Novel therapeutic interventions for p53-altered tumors through manipulation of its family members, p63 and p73

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 DN isoforms. We recently demonstrated that deletion of either DNp63 or DNp73 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 DNp63 and DNp73 in combination accelerates tumor regression and increases survival of p53-deficient mice. We report that inhibition of both DNp63 and DNp73 in combination results in upregulation of 3 key metabolic regulators, IAPP, GLS2, and TIGAR resulting in an increase in apoptosis and tumor regression in DNp63/DNp73/p53 deficient thymic lymphomas. These data highlight the value of generating inhibitors that will simultaneously target DNp63 and DNp73 to treat cancer patients with alterations in p53.

The p53 family orchestrates the regulation of metabolism: physiological regulation and implications for cancer therapy

“…Independently of p53, both TAp63 and TAp73 can achieve the same effect through the induction of IAPP (Venkatanarayan et al , 2015); its gene product amylin is an inhibitor of hexokinase II preventing G6P formation and utilisation for the PPP. The relevance of amylin's tumour suppressive and preventive activity was demonstrated by its synthetic analogue pramlintide, an FDA approved antidiabetic drug that leads to tumour regression in p53−/− mice (Venkatanarayan et al , 2015, 2016). …”

“…As tumour regression associated with loss of Δ Np63 is also accompanied by metabolic reprogramming (Venkatanarayan et al , 2015), it would be interesting to verify whether the therapeutic activity of HDACi may partially rely on alterations in metabolism caused by the reactivation of TAp63 and TAp73. Once these two transcription factors are released from the inhibition of a dominant negative member of the family (namely mutant p53, ΔNp63, or ΔNp73), they induce the expression of IAPP , whose synthetic analogue, pramlintide, was proven to act as a potent anticancer drug in preclinical models (Venkatanarayan et al , 2015, 2016). …”

Reactivation of TAp73 tumor suppressor by protoporphyrin IX, a metabolite of aminolevulinic acid, induces apoptosis in TP53-deficient cancer cells

“…Acute genetic ablation of ∆N isoforms triggers rapid regression of thymic lymphomas developed in p53-null mice 18 . Thus, deletion of ∆Np63 or ∆Np73 can compensate for p53 tumor suppression in thymic lymphomas, and this occurs due to accumulation of TA isoforms of p63 and p73 and induction of apoptosis 19 . Therefore, accumulated TAp73, similarly to p53, can be considered a promising therapeutic target in tumors deficient or mutant for TP53 gene.…”

Silencing E3 Ubiqutin ligase ITCH as a potential therapy to enhance chemotherapy efficacy in p53 mutant neuroblastoma cells

“…Attempts to restore or reactivate the wide-type p53 function for tumour therapy [9][10][11][12][13][14] are under investigation but it may be possible to utilize alternative pathways to compensate for the missing p53 function [15][16][17] . TP73 is a homologous molecule of p53 and shares significant sequence similarity particularly in the DNA binding domain (DBD), activation domain (AD) and tetramerization domain (TD) 18 .…”