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Novel regulatory molecules in tumor immunity and cancer immunotherapy

The traditional cancer therapy is organ- and tissue-based, which has been ineffective in terms of cure rate, and which also frequently leads to therapy resistance and disease relapse. Recently, more common genetic features across cancer types are beginning to come to light by extensive genomic information now available on tumors. A new paradigm is thus emerging that combinations of a few key mutations in critical biological pathways may underlie broad arrays of malignant development and aggression. Targeting these common and vital points of tumorigenic regulation may yield much greater impact on cancer therapy across the spectrum than aiming at narrowly focused, individual cancer specific targets, if systemic toxicity can be avoided. Our recent clinical and laboratory investigations have identified UBR5, a novel HECT domain E3 ubiquitin ligase of fundamental importance, as an essential cross-cancer regulator of tumorigenesis and anti-tumor immunity. UBR5 gene alterations (predominantly amplifications and overexpression) occur in ~45% of prostate cancer, 25-35% of breast and ovarian cancers, close to 20% of bladder, liver, uterine, and stomach cancers, and in 10% of many other types of solid tumors. In addition, genetic lesions in UBR5 have been found strongly associated with reduced survival of breast, ovarian, prostate, and pancreatic cancer patients. Yet, how UBR5 promotes cancer progression is highly obscure. We and our collaborators are using state of the art technologies, unconventional and creative experimental strategies to explore the pathophysiology and immunobiology of this mysterious molecule of great clinical potentials. We are exploring UBR5’s immunological role and identify “neoantigens” induced in UBR5-targeted tumors that may trigger T cell responses for prospective cancer vaccine development and immunotherapy. Targeting the UBR5 pathway will not only bring immediate clinical benefits to patients of a wide array of highly aggressive and therapy-resistant malignancies by abrogating cancer growth and metastasis, but also lead to immune activation that will result in the generation of T cell memories and delicate immunosurveillance against cancer recurrence and drug resistance.

Specific projects: (1) to investigate how UBR5 promotes tumor metastasis by regulating epithelial to mesenchymal transition (EMT) in a cell intrinsic manner; (2) to identify UBR5’s E3 ligase substrates and interacting protein partners; (3) to identify potential “neoantigens” induced in UBR5-deficient tumors that trigger T cell responses for future cancer vaccine development and immunotherapy; (4) to identify prototypical molecular “degraders” of UBR5 via Proteolysis Targeting Chimera (PROTAC).