title: Effects of Src kinase inhibition by saracatinib (AZD0530) on bone turnover in advanced malignancy in a Phase I study.
abstract: Saracatinib (AZD0530) is an orally active once-daily Src kinase inhibitor which modulates key signaling pathways in cancer cells. In a Phase I study in patients with advanced solid malignancies resistant to standard treatment we assessed the effect of saracatinib on bone turnover. Fifty-one patients were randomized into three parallel groups to receive saracatinib 50, 125 or 175 mg/day. After a single dose followed by a 7-day washout, patients received once-daily doses for 21 days. Bone turnover markers were measured in serum and urine samples collected before dosing on days 1, 2, 3, 17 and 28. Samples were available at baseline and more than one other time point for 44 patients. Bone resorption markers were significantly decreased by saracatinib. Serum cross-linked C-terminal telopeptide of type I collagen (sCTX) changed in the 50, 125 and 175 mg/day groups by -36% (95% CI -58, -4), -64% (95% CI -75, -48) and -75% (95% CI -83, -61), respectively, at day 28. Urinary cross-linked N-terminal telopeptide of type I collagen/creatinine ratio (uNTX/Cr) changed in the 50, 125 and 175 mg/day groups by; -13% (95% CI -33, 13), -48% (95% CI -59, -34) and -50% (95% CI -62, -35), respectively, at day 28. The significant decreases in bone resorption markers indicate that suppression of Src kinase inhibits osteoclast activity in patients with advanced cancer. This result suggests that saracatinib may have therapeutic benefit in metastatic bone disease.
authors.affiliation: Academic Unit of Bone Metabolism, University of Sheffield, Sheffield, UK.
authors.forename: Rosemary A
authors.initials: RA
authors.lastname: Hannon
authors.forename: Richard D
authors.initials: RD
authors.lastname: Finkelman
authors.forename: Glen
authors.initials: G
authors.lastname: Clack
authors.forename: Renee B
authors.initials: RB
authors.lastname: Iacona
authors.forename: Martin
authors.initials: M
authors.lastname: Rimmer
authors.forename: Fatma
authors.initials: F
authors.lastname: Gossiel
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.forename: Richard
authors.initials: R
authors.lastname: Eastell
mesh_terms: D000328:Adult; D000368:Aged; D052117:Benzodioxoles / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D016723:Bone Remodeling / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000503:physiopathology*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D011799:Quinazolines / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D055815:Young Adult; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D052117:Benzodioxoles; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C515233:saracatinib; D019061:src-Family Kinases