin, an anti-proliferative, broad-spectrum toxin derived from the filamentous fungus Chaetomiun sp. Our main hypothesis is that caveolae-targeted antibody-drug conjugates (CTAs), will dramatically increase delivery of ultra-potent toxins specifically into tumors, thereby requiring much lower dosages and dramatically enhancing efficacy of cancer treatment. This hypothesis will be tested by the following specific aims:
In Aim 1, we will design and characterize novel hAnnA1-toxin CTAs. We will optimize their physicochemical properties, stability, release kinetics in the tumor interstitium, and binding affinity towards the human Annexin A1 protein.
In Aim 2, we will evaluate therapeutic efficacy, drug delivery and off-target effects of candidate CTAs in human tumor models of breast cancer using intravital microscopy (IVM).
In Aim 3, we will examine the therapeutic efficacy of the select CTAs in metastatic tumor models and in patient-derived xenograft (PDX) models. We will also prepare a foundation for clinical testing, where successful targeted therapeutics will be selected as candidates for future Phase 1 safety trial. Tumor targeting, delivery and accumulation of these novel therapies will be assessed in rodents using x-ray/CT imaging, IVM, and histology. The long-term goal is to translate our key basic discoveries into a unique, innovative delivery platform that may vastly improve treatments for solid cancers.

Public Health Relevance

) The goal of this project is to develop safer and more effective treatments for primary and metastatic breast cancer by taking advantage of our recent discovery of a mechanism to pump molecules specifically into breast tumors. We aim to revolutionize breast cancer treatments by linking the AnnA1 antibody, the first antibody that rapidly and actively penetrates solid tumors, to novel, ultra-potent toxins that kill both rapidly dividing and dormant, stem-like tumor cells. We expect that by improving the targeted delivery of toxins directly into primary and metastatic tumors we will significantly increase drug potency and efficacy as well as reduce side toxicities for patients and the likelihood of recurrent cancers.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Developmental Therapeutics Study Section (DT)
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Fu, Yali
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Proteogenomics Research Institute/Sys/ Med
La Jolla
United States
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