Gene expression changes upon treatment of T47D breast cancer cells with the Pan-PI3 kinase inhibitor GDC-0941
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: O'Brien C
PROVIDER: S-ECPF-GEOD-20719 | biostudies-other | 2010 Jul
REPOSITORIES: biostudies-other
Similar Datasets
Project description:We sought to determine genes whose expression changed upon treatment with a selective inhibitor of class I PI3 kinase. Total of 6 samples: cells were treated with GDC-0941 at a concentration of 1mM for 6 hours (3 replicates) and control (3 replicates)
2010-06-08 | E-GEOD-20719 | biostudies-arrayexpress
Project description:We sought to determine genes whose expression changed upon treatment with a selective inhibitor of class I PI3 kinase.
2010-05-25 | GSE20719 | GEO
Project description:Background CLR457 is an orally bioavailable pan-phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitor. Methods CLR457 anti-tumor activity and pharmacokinetics (PK) were characterized by in vitro biochemical assays and in vivo tumor xenografts. A first-in-human study was conducted to determine the maximum tolerated dose (MTD), safety, PK, and efficacy of CLR457. Successive cohorts of patients with advanced solid tumors with PI3K pathway activation received increasing CLR457 doses according to a Bayesian escalation model based on the rate of dose limiting toxicity (DLT) in the first 28-day cycle. Results CLR457 inhibited p110α, p110β, p110δ and p110γ isoforms with an IC50 of 89 ± 29 nM, 56 ± 35 nM, 39 ± 10 nM and 230 ± 31 nM, respectively. CLR457 exhibited dose-dependent antitumor activity and interfered with glucose homeostasis in PI3K-mutant tumor xenografts. 31 patients received doses ranging from 5 to 100 mg. DLTs included grade 3 hyperglycemia and rash (3). In the 100 mg cohort (n = 11), 3 (27.3%) patients had DLTs and all patients (100%) experienced ≥ grade 3 toxicity with rash (45.5%) as the most common event. The MTD was not determined. For the entire study population, stomatitis (45.2%), diarrhea (38.7%), rash (35.5%) were the most common any grade toxicities-51.6% patients experienced ≥ Grade 3 toxicity. CLR457 was rapidly absorbed with limited accumulation and linear PK. PK modeling indicated that pharmacologically active concentrations were achieved at the highest dose tested (100 mg), though no objective responses were observed. Conclusion CLR457 clinical development was terminated due to poor tolerability and limited antitumor activity. These results emphasize the difficulty of achieving a wide therapeutic index when targeting all class I PI3K-isoforms.
| S-EPMC6440935 | biostudies-literature
Project description:BACKGROUND:Activating mutations in the pathway of phosphatidylinositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) occur in 43-70% of breast cancer brain metastasis patients. To date, the treatment of these patients presents an ongoing challenge, mainly because of the lack of targeted agents that are able to sufficiently penetrate the blood-brain barrier. GDC-0068 is a pan-Akt inhibitor that has shown to be effective in various preclinical tumor models as well as in clinical trials. The purpose of this study was to analyze the efficacy of GDC-0068 in a breast cancer brain metastases model. METHODS:In in vitro studies, antitumor activity of GDC-0068 was assessed in breast cancer cells of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutant and PIK3CA-wildtype breast cancer cell lines using cell viability and apoptosis assays, cell cycle analysis, and western blots. In vivo, the efficacy of GDC-0068 was analyzed in a PIK3CA-mutant breast cancer brain metastasis orthotopic xenograft mouse model and evaluated by repeated bioluminescent imaging and immunohistochemistry. RESULTS:GDC-0068 decreased cell viability, induced apoptosis, and inhibited phosphorylation of proline rich Akt substrate 40 kDa and p70 S6 kinase in a dose-dependent manner in PIK3CA-mutant breast cancer brain metastatic cell lines compared with PIK3CA-wildtype cell lines. In vivo, treatment with GDC-0068 notably inhibited the growth of PIK3CA-mutant tumors and resulted in a significant survival benefit compared with sham, whereas no effect was detected in a PIK3CA-wildtype model. CONCLUSIONS:This study suggests that the Akt inhibitor GDC-0068 may be an encouraging targeted treatment strategy for breast cancer brain metastasis patients with activating mutations in the PI3K pathway. These data provide a rationale to further evaluate the efficacy of GDC-0068 in patients with brain metastases.
| S-EPMC6827829 | biostudies-literature
Project description:Trastuzumab, an anti-ErbB2 humanized antibody, brings benefit to patients with ErbB2-amplified metastatic breast cancers. However, the resistance to trastuzumab is common. Our previously reported H2-18, an anti-ErbB2 antibody, potently induced programmed cell death in trastuzumab-resistant breast cancer cells. Here, we aim to investigate the antitumor efficacy of H2-18 in combination with the pan-PI3K inhibitor GDC-0941 in trastuzumab-resistant breast cancer cell lines. The results showed that H2-18 and GDC-0941 synergistically inhibited the in vitro proliferation of BT-474, SKBR-3, HCC-1954 and HCC-1419 breast cancer cells. H2-18 plus GDC-0941 showed significantly enhanced programmed cell death-inducing activity compared with each drug used alone. The combination of H2-18 and GDC-0941 did not increase the effect of single agent on ROS production, cell cycle and ErbB2 signaling. Importantly, the in vivo antitumor efficacy of H2-18 plus GDC-0941 was superior to that of single agent. Thus, the enhanced in vivo antitumor efficacy of H2-18 plus GDC-0941 may mainly be attributable to its increased programmed cell death-inducing activity. Collectively, H2-18 plus GDC-0941 could effectively inhibit tumor growth, suggesting the potential to be translated into clinic as an efficient strategy for ErbB2-overexpressing breast cancers.
| S-EPMC5581078 | biostudies-literature
Project description:Medulloblastoma is the most common malignant brain tumor in children. Aberrant activation of the hedgehog signaling pathway is strongly implicated in the development of some cases of medulloblastoma. A 26-year-old man with metastatic medulloblastoma that was refractory to multiple therapies was treated with a novel hedgehog pathway inhibitor, GDC-0449; treatment resulted in rapid (although transient) regression of the tumor and reduction of symptoms. Molecular analyses of tumor specimens obtained before treatment suggested that there was activation of the hedgehog pathway, with loss of heterozygosity and somatic mutation of the gene encoding patched homologue 1 (PTCH1), a key negative regulator of hedgehog signaling.
| S-EPMC5317279 | biostudies-literature
Project description:The development of a fluorescent LCK inhibitor that exhibits favourable solvatochromic properties upon binding the kinase is described. Fluorescent properties were realised through the inclusion of a prodan-derived fluorophore into the pharmacophore of an ATP-competitive kinase inhibitor. Fluorescence titration experiments demonstrate the solvatochromic properties of the inhibitor, in which dramatic increase in emission intensity and hypsochromic shift in emission maxima are clearly observed upon binding LCK. Microscopy experiments in cellular contexts together with flow cytometry show that the fluorescence intensity of the inhibitor correlates with the LCK concentration. Furthermore, multiphoton microscopy experiments demonstrate both the rapid cellular uptake of the inhibitor and that the two-photon cross section of the inhibitor is amenable for excitation at 700 nm.
| S-EPMC6851755 | biostudies-literature
Project description:Acute lymphoblastic leukemia (ALL) is characterized by leukemic expansion of lymphoid blasts in hematopoietic tissues. Despite improved therapy only a subset of patients can be cured. Therefore, current research is focusing on new drug-targets. Members of the BCL-2 family and components of the PI3-kinase/mTOR pathway are critically involved in the regulation of growth and survival of ALL cells. We examined the effects of the pan-BCL-2 blocker obatoclax and the PI3-kinase/mTOR-inhibitor BEZ235 on growth and survival of ALL cells. In 3H-thymidine uptake experiments, both drugs suppressed the in vitro proliferation of leukemic cells in all patients with Philadelphia chromosome-positive (Ph+) ALL and Ph- ALL (obatoclax IC50: 0.01-5 μM; BEZ235, IC50: 0.01-1 μM). Both drugs were also found to produce growth-inhibitory effects in all Ph+ and all Ph- cell lines tested. Moreover, obatoclax and BEZ235 induced apoptosis in ALL cells. In drug-combination experiments, obatoclax and BEZ235 exerted synergistic growth-inhibitory effects on ALL cells. Finally, we confirmed that ALL cells, including CD34+/CD38- stem cells and all cell lines express transcripts for PI3-kinase, mTOR, BCL-2, MCL-1, and BCL-xL. Taken together, this data shows that combined targeting of the PI3-kinase/mTOR-pathway and BCL-2 family-members is a potent approach to counteract growth and survival of ALL cells.
| S-EPMC5620205 | biostudies-literature
Project description:The PI3 kinase family of lipid kinases promotes cell growth and survival by generating the second messenger phosphatidylinositol-3,4,5-trisphosphate. To define targets critical for cancers driven by activation of PI3 kinase, we screened a panel of potent and structurally diverse drug-like molecules that target this enzyme family. Surprisingly, a single agent (PI-103) effected proliferative arrest in glioma cells, despite the ability of many compounds to block PI3 kinase signaling through its downstream effector, Akt. The unique cellular activity of PI-103 was traced directly to its ability to inhibit both PI3 kinase alpha and mTOR. PI-103 showed significant activity in xenografted tumors with no observable toxicity. These data demonstrate an emergent efficacy due to combinatorial inhibition of mTOR and PI3 kinase alpha in malignant glioma.
| S-EPMC2925230 | biostudies-literature
Project description:Expression profile of MCF7 and T47D human breast cancer cell lines upon treatment with the BET bromodomian inhibitor JQ1
2017-05-08 | GSE95287 | GEO