Ted Hupp: Developing New Approaches For The Next Generation of Drug Discovery In Cancer
Drugging protein-protein interactions to activate the p53 tumour suppressor
Discovering protein-protein interactions (PPIs) remains a major challenge in the life sciences. The emerging view is that drugging PPIs remains an unexplored landscape in the drug discovery field. We focus on two oncoproteins that inhibit p53 function through chaperonin activities. In addition to studying signals that drive allosteric MDM2 protein-protein landscape changes (Way et al., 2016; Proteomics. 16:2327-44), we are also targetting the hexameric AAA+ superfamily of chaperonins. New chemical tools have been developed that target the ATP pocket of Ruvbl2/Reptin and we are exploring impacts of such drug-leads on Reptin oligomerization and p53 reactivation (Healy et al., Discovery of a novel ligand that modulates the protein–protein interactions of the AAA+ superfamily oncoprotein reptin, 2015; Chemical Science, 6: 3109-3116).
Secretory pathway as a driver in oesophageal cancer
Genomics and proteomics (e.g. proteogenomics) are emerging as key technologies to identify mechanisms of oesophageal cancer development and drug resistance. Such approaches have been used to identify a dominant endoplasmic-reticulum resident molecular chaperone (Anterior Gradient-2 (AGR2)) that is upregulated in a large number of human cancers. Three biological paradigms have emerged from studies on AGR2. AGR2 assembles the dorso-anterior ectoderm that forms the cement gland mediating the attachment of growing epithelium to a solid support. This “adhesion” function of AGR2 is used to drive cancer metastasis. Secondly, AGR2 can mediate limb regeneration. This cell migration property of AGR2 in limb regeneration is exploited in human cancer cell invasion. Third, AGR2-null animals are defective in mucin production, have alterations in asthma incidence, and are primed to develop inflammatory bowel disease. AGR2 sculpts the receptor landscape that can in turn be exploited as an oncogenic signal. The lab is therefore developing therapeutic approaches to target the AGR2 pathway (Brychtova et al., Mechanisms of AGR2 function and regulation in cancer, Seminars in Cancer Biology, 2015; 33:16-24)
Immunotherapeutics, monoclonal antibodies, and vaccinology platforms
Immunotherapies are emerging as potentially revolutionary in precision and personalized anti-cancer therapeutics. This form of treatment acts by reawakening the patients own immune system to eradicate cancer as it would an invading foreign pathogen. As such novel monoclonal antibodies are being developed targetting immune blockade receptors to support development of new preclinical models including those at the canine-human interface. In addition, proteogenomics vaccinology platforms are being used to build a deeper reservoir from which to identify tumour specific antigens. Key scientific questions include: 1. What are the sources of tumour-specific neoantigens that emerge from exon mutations, indels, and novel DNA fusions, production of pioneer translation products from introns/UTRs, and translation of RNA editing events?; 2. To what extent are the sources of tumour specific neoantigens different within a primary tumour mass?; and 3. Can we develop human tumour:immune synapse cell models for optimizing neoantigen discovery? Together these technology platforms aims to advance anti-cancer immunotherapies and vaccinology treatments (Jain et al., The Development of a Recombinant scFv Monoclonal Antibody Targeting Canine CD20 for Use in Comparative Medicine; 2016; PLOS ONE, 11:e0148366. doi: 10.1371/journal.pone.0148366.