title: Evaluation of in vivo responses of sorafenib therapy in a preclinical mouse model of PTEN-deficient of prostate cancer.
abstract: BACKGROUND
  Despite recent advances in the treatment for advanced prostate cancer, outcomes remain poor. This lack of efficacy has prompted the development of alternative treatment strategies. In the present study we investigate the effects of the multikinase inhibitor sorafenib in a genetically engineered mouse model of prostate cancer and explore the rational combination with the mTOR inhibitor everolimus.
  
  
  METHODS
  Conditional prostate specific PTEN-deficient knockout mice were utilized to determine the pharmacodynamic and chemopreventive effects of sorafenib. This mouse model was also used to examine the therapeutic efficacy of sorafenib alone or in combination with everolimus. Preclinical efficacy was assessed by comparing the reduction of tumor burden, proliferation, angiogenesis and the induction of apoptosis. Molecular responses were assessed by immunohistochemical, TUNEL and western blot assays.
  
  
  RESULTS
  Pharmacodynamic analysis revealed that a single dose of sorafenib decreased activation of the PI3K/AKT/mTOR signaling axis at doses of 30-60 mg/kg, but activated JAK/STAT3 signaling. Levels of cleaved casapase-3 increased in a dose dependent manner. Chemoprevention studies showed that chronic sorafenib administration was capable of inhibiting tumor progression through the reduction of cancer cell proliferation, angiogenesis and the induction of apoptosis. In intervention models of established castration-naïve and castration-resistant prostate cancer, treatment with sorafenib provided modest but statistically insignificant reduction in tumor burden. However, sorafenib significantly inhibited cancer cell proliferation and MVD but had minimal effects on the induction of apoptosis. Interestingly, the administration of sorafenib increased the expression levels of the androgen receptor, p-GSK3β and p-ERK1/2 in castration-resistant prostate cancers. In both intervention models, combination therapy demonstrated a clear tendency of enhanced antitumor effects over monotherapy. Notably, the treatment combination of sorafenib and everolimus overcame therapeutic escape from single agent therapy in castration-resistant prostate cancers.
  
  
  CONCLUSIONS
  In summary, we provide insights into the molecular responses of sorafenib therapy in a clinically relevant model of prostate cancer and present preclinical evidence for the development of targeted treatment strategies based on the use of multikinase inhibitors in combination with mTOR inhibitors for the treatment of advanced prostate cancer.
authors.affiliation: Department of Urology, Kinki University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan. yutakyankunkun@yahoo.co.jp.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Department of Urology, Kinki University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan. mdev@med.kindai.ac.jp.|Department of Genome Biology, Kinki University Faculty of Medicine, Osaka-Sayama, 589-8511, Japan. mdev@med.kindai.ac.jp.
authors.forename: Marco A
authors.initials: MA
authors.lastname: De Velasco
authors.affiliation: Department of Urology, Kinki University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan. yurie.kinkiurology@ymail.com.
authors.forename: Yurie
authors.initials: Y
authors.lastname: Kura
authors.affiliation: Department of Urology, Kinki University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan. nozawa06@med.kindai.ac.jp.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nozawa
authors.affiliation: Department of Urology, Kinki University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan. yhkhch@yahoo.co.jp.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Hatanaka
authors.affiliation: Department of Urology, Kinki University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan. oki24otoko@yahoo.co.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Oki
authors.affiliation: Department of Urology, Kinki University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan. takayuki60210891@yahoo.co.jp.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ozeki
authors.affiliation: Department of Urology, Kinki University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan. shimizun@med.kindai.ac.jp.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Shimizu
authors.affiliation: Department of Urology, Kinki University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan. minami@med.kindai.ac.jp.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Minami
authors.affiliation: Department of Urology, Kinki University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan. yoshimur@med.kindai.ac.jp.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yoshimura
authors.affiliation: Promoting Center for Clinical Research, Aichi Medical University, School of Medicine, Nagakute, Aichi, 480-1195, Japan. yoshikaw@aichi-med-u.ac.jp.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yoshikawa
authors.affiliation: Department of Genome Biology, Kinki University Faculty of Medicine, Osaka-Sayama, 589-8511, Japan. knishio@med.kindai.ac.jp.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
authors.affiliation: Department of Urology, Kinki University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan. huemura@med.kindai.ac.jp.
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Uemura
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis; D049109:Cell Proliferation; D004195:Disease Models, Animal; D000068338:Everolimus / Q000008:administration & dosage; D005818:Genetic Engineering / Q000379:methods; D006720:Homozygote; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics*; D009389:Neovascularization, Pathologic; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D015398:Signal Transduction; D000077157:Sorafenib
chemical_list: D010671:Phenylurea Compounds; D009536:Niacinamide; D000068338:Everolimus; D000077157:Sorafenib; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse