title: 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 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 ΔNp63 and ΔNp73 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 ΔNp63/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.
authors.affiliation: a Department of Molecular and Cellular Oncology , The University of Texas M.D. Anderson Cancer Center , Houston , TX , USA.|b Department of Translational Molecular Pathology , The University of Texas M.D. Anderson Cancer Center , Houston , TX , USA.|c Graduate School of Biomedical Sciences, The University of Texas M.D. Anderson Cancer Center , Houston , TX USA.
authors.forename: Avinashnarayan
authors.initials: A
authors.lastname: Venkatanarayan
authors.affiliation: b Department of Translational Molecular Pathology , The University of Texas M.D. Anderson Cancer Center , Houston , TX , USA.|c Graduate School of Biomedical Sciences, The University of Texas M.D. Anderson Cancer Center , Houston , TX USA.
authors.forename: Payal
authors.initials: P
authors.lastname: Raulji
authors.affiliation: d Department of Veterinary Medicine and Surgery , The University of Texas M.D. Anderson Cancer Center , Houston ; TX , USA.
authors.forename: William
authors.initials: W
authors.lastname: Norton
authors.affiliation: a Department of Molecular and Cellular Oncology , The University of Texas M.D. Anderson Cancer Center , Houston , TX , USA.|b Department of Translational Molecular Pathology , The University of Texas M.D. Anderson Cancer Center , Houston , TX , USA.|c Graduate School of Biomedical Sciences, The University of Texas M.D. Anderson Cancer Center , Houston , TX USA.
authors.forename: Elsa R
authors.initials: ER
authors.lastname: Flores
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D058228:Islet Amyloid Polypeptide / Q000819:agonists / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D008223:Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics*; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics*; D010744:Phosphoric Monoester Hydrolases; D011506:Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D013953:Thymus Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics*; D000637:Transaminases / Q000235:genetics / Q000378:metabolism; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics*
chemical_list: D016588:Anticarcinogenic Agents; D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D007004:Hypoglycemic Agents; D058228:Islet Amyloid Polypeptide; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011506:Proteins; C000606460:TP73 protein, human; D015534:Trans-Activators; C486419:Trp63 protein, mouse; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C000606369:delta Np73 protein, human; C105254:pramlintide; D000637:Transaminases; C020656:glutamine-pyruvate aminotransferase; D010744:Phosphoric Monoester Hydrolases; C554952:TIGAR protein, mouse
keywords: p53 family; targeted therapy; tumor suppressors