Dual targeting of phosphoinositide 3-kinase and mammalian target of rapamycin using NVP-BEZ235 as a novel therapeutic approach in human ovarian carcinoma.

This study evaluates the effect of dual PI3K and mTOR inhibition using NVP-BEZ235 in preclinical models of ovarian cancer as a potential novel therapeutic strategy. Inhibition of PI3K/Akt/mTOR signaling by NVP-BEZ235 was demonstrated by immunoblotting. The effect on cell proliferation was assessed in 18 ovarian cancer cell lines, including four pairs of syngeneic cisplatin-sensitive and cisplatin-resistant cell lines. The in vivo effects of NVP-BEZ235 on established tumor growth were evaluated using an immunocompetent, transgenic murine ovarian cancer model (LSL-K-ras(G12D/+)Pten(loxP/loxP)). NVP-BEZ235 decreased cell proliferation in all ovarian cancer cell lines assayed and sensitized cisplatin-resistant cells to the cytotoxic effects of cisplatin. Cell lines with PI3K-activating mutations or Pten deletions were significantly more sensitive to the effect of NVP-BEZ235 than cell lines without these mutations (P < 0.05). A statistically significant correlation was found between relative levels of p4E-BP1 and the IC(50) for NVP-BEZ235. In LSL-K-ras(G12D/+)Pten(loxP/loxP) mice with established intraperitoneal tumor disease, oral administration of NVP-BEZ235 decreased pAkt, p4E-BP1 and Ki67 in tumor tissue, and resulted in significantly longer survival compared to control animals (P < 0.05). NVP-BEZ235 also induced cell cycle arrest, caspase 3 activity, and reduced cell migration. Targeting PI3K and mTOR simultaneously using NVP-BEZ235 effectively inhibits ovarian cancer cell growth even in the presence of platinum resistance and prolongs survival of mice with intra-abdominal ovarian tumor disease. We propose that dual PI3K and mTOR inhibition using NVP-BEZ235 may be an effective novel therapeutic approach in patients with ovarian cancer.

Santiskulvong C ，Konecny GE ，Fekete M ，Chen KY ，Karam A ，Mulholland D ，Eng C ，Wu H ，Song M ，Dorigo O ... -  《-》

Genotype-dependent efficacy of a dual PI3K/mTOR inhibitor, NVP-BEZ235, and an mTOR inhibitor, RAD001, in endometrial carcinomas.

Shoji K ，Oda K ，Kashiyama T ，Ikeda Y ，Nakagawa S ，Sone K ，Miyamoto Y ，Hiraike H ，Tanikawa M ，Miyasaka A ，Koso T ，Matsumoto Y ，Wada-Hiraike O ，Kawana K ，Kuramoto H ，McCormick F ，Aburatani H ，Yano T ，Kozuma S ，Taketani Y ... -  《PLoS One》

Dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 has a therapeutic potential and sensitizes cisplatin in nasopharyngeal carcinoma.

Yang F ，Qian XJ ，Qin W ，Deng R ，Wu XQ ，Qin J ，Feng GK ，Zhu XF ... -  《PLoS One》

Cell cycle-dependent activity of the novel dual PI3K-MTORC1/2 inhibitor NVP-BGT226 in acute leukemia.

Kampa-Schittenhelm KM ，Heinrich MC ，Akmut F ，Rasp KH ，Illing B ，Döhner H ，Döhner K ，Schittenhelm MM ... -  《Molecular Cancer》

Increased activation of PI3K/AKT signaling pathway is associated with cholangiocarcinoma metastasis and PI3K/mTOR inhibition presents a possible therapeutic strategy.

Yothaisong S ，Dokduang H ，Techasen A ，Namwat N ，Yongvanit P ，Bhudhisawasdi V ，Puapairoj A ，Riggins GJ ，Loilome W ... -  《-》