title: Targeting mTOR and p53 Signaling Inhibits Muscle Invasive Bladder Cancer In Vivo.
abstract: Urothelial tumors, accompanied by mutations of the tumor suppressor protein TP53 and dysregulation of mTOR signaling, are frequently associated with aggressive growth and invasiveness. We investigated whether targeting these two pathways would inhibit urothelial tumor growth and progression. Six-week-old transgenic UPII-SV40T male mice (n = 15/group) were fed control diet (AIN-76A) or experimental diets containing mTOR inhibitor (rapamycin, 8 or 16 ppm), p53 stabilizing agent [CP31398 (CP), 150 ppm], or a combination. Mice were euthanized at 40 weeks of age. Urinary bladders were collected and evaluated to determine tumor weight and histopathology. Each agent alone, and in combination, significantly inhibited tumor growth. Treatment with rapamycin alone decreased tumor weight up to 67% (P < 0.0001). Similarly, CP showed approximately 77% (P < 0.0001) suppression of tumor weight. The combination of low-dose rapamycin and CP led to approximately 83% (P < 0.0001) inhibition of tumor weight. There was no significant difference in tumor weights between rapamycin and CP treatments (P > 0.05). However, there was a significant difference between 8 ppm rapamycin and the combination treatment. Tumor invasion was also significantly inhibited in 53% (P < 0.005) and 66% (P < 0.0005) mice after 8 ppm and 16 ppm rapamycin, respectively. However, tumor invasion was suppressed in 73% (P < 0.0001) mice when CP was combined with 8 ppm rapamycin. These results suggest that targeting two or more pathways achieve better treatment efficacy than a single-agent high-dose strategy that could increase the risk of side effects. A combination of CP and rapamycin may be a promising method of inhibiting muscle-invasive urothelial transitional cell carcinoma.
authors.affiliation: Center for Cancer Prevention and Drug Development, Hem-Onc Section, Department of Medicine, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Venkateshwar
authors.initials: V
authors.lastname: Madka
authors.affiliation: Center for Cancer Prevention and Drug Development, Hem-Onc Section, Department of Medicine, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Altaf
authors.initials: A
authors.lastname: Mohammed
authors.affiliation: Center for Cancer Prevention and Drug Development, Hem-Onc Section, Department of Medicine, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.affiliation: Center for Cancer Prevention and Drug Development, Hem-Onc Section, Department of Medicine, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Center for Cancer Prevention and Drug Development, Hem-Onc Section, Department of Medicine, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Laura
authors.initials: L
authors.lastname: Biddick
authors.affiliation: Center for Cancer Prevention and Drug Development, Hem-Onc Section, Department of Medicine, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Jagan M R
authors.initials: JM
authors.lastname: Patlolla
authors.affiliation: Center for Cancer Prevention and Drug Development, Hem-Onc Section, Department of Medicine, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Stan
authors.initials: S
authors.lastname: Lightfoot
authors.affiliation: Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma.
authors.forename: Rheal A
authors.initials: RA
authors.lastname: Towner
authors.affiliation: Department of Urology, NYU Medical Center, New York, New York.
authors.forename: Xue-Ru
authors.initials: XR
authors.lastname: Wu
authors.affiliation: Division of Cancer Prevention, Chemoprevention Agent Development Research Group, National Cancer Institute, Bethesda, Maryland.
authors.forename: Vernon E
authors.initials: VE
authors.lastname: Steele
authors.affiliation: Division of Cancer Prevention, Chemoprevention Agent Development Research Group, National Cancer Institute, Bethesda, Maryland.
authors.forename: Levy
authors.initials: L
authors.lastname: Kopelovich
authors.affiliation: Center for Cancer Prevention and Drug Development, Hem-Onc Section, Department of Medicine, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. cv-rao@ouhsc.edu.
authors.forename: Chinthalapally V
authors.initials: CV
authors.lastname: Rao
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D007249:Inflammation; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009132:Muscles / Q000473:pathology*; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D011073:Polyamines / Q000737:chemistry; D015398:Signal Transduction; D020123:Sirolimus / Q000737:chemistry; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D001743:Urinary Bladder / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D011073:Polyamines; D016159:Tumor Suppressor Protein p53; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus