Cellular and in vivo activity of a novel PI3K inhibitor, PX-866, against human glioblastoma

Department of Neuro-Oncology, Unit 100, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Neuro-Oncology (Impact Factor: 5.29). 02/2010; 12(6):559-69. DOI: 10.1093/neuonc/nop058
Source: PubMed

ABSTRACT The phosphatidylinositol-3-kinase (PI3K)/Akt oncogenic pathway is critical in glioblastomas. Loss of PTEN, a negative regulator
of the PI3K pathway or activated PI3K/Akt pathway that drive increased proliferation, survival, neovascularization, glycolysis,
and invasion is found in 70%–80% of malignant gliomas. Thus, PI3K is an attractive therapeutic target for malignant glioma.
We report that a new irreversible PI3K inhibitor, PX-866, shows potent inhibitory effects on the PI3K/Akt signaling pathway
in glioblastoma. PX-866 did not induce any apoptosis in glioma cells; however, an increase in autophagy was observed. PX-866
inhibited the invasive and angiogenic capabilities of cultured glioblastoma cells. In vivo, PX-866 inhibited subcutaneous
tumor growth and increased the median survival time of animals with intracranial tumors. We also assessed the potential of
proton magnetic resonance spectroscopy (MRS) as a noninvasive method to monitor response to PX-866. Our findings show that
PX-866 treatment causes a drop in the MRS-detectable choline-to-NAA, ratio and identify this partial normalization of the
tumor metabolic profile as a biomarker of molecular drug action. Our studies affirm that the PI3K pathway is a highly specific
molecular target for therapies for glioblastoma and other cancers with aberrant PI3K/PTEN expression.

Download full-text


Available from: Yong-Wan Kim, Aug 01, 2015
1 Follower
  • [Show abstract] [Hide abstract]
    ABSTRACT: 2-(1H-Indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) is a novel small molecule inhibitor of the phosphatidylinositol 3-kinase (PI3K) pathway currently evaluated in the clinic as an anticancer agent. The objectives of this study were to determine in vitro whether GDC-0941 was a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp1) and to investigate the impact of these transporters on the pharmacokinetics, brain penetration, and activity of GDC-0941 in FVBn mice (wild-type) and Mdr1a/b(-/-), Bcrp1(-/-), and Mdr1a/b(-/-)/Bcrp1(-/-) knockout mice. Studies with Madin-Darby canine kidney cells transfected with P-gp or Bcrp1 established that this compound was a substrate of both transporters. After administrations to mice, GDC-0941 brain-to-plasma ratio ranged from 0.02 to 0.06 in the wild-type and Bcrp1(-/-) mice and was modestly higher in the Mdr1a/b(-/-) mice, ranging from 0.08 to 0.11. In contrast, GDC-0941 brain-to-plasma ratio in Mdr1a/b(-/-)/Bcrp1(-/-) triple knockout mice was 30-fold higher than in the wild-type mice. The plasma clearance of GDC-0941 was similar in wild-type and all knockout mice, ranging from 15 to 25 ml/(min . kg) in the wild-type mice and from 18 to 35 ml/(min . kg) in the knockout mice. Exposure after oral administration was comparable in the four strains of mice. The PI3K pathway was markedly inhibited in the brain of Mdr1a/b(-/-)/Bcrp1(-/-) mice for up to 6 h postdose, as evidenced by a 60% suppression of the phosphorylated Akt signal, whereas no inhibition was detected in the brain of wild-type mice. The concerted effects of P-gp and Bcrp1 in restricting GDC-0941 access and pathway modulation in mouse brain may have implications for the treatment of patients with brain tumors.
    Drug metabolism and disposition: the biological fate of chemicals 09/2010; 38(9):1422-6. DOI:10.1124/dmd.110.034256 · 3.33 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Osteosarcoma is the most common primary malignant bone tumor, occurring mainly in children and adolescents, and survival largely depends on their response to chemotherapy. However, the risk of relapse and adverse outcomes is still high. We investigated the synergistic anti-cancer effects of ionizing radiation combined with arsenic trioxide (ATO) and the mechanisms underlying apoptosis or autophagy induced by combined radiation and ATO treatment in human osteosarcoma cells. We found that exposure to radiation increased the population of HOS cells in the G(2)/M phase within 12 h in a time-dependent manner. Radiation combined with ATO induced a significantly prolonged G(2)/M arrest, consequently enhancing cell death. Furthermore, combined treatment resulted in enhanced ROS generation compared to treatment with ATO or radiation alone. The enhanced cytotoxic effect of combined treatment occurred from the increased induction of autophagy and apoptosis through inhibition of the PI3K/Akt signaling pathway in HOS cells. The combined treatment of HOS cells pretreated with Z-VAD, 3-MA or PEG-catalase resulted in a significant reduction of cytotoxicity. In addition, G(2)/M arrest and ROS generation could be involved in the underlying mechanisms. The data suggest that a combination of radiation and ATO could be a new potential therapeutic strategy for the treatment of osteosarcoma.
    Radiation Research 03/2011; 175(5):547-60. DOI:10.1667/RR2380.1 · 2.45 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Several small molecules that inhibit the PI3 kinase (PI3K)-Akt signaling pathway are in clinical development. Although many of these molecules have been effective in preclinical models, it remains unclear whether this strategy alone will be sufficient to interrupt the molecular events initiated and maintained by signaling along the pathways because of the activation of other pathways that compensate for the inhibition of the targeted kinase. In this study, we performed a synthetic lethality screen to identify genes or pathways whose inactivation, in combination with the PI3K inhibitors PX-866 and NVPBEZ-235, might result in a lethal phenotype in glioblastoma multiforme (GBM) cells. We screened GBM cells (U87, U251, and T98G) with a large-scale, short hairpin RNA library (GeneNet), which contains 43 800 small interfering RNA sequences targeting 8500 well-characterized human genes. To decrease off-target effects, we selected overlapping genes among the 3 cell lines that synergized with PX-866 to induce cell death. To facilitate the identification of potential targets, we used a GSE4290 dataset and The Cancer Genome Atlas GBM dataset, identifying 15 target genes overexpressed in GBM tissues. We further analyzed the selected genes using Ingenuity Pathway Analysis software and showed that the 15 genes were closely related to cancer-promoting pathways, and a highly interconnected network of aberrations along the MYC, P38MAPK, and ERK signaling pathways were identified. Our findings suggest that inhibition of these pathways might increase tumor sensitivity to PX-866 and therefore represent a potential clinical therapeutic strategy.
    Neuro-Oncology 04/2011; 13(4):367-75. DOI:10.1093/neuonc/nor012 · 5.29 Impact Factor
Show more