title: Preclinical validation of a novel compound targeting p70S6 kinase in breast cancer.
abstract: Breast cancer is a frequent and treatable disease. However, when recurrent, breast cancer often becomes refractory to therapy and progresses into metastatic forms that are typically incurable. Thus, understanding and targeting the critical pathways underlying breast cancer recurrence is urgently needed to eradicate primary disease and achieve better prognosis. Recently, we have demonstrated that the ribosomal protein p70S6K is activated in residual breast cancer cells as a result of post-surgical inflammation and that interfering with its activity in the peri-operative setting strongly suppresses recurrence in a mouse model. In order to develop clinically-exploitable treatments targeting p70S6K, we have tested a newly generated compound, called FS-115. FS-115 potently inhibited p70S6K1 (IC50 35nM) with high selectivity over other AGC kinases or PI3K pathway kinases. In vitro, treatment with FS-115 efficiently blocked p70S6K activity in breast cancer cell lines and impaired colony formation and anchorage independent growth. Pharmacokinetic profiling showed that FS-115 exhibited high oral bioavailability, optimal plasma distribution and high brain penetrance. In nude mice, FS-115 strongly suppressed tumor take-rate and primary tumor growth. Oral dosing with FS-115 in a peri-operative schedule was effective in decreasing local recurrence of breast cancer and a long-term treatment schedule was well tolerated and efficiently suppressed distant metastasis formation. Altogether, we propose that FS-115 might be a good candidate for the treatment of breast cancer patients at high risk to relapse.
  
  
  
  Our results confirm that inhibition of p70S6K represents a valuable opportunity for restraining loco-regional relapse and metastasis in breast cancer and identify in FS-115 a promising candidate-inhibitor to move from preclinical to clinical treatments.
authors.affiliation: Division of Molecular Oncology, CRO, National Cancer Institute, Aviano 33081, Italy.
authors.forename: Ilenia
authors.initials: I
authors.lastname: Segatto
authors.affiliation: Breast Surgery Unit, CRO, National Cancer Institute, Aviano 33081, Italy.
authors.forename: Samuele
authors.initials: S
authors.lastname: Massarut
authors.affiliation: Sentinel Oncology Limited, Cambridge, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Boyle
authors.affiliation: Division of Molecular Oncology, CRO, National Cancer Institute, Aviano 33081, Italy.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Baldassarre
authors.affiliation: Sentinel Oncology Limited, Cambridge, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Walker
authors.affiliation: Division of Molecular Oncology, CRO, National Cancer Institute, Aviano 33081, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Belletti
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors*
chemical_list: D047428:Protein Kinase Inhibitors; D038762:Ribosomal Protein S6 Kinases, 70-kDa
keywords: breast cancer; inhibitor; p70S6K; proliferation; recurrence; signaling pathway; survival