Combinatorial Inactivation of ERBB Receptors in Breast Cancer using Therapeutic Stapled Peptides

DESCRIPTION provided by applicant In metastatic breast cancer the Epidermal Growth Factor Receptor family of transmembrane tyrosine kinases ErbB drives proliferation and metastasis EGFR HER and ErbB are known to be highly expressed and active in both the HER and Triple Negative Basal subtypes of breast cancer and have been targeted with varying effectiveness Importantly targeting of a single receptor member typically results in activity in the remaining receptor members making simultaneous targeting of all receptors a needed therapeutic development Furthermore while the tyrosine kinase domain of these receptors is a significant driver of transformation kinase inhibitors fail to induce cell death indicating that a non kinase function of the ErbB receptors is important in driving cancer progression While the tyrosine kinase activity of these receptors is well known less appreciated are the non canonical activities of this family including the modulation of mitochondrial function calcium signaling and nuclear translocation and activity as transcriptional co factors These functions are regulated simultaneously by the juxtamembrane domains JD of the ErbB receptors which are also responsible for active homo and hetero dimerization The non kinase JD forms anti parallel dimers between the receptors upon ligand binding resulting in receptor transphosphorylation Calmodulin activation intracellular trafficking of the receptors and signal transduction These functions drive ErbB dependent survival migration growth and therapeutic resistance We have previously demonstrated that peptides mimicking this JD can act in a dominant negative fashion promoting the formation of non functional ErbB dimers consisting of EGFR HER and ErbB that induce rapid ErbB dependent cell death Using Cell Penetrating Peptides synthesized in tandem with the JD EJ peptides rapidly cross the plasma membrane bind the ErbB receptors and induce cell death in cell lines and PDX lines grown in culture Death results from a combination of apoptotic and necrotic mechanisms due to inactivation of ErbB kinases and modulation of mitochondrial and calcium signaling Initial results showed that although these peptides display rapid ErbB dependent cell death in vitro the peptides have moderate efficacy in vivo To stabilize in vivo activity the active peptide which is an alpha helix was stabilized with hydrocarbon staples SAH EJ resulting in a fold increase in the activity of the peptide Based on these data we hypothesize that SAH EJ will serve as an effective and stable therapeutic for the treatment of ErbB dependent breast cancer We plan to investigate this hypothesis by Performing the preliminary in vivo Pharmacokinetics studies for SAH EJ and Determining the activity of SAH EJ in PDX models of metastatic breast cancer that express EGFR HER and or ErbB PUBLIC HEALTH RELEVANCE Arizona Cancer Therapeutics LLC ACT proposes a preclinical research project to develop a new anti cancer drug EJ This therapeutic has been shown to block specific interactions that drive EGFR signaling for tumor growth and spread of metastatic breast cancer This innovative drug targets a domain outside of the kinase domain of EGFR making it highly unique as well as less toxic than current standard of care It has been validated using in vivo models and an optimized formulation will be tested in the proposed studies This work is vital to advance the drug through IND enabling work FDA approval and commercialization This type of breast cancer results in deaths in the U S every year and therefore by advancing this unique anti tumor drug aligns ACTandapos s efforts to the National Institute of Healthandapos s mission to enhance health lengthen life and reduce the burden of illness and disability