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Preclinical evaluation of novel PI3K/mTOR dual inhibitor SN202 as potential anti-renal cancer agent.

ABSTRACT: ABSTRACT The PI3K/mTOR pathway is one of the most frequently aberrantly activated pathways in human malignancies, such as renal cell carcinoma (RCC), and contributes to resistance to antitumor therapies. Thus, PI3K/mTOR is an attractive target for the development of antitumor agents. In this study, we evaluated the preclinical effects of a novel inhibitor SN202. We examined Akt/mTOR activities in renal cancer cells after SN202 treatment. The preclinical effects of SN202 on tumor growth were evaluated in renal cancer cells in vitro and in murine xenografts in vivo. SN202 inhibits PI3Kα, PI3Kγ, and mTOR, the corresponding IC50 values were 3.2, 3.3, and 1.2 nM, respectively. In A498, 786-0, and ACHN renal cancer cell lines, SN202 inhibits cell proliferation in a dose-dependent manner and significantly inhibits 786-0 cell growth. Western blot analysis revealed that SN202 decreases the phosphorylation of PI3K downstream signaling molecules, Akt and S6K, in 786-0 renal cancer cells. Furthermore, oral administration of SN202 results in significant inhibition in human renal carcinoma xenografts in nude mice and favourable pharmacokinetic properties in rats. These results suggest that SN202 might be a promising therapeutic agent against RCC as a dual PI3K/mTOR inhibitor.

SUBMITTER: Wang W

PROVIDER: S-EPMC6301802 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Preclinical evaluation of novel PI3K/mTOR dual inhibitor SN202 as potential anti-renal cancer agent.

Wang Wan W Liao Lidong L Wang Yujun Y Li Hui H Suo Zili Z Long Kai K Tang Peixiao P

Cancer biology & therapy 20180927 11

<b>ABSTRACT</b> The PI3K/mTOR pathway is one of the most frequently aberrantly activated pathways in human malignancies, such as renal cell carcinoma (RCC), and contributes to resistance to antitumor therapies. Thus, PI3K/mTOR is an attractive target for the development of antitumor agents. In this study, we evaluated the preclinical effects of a novel inhibitor SN202. We examined Akt/mTOR activities in renal cancer cells after SN202 treatment. The preclinical effects of SN202 on tumor growth we ...[more]

PMID: 29799306

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Project description:Glioblastoma (GBM) is an ideal candidate disease for signal transduction targeted therapy because the majority of these tumors harbor genetic alterations that result in aberrant activation of growth factor signaling pathways. Loss of heterozygosity of chromosome 10, mutations in the tumor suppressor gene PTEN, and PI3K mutations are molecular hallmarks of GBM and indicate poor prognostic outcomes in many cancers. Consequently, inhibiting the PI3K pathway may provide therapeutic benefit in these cancers. PI3K inhibitors generally block proliferation rather than induce apoptosis. To restore the sensitivity of GBM to apoptosis induction, targeted agents have been combined with conventional therapy. However, the molecular heterogeneity and infiltrative nature of GBM make it resistant to traditional single agent therapy. Our objectives were to test a dual PI3K/mTOR inhibitor that may cross the blood-brain barrier (BBB) and provide the rationale for using this inhibitor in combination regimens to chemotherapy-induced synergism in GBM. Here we report the preclinical potential of a novel, orally bioavailable PI3K/mTOR dual inhibitor, DS7423 (hereafter DS), in in-vitro and in-vivo studies. DS was tested in mice, and DS plasma and brain concentrations were determined. DS crossed the BBB and led to potent suppression of PI3K pathway biomarkers in the brain. The physiologically relevant concentration of DS was tested in 9 glioma cell lines and 22 glioma-initiating cell (GIC) lines. DS inhibited the growth of glioma tumor cell lines and GICs at mean 50% inhibitory concentration values of less than 250 nmol/L. We found that PI3K mutations and PTEN alterations were associated with cellular response to DS treatment; with preferential inhibition of cell growth in PI3KCA-mutant and PTEN altered cell lines. DS showed efficacy and survival benefit in the U87 and GSC11 orthotopic models of GBM. Furthermore, administration of DS enhanced the antitumor efficacy of temozolomide against GBM in U87 glioma models, which shows that PI3K/mTOR inhibitors may enhance alkylating agent-mediated cytotoxicity, providing a novel regimen for the treatment of GBM. Our present findings establish that DS can specifically be used in patients who have PI3K pathway activation and/or loss of PTEN function. Further studies are warranted to determine the potential of DS for glioma treatment.

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Preclinical evaluation of novel PI3K/mTOR dual inhibitor SN202 as potential anti-renal cancer agent.

Publications

Preclinical evaluation of novel PI3K/mTOR dual inhibitor SN202 as potential anti-renal cancer agent.

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