Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA100451 | ENA |
REPOSITORIES: ENA
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Project description:Background There is much discussion in the cancer drug development community about how to incorporate molecular tools into early-stage clinical trials to assess target modulation, measure anti-tumor activity, and enrich the clinical trial population for patients who are more likely to benefit. Small, molecularly focused clinical studies offer the promise of the early definition of optimal biologic dose and patient population. Methods and Findings Based on preclinical evidence that phosphatase and tensin homolog deleted on Chromosome 10 (PTEN) loss sensitizes tumors to the inhibition of mammalian target of rapamycin (mTOR), we conducted a proof-of-concept Phase I neoadjuvant trial of rapamycin in patients with recurrent glioblastoma, whose tumors lacked expression of the tumor suppressor PTEN. We aimed to assess the safety profile of daily rapamycin in patients with glioma, define the dose of rapamycin required for mTOR inhibition in tumor tissue, and evaluate the antiproliferative activity of rapamycin in PTEN-deficient glioblastoma. Although intratumoral rapamycin concentrations that were sufficient to inhibit mTOR in vitro were achieved in all patients, the magnitude of mTOR inhibition in tumor cells (measured by reduced ribosomal S6 protein phosphorylation) varied substantially. Tumor cell proliferation (measured by Ki-67 staining) was dramatically reduced in seven of 14 patients after 1 wk of rapamycin treatment and was associated with the magnitude of mTOR inhibition (p = 0.0047, Fisher exact test) but not the intratumoral rapamycin concentration. Tumor cells harvested from the Ki-67 nonresponders retained sensitivity to rapamycin ex vivo, indicating that clinical resistance to biochemical mTOR inhibition was not cell-intrinsic. Rapamycin treatment led to Akt activation in seven patients, presumably due to loss of negative feedback, and this activation was associated with shorter time-to-progression during post-surgical maintenance rapamycin therapy (p < 0.05, Logrank test). Conclusions Rapamycin has anticancer activity in PTEN-deficient glioblastoma and warrants further clinical study alone or in combination with PI3K pathway inhibitors. The short-term treatment endpoints used in this neoadjuvant trial design identified the importance of monitoring target inhibition and negative feedback to guide future clinical development. Keywords: Comparative Genomic Hybridization
2008-01-29 | GSE7344 | GEO
Project description:Purpose: Deregulated phosphatidylinositol 3-kinase pathway signaling through AGC kinases including AKT, p70S6 kinase, PKA, SGK and Rho kinase, is a key driver of multiple cancers. The simultaneous inhibition of multiple AGC kinases may increase antitumor activity and minimize clinical resistance compared with a single pathway component. Experimental Design: We investigated the detailed pharmacology and antitumor activity of the novel clinical drug candidate AT13148, an oral ATP-competitive multi-AGC kinase inhibitor. Gene expression microarray studies were undertaken to characterize the molecular mechanisms of action of AT13148. Results: AT13148 caused substantial blockade of AKT, p70S6K, PKA, ROCK and SGK substrate phosphorylation and induced apoptosis in a concentration and time-dependent manner in cancer cells with clinically relevant genetic defects in vitro and in vivo. Antitumor efficacy in HER2-positive, PIK3CA-mutant BT474 breast, PTEN-deficient PC3 human prostate cancer and PTEN-deficient MES-SA uterine tumor xenografts was demonstrated. We show for the first time that induction of AKT phosphorylation at serine 473 by AT13148, as reported for other ATP-competitive inhibitors of AKT, is not a therapeutically relevant reactivation step. Gene expression studies showed that AT13148 has a predominant effect on apoptosis genes, whereas the selective AKT inhibitor CCT128930 modulates cell cycle genes. Induction of upstream regulators including IRS2 and PIK3IP1 due to compensatory feedback loops was observed. Conclusions: The clinical candidate AT13148 is a novel oral multi-AGC kinase inhibitor with potent pharmacodynamic and antitumor activity, which demonstrates a distinct mechanism of action from other AKT inhibitors. AT13148 will now be assessed in a first-in-human Phase I trial. The PTEN-deficient U87MG glioblastoma cell line was treated for 6 hours with vehicle control (DMSO) or to different concentrations of AT13148 and CCT128930 (0.1uM, 1xGI50 and 3XGI50).
2012-07-19 | E-GEOD-38008 | biostudies-arrayexpress
Project description:Purpose: Deregulated phosphatidylinositol 3-kinase pathway signaling through AGC kinases including AKT, p70S6 kinase, PKA, SGK and Rho kinase, is a key driver of multiple cancers. The simultaneous inhibition of multiple AGC kinases may increase antitumor activity and minimize clinical resistance compared with a single pathway component. Experimental Design: We investigated the detailed pharmacology and antitumor activity of the novel clinical drug candidate AT13148, an oral ATP-competitive multi-AGC kinase inhibitor. Gene expression microarray studies were undertaken to characterize the molecular mechanisms of action of AT13148. Results: AT13148 caused substantial blockade of AKT, p70S6K, PKA, ROCK and SGK substrate phosphorylation and induced apoptosis in a concentration and time-dependent manner in cancer cells with clinically relevant genetic defects in vitro and in vivo. Antitumor efficacy in HER2-positive, PIK3CA-mutant BT474 breast, PTEN-deficient PC3 human prostate cancer and PTEN-deficient MES-SA uterine tumor xenografts was demonstrated. We show for the first time that induction of AKT phosphorylation at serine 473 by AT13148, as reported for other ATP-competitive inhibitors of AKT, is not a therapeutically relevant reactivation step. Gene expression studies showed that AT13148 has a predominant effect on apoptosis genes, whereas the selective AKT inhibitor CCT128930 modulates cell cycle genes. Induction of upstream regulators including IRS2 and PIK3IP1 due to compensatory feedback loops was observed. Conclusions: The clinical candidate AT13148 is a novel oral multi-AGC kinase inhibitor with potent pharmacodynamic and antitumor activity, which demonstrates a distinct mechanism of action from other AKT inhibitors. AT13148 will now be assessed in a first-in-human Phase I trial.
2012-07-20 | GSE38008 | GEO
Project description:Ulixertinib has shown promising antitumor activity in a Phase 1 clinical trial for advanced solid tumors. In this study, we demonstrated that in NB cells, ulixertinib effectively suppressed ERK function of phosphorylating RSK and induced degradation of MYC that promotes NB development.
2021-05-25 | MSV000087511 | MassIVE
Project description:Glioblastoma (GBM) is the most lethal brain tumour that occurs in adults and treatment for GBM has been largely unsuccessful. Ionizing radiation (IR) and chemotherapeutic agents are employed as standard of care treatment for GBM patients and both result in DNA damage. Previous data identified phosphorylation of PTEN at tyrosine 240 (pY240) in samples from patients with recurrent GBM receiving standard of care treatment and was associated with decreased overall survival. Here we demonstrate that pY240 PTEN that was triggered by FGFR2 signaling, enhanced DNA repair by facilitating the loading of PTEN onto chromatin through its interaction with KI-67 and subsequent recruitment of the DNA repair protein, RAD51, to sites of DNA damage. Thus, tumour cells with pY240 PTEN are efficient at repairing DNA damage which would be predicted to result in resistance to therapy. These findings suggest the FGFR-pY240 PTEN-DNA repair mechanism as a therapeutic target for enhancing GBM therapy.
2017-08-07 | MSV000081423 | MassIVE
Project description:We have previously developed the use of genetically engineered herpes simplex virus type 1 ("G207") for the experimental treatment of malignant glioma (PMID: 18957964). We demonstrated that G207 propagates in and kills nervous system tumor cells with little to no evidence of viral encephalitis. Here, six adult patients with recurrent glioblastoma were recruited onto a phase Ib clinical trial to test G207 safety and efficacy in anti-tumor response. We obtained resected tumor tissue before and after (within 2-5 days) inoculation with G207. RNA was extracted from all tissues and subject to library preparation for RNA sequencing on Illumina instrumentation.
2021-12-31 | GSE162643 | GEO
Project description:Recurrent glioblastoma (GBM) has a grim prognosis, though MGMT promoter methylation and IDH mutation provide a significant survival advantage. The product of IDH mutation, 2-hydroxyglutarate, increases global DNA methylation by inhibiting demethylases. While lower-grade IDH-mutant gliomas demonstrate increased methylation as a result of this process, DNA becomes relatively hypomethylated during progression from low-grade glioma to secondary (IDH-mutant) GBM. Here we show that global DNA hypomethylation also occurs during primary (IDH-wild type) GBM recurrence. Moreover, in a phase I trial of 14 patients with recurrent (IDH-wild type) GBM, we targeted DNA hypomethylation using a methyl donor treatment. In autopsied tumors from patients treated, we observed a global increase in DNA methylation compared to initial tumor. These results suggest that hypomethylation is a marker for recurrence, and its reprogramming represents a potential therapeutic vulnerability.
2021-12-31 | GSE111627 | GEO
Project description:We have previously developed the use of genetically engineered herpes simplex virus type 1 (G207) for the experimental treatment of malignant glioma (PMID: 18957964). We demonstrated that G207 propagates in and kills nervous system tumor cells with little to no evidence of viral encephalitis. Here, six adult patients with recurrent glioblastoma were recruited onto a phase 1b clinical trial to test safety and efficacy of G207 in anti-tumor response. We obtained resected tumor tissue before and after (within 2-5 days) inoculation with G207. RNA was extracted from all tissues and subject to gene expression profiling using NanoString Pancancer Immune panel. Our data indicate in the post-G207 samples that interferon immune response and the subsequent recruitment of an adaptive immune response strongly associated with overall survival after inoculation with oncolytic virus G207 in patients with recurrent malignant glioma.
2021-12-31 | GSE164104 | GEO
Project description:H3K27ac is an active enhancer mark, which is associated with higher activation of transcription. To determine the downstream transcriptional targets and pathways of H3K27ac in PTEN-deficient glioblastoma, ChIP-seq was performed in SF763 PTEN-KO and U87 cells.
2018-11-08 | GSE122283 | GEO
Project description:Metastatic ovarian cancer lacks curative and therapeutic options in the recurrent setting, particularly refractory or platinum-resistant disease. Our phase 2 clinical trial (NCT02853318) combined pembrolizumab with bevacizumab to enhance T cell infiltration to the tumor microenvironment and oral cyclophosphamide to deplete regulatory T cells. This trial accrued 40 heavily pretreated recurrent ovarian cancer patients and resulted in an objective response rate of 47.5%, a median progression-free survival of 10 months, and disease control in 30% of patients over 12 months with good quality of life. To better assess the biological etiology underlying patient responses, we performed comprehensive molecular, immune, microbiome, and metabolic profiling in tumor, stroma, and fecal samples from patients on trial. Our unique findings point to predicted differences in T- and B-cell infiltration and glycerophospholipid dysregulation underlying combination therapeutic response. Overall, this study suggests the immune milieu may be leveraged as a target in non-responding patients to improve anti-tumor response and warrants further investigation.
2023-05-17 | GSE206422 | GEO