Pazopanib and trametinib as a synergistic strategy against osteosarcoma: Preclinical activity and molecular insights

Receptor tyrosine kinases (RTKs) inhibitors’ activity in advanced osteosarcoma is significant but short-lived. To prevent or at least delay drug resistance, we explored a vertical inhibition by combining drugs acting at different levels of the RTK pathways (pazopanib + trametinib). We studied pazopanib + trametinib antitumor activity both in vitro and in vivo (MNNG-HOS and KHOS xenografts in NOD/SCID mice) investigating the molecular mechanisms and potential escapes. The involvement of MAPK-PI3K pathways was validated by Nanostring technology, western blot and by silencing/overexpression experiments. Pazopanib targets were expressed on seven osteosarcoma cell lines and their pathways were activated. Pazopanib + trametinib exhibited synergistic antitumor activity by inducing apoptosis and inhibiting ERK1/2 and Akt. In vivo antitumor activity was shown in osteosarcoma-bearing mice. The drug combination significantly down-modulated RTK Ephrin Type-A Receptor 2 (EphA2) and Interleukin-7 Receptor (IL-7R), whereas induced mitogen-activated protein-kinase kinase (MAPKK) MEK6. EphA2 silencing significantly reduced osteosarcoma cell proliferation and migration, while impeding MEK6 up-regulation in the treated cells significantly increased the antitumor effect of the studied drugs. Moreover, the up-regulation of MEK6 reduced combination activity. Pazopanib + trametinib demonstrated synergistic antitumor effects in osteosarcoma models through ERK and Akt inhibition and EphA2 and IL-7R down-modulation. MEK6 up-regulation might evoke escaping mechanism

Il problema obesit\ue0

INDICE: 1. Obesit\ue0: definizione di un problema. 2. L'obesit\ue0 come fattore di rischio per la salute. 3. Il piacere del cibo in un alettrua PNEI. 4. I comportamenti alimentari nell'obesit\ue0. 5. Emozioni e obesit\ue0. 6. Il rapporto con il proprio corpo nell'obesit\ue0. 7. Strumenti per l'analisi psicometrica dell'obesit\ue0. 8. Approcci alla gestione dell'obesit\ue0. 9. Obesit\ue0 e epistemologia relazionale. 10.Terapia cognitivo-comportamentale dell'besit\ue0. 11. Trattamento cognitivo-comportamentale dell'obesit\ue0: alcuni casi clinici. 12. La gestione dell'obesit\ue0 in cardiologia riabilitativa. 13. L'obesit\ue0 in et\ue0 evolutiva