Antibodies against receptor tyrosine kinases form an important and effective class of therapeutics for breast cancer. However, the majority of patients with metastatic breast cancer who initially respond to antibody therapy eventually develop resistance. This clinical problem calls for the development of alternative biologics for the treatment of breast cancer. Because SH2 domains form important nodes in tyrosine kinase signaling, they represent valuable targets for the development of alternative therapies. However, a typical SH2-phosphotyrosine target interaction is 2-3 orders of magnitude weaker than an antibody-antigen interaction. This moderate binding affinity for a natural SH2 domain has so far impeded the development of SH2 domain-based therapies. In collaboration with the Sidhu lab (Toronto), we have recently identified several SH2 variants, called “superbinders”, that are capable of binding to physiological phosphotyrosine (pTyr) targets with markedly enhanced affinities than the natural counterpart. Because these superbinders potently inhibit EGFR/HER2 activity, they are promising alternatives to therapeutic antibodies by targeting intracellular phosphotyrosine signaling pathways.
We are developing peptide and protein microarrays that allow for systematic characterization of the PTM network associated with individual forms of cancer for accurate disease diagnosis and precise treatment.