Gene therapy for cancer using p53 hybrids that target the mitochondrial apoptotic pathway.

Ovarian cancer is one of the most lethal gynecological malignancies as it accounts for 1.3% of new cancer cases but over 5% of cancer deaths. The low survival rate of only 30% is due in large part to this cancer's ability to develop significant drug resistance to available chemotherapies. Studies have found that over 90% of ovarian cancers have mutations in the p53 suppressor gene, yet developing targeted therapies for ovarian cancer is difficult given the high heterogeneity of the cancer.

University of Utah researchers have developed a potential gene therapy for ovarian and other cancers that overcome the limitations of prior p53-based therapies. By fusing p53 with a pro-apoptotic sensitizer protein that targets the intrinsic mitochondrial apoptotic pathway, the dominant negative effects of p53 mutations can be bypassed. This fusion also ensures that both factors are present at the mitochondria, creating a potent therapy that can trigger apoptotic "collapse" by simultaneously activating both apoptotic pathways and inhibiting pro-survival pathways (cytochrome C release, caspase activation, etc.).

Concept

• Bypasses dominant negative inhibition seen with nuclear p53 therapies.
• Multiple mechanisms of action to bypass typical chemotherapy resistance mechanisms (efflux pumps, etc.).
• Potentially can be combined with other chemotherapies to increase treatment effectiveness regardless of genetic heterogeneity.

Lu P, et al. (2019). p53-Bad: A Novel Tumor Suppressor/Proapoptotic Factor Hybrid Directed to the Mitochondria for Ovarian Cancer Gene Therapy. Mol Pharmaceutics, 16(8), 3386-3398. doi: 10.1021/acs.molpharmaceut.9b00136

Bowman K, et al. (2019). Narrowing the field: cancer-specific promoters for mitochondrially-targeted p53-BH3 fusion gene therapy in ovarian cancer. J Ovarian Res, 30; 12(1): 38. doi: 10.1186/s13048-019-0514-4

Publication Number: US-2019-0367573-A1
Patent Title: p53-BH3 hybrids for cancer gene therapy
Jurisdiction/Country: United States
Application Type: Non-Provisional

Jason Young
(801) 587-0519
jason.r.young@utah.edu