A first-in-human phase I study to determine the maximum tolerated dose of the oral Src/ABL inhibitor AZD0424

BACKGROUND: Src is involved in cancer invasion and metastasis. AZD0424, an oral inhibitor of Src and ABL1, has shown evidence of anti-tumour activity in pre-clinical studies. METHODS: A phase Ia, dose escalation study was performed to assess the safety of continuous oral dosing with AZD0424 in advanced solid tumours. Secondary objectives included investigation of AZD0424 pharmacokinetics, effect on Src activity using markers of bone turnover, and anti-tumour activity. RESULTS: 41 patients were treated; 34 received AZD0424 once-daily at doses ranging from 5 mg to 150 mg, and 7 received 40 mg bi-daily 41.5% of patients experienced at least one AZD0424-related adverse event that was Grade 3-5 in severity, with patients treated at doses above 60 mg per day experiencing multiple treatment-related toxicities. The most commonly observed AZD0424-related adverse events were nausea, fatigue, anorexia and alopecia. Cmaxand AUC increased linearly with dose and the mean±standard deviation t1/2was 8.4±2.8 h. Clear evidence of Src target inhibition was seen at doses ⩾20 mg per day. No responses were observed and 7 patients (17.1%) achieved stable disease lasting 6 weeks or more. CONCLUSIONS: AZD0424 displayed no evidence of efficacy as monotherapy despite a clear pharmacodynamic effect. Further evaluation of AZD0424 monotherapy in patients with solid tumours is not recommended

Continental-scale geographic change across zealandia during paleogene subduction initiation

Data from International Ocean Discovery Program (IODP) Expedition 371 reveal vertical movements of 1-3 km in northern Zealandia during early Cenozoic subduction initiation in the western Pacific Ocean. Lord Howe Rise rose from deep (~1 km) water to sea level and subsided back, with peak uplift at 50 Ma in the north and between 41 and 32 Ma in the south. The New Caledonia Trough subsided 2-3 km between 55 and 45 Ma. We suggest these elevation changes resulted from crust delamination and mantle flow that led to slab formation. We propose a "subduction resurrection" model in which (1) a subduction rupture event activated lithospheric-scale faults across a broad region during less than ~5 m.y., and (2) tectonic forces evolved over a further 4-8 m.y. as subducted slabs grew in size and drove plate-motion change. Such a subduction rupture event may have involved nucleation and lateral propagation of slip-weakening rupture along an interconnected set of preexisting weaknesses adjacent to density anomalies

YB-1 is a transcription/translation factor that orchestrates the oncogenome by hardwiring signal transduction to gene espression

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