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**BBI608 + pemetrexed + cisplatin** is a combination therapy consisting of three agents:\ \ - **BBI608 (napabucasin):** an orally available small molecule derived from natural naphthoquinones, primarily developed as a cancer stem cell inhibitor. It acts by inhibiting signal transducer and activator of transcription 3 (STAT3), NAD(P)H:quinone oxidoreductase 1 (NQO1), and thioredoxin reductase 1 (TrxR1), among other targets, leading to suppressed cancer cell proliferation, induced apoptosis, reduced cancer stemness, increased reactive oxygen species, and radiosensitization. \ - **Pemetrexed:** a folate antimetabolite chemotherapy drug, administered intravenously, which inhibits multiple enzymes involved in folate metabolism and DNA synthesis, resulting in anti-proliferative and cytotoxic effects against tumor cells. \ - **Cisplatin:** a platinum-based chemotherapy agent, administered intravenously, that forms DNA crosslinks causing apoptosis in rapidly dividing cancer cells.\ \ This regimen is under investigation for the first-line treatment of **malignant pleural mesothelioma (MPM)** and has also been tested in non-small cell lung cancer (NSCLC) in early-phase trials. The rationale is based on the potential synergistic anticancer effects of the stemness inhibitor napabucasin with established cytotoxics pemetrexed and cisplatin[1][2][3][5][6][7].
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