Abstract SY18-03: Therapeutically targeting the p53 pathway using miRNA-based approaches in mouse models of cancer

Abstract

Abstract The tumor suppressor gene, p53, is commonly mutated or lost in human cancer, and p53 reactivation has been shown to suppress tumors in-vivo. This strategy has proven difficult to implement therapeutically. One alternative strategy to overcome p53 loss is to manipulate the p53 family members, p63 and p73, which interact with p53 extensively to suppress tumorigenesis. Both p63 and p73 are composed of multiple isoforms. The isoforms can be placed into two groups: the TA isoforms, which structurally resemble p53 and act as tumor suppressors, and the ΔN isoforms, which bind to p53, TAp63, and TAp73 and inhibit their function, thus acting as oncogenes. Many current therapeutic strategies to target p53 focus on p53 solely, ignoring the existence of the other p53 family members. Over the last decade, we have learned that this family of genes acts together to suppress tumorigenesis and metastasis; therefore, a clear understanding of the cross talk between the p53 family as a whole is needed to effectively treat cancers with alterations in the p53 family of genes. Recently, my laboratory has shown that in vivo inactivation of ΔNp63 or ΔNp73 in the p53-deficient mouse model of thymic lymphoma leads to massive tumor regression and increased survival through upregulation of TAp63 and TAp73 and subsequent transactivation of a large network of genes and miRNAs identified through RNA sequencing (Venkatanarayan et al., Nature, 2014 Nov 17, doi: 10.1038/nature13910). Importantly, we have previously shown that Dicer and DGCR8 are transcriptional targets of p63 (Su et al., Nature, 2010 Oct 21;467(7318):986-90 and Chakravarti et al., Proc Natl Acad Sci U S A, 2014 Feb 4;111(5):E572-81. doi: 10.1073/pnas.1319743111). To identify inhibitors of ΔNp63 or ΔNp73 as a means to identify compounds that may be used to target the p53 pathway therapeutically, we screened a drug library of more than 850 FDA approved compounds. We found several small molecules that were able to reduce ΔNp63 protein stability and a specific set of miRNAs essential for the effectiveness of the drugs. In vivo analyses of these compounds as well as of these miRNA inhibitors have shown their efficacy in counteracting tumor formation and progression in genetically engineered mouse models deficient for p53 and in patient derived xenograft (PDX) mouse models with tumors that have p53 mutations. In summary, we have now identified multiple modalities to therapeutically target the p53 pathway through manipulation of p63 and p73. Citation Format: Elsa R. Flores. Therapeutically targeting the p53 pathway using miRNA-based approaches in mouse models of cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY18-03. doi:10.1158/1538-7445.AM2015-SY18-03