Novel therapeutic interventions for p53-altered tumors through manipulation of its family members, p63 and p73. Issue 2 (17th January 2016)

• Record Type: Journal Article
• Authors: Venkatanarayan, Avinashnarayan; Raulji, Payal; Norton, William; Flores, Elsa R.
• Is Part Of: Cell cycle. Volume 15:Issue 2(2016)
• Page Start: 164
• Page End: 171
• Publication Date: 2016-01-17
• Subjects: p53 family; targeted therapy; tumor suppressors; Cell cycle -- Periodicals; 571.84377
• DOI: 10.1080/15384101.2015.1121333
• Languages: English
• ISSNs: 1538-4101

Abstract

ABSTRACT: TP53 is highly mutated in human cancers, thus targeting this tumor suppressor pathway is highly desirable and will impact many cancer patients. 1, 2 Therapeutic strategies to reactivate the p53-pathway have been challenging, 3, 4 and no effective treatment exists. 5 We utilized the p53-family members, p63 and p73, which are not frequently mutated in cancer, to treat p53-defective cancers. The N-terminal splice variants of p63 and p73 are denoted as the TA and ΔN isoforms. We recently demonstrated that deletion of either ΔNp63 or ΔNp73 in p53 -deficient mouse tumors results in tumor regression mediated by metabolic programming. Using this strategy, we identified pramlintide, a synthetic analog of amylin, as an effective treatment for p53 deficient and mutant tumors. Here, we show the utility of using pramlintide, as a potential cancer preventive option for p53-deficient tumors in mouse models. Additionally, we found that in vivo inhibition of both Δ Np63 and Δ Np73 in combination accelerates tumor regression and increases survival of p53- deficient mice. We report that inhibition of both ΔNp63 and ΔNp73 in combination results in upregulation of 3 key metabolic regulators, IAPP, GLS2, and TIGAR resulting in an increase in apoptosis and tumor regression in Δ Np63/ΔNp73/p53 deficient thymic lymphomas. These data highlight the value of generating inhibitors that will simultaneously target ΔNp63 and ΔNp73 to treat cancer patients with alterations in p53.