Window of opportunity trial reveals mechanisms of response and resistance to navtemadlin in patients with recurrent glioblastoma [patients]
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PROVIDER: PRJNA1181519 | ENA |
REPOSITORIES: ENA
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Project description:Window of opportunity trial reveals mechanisms of response and resistance to navtemadlin in patients with recurrent glioblastoma
| PRJNA1180994 | ENA
Project description:To investigate the effectiveness of p53 reactivation in treating glioblastoma, we conducted a surgical window-of-opportunity trial (NCT03107780) of the MDM2 inhibitor navtemadlin (KRT-232) on 21 patients and determined achievable drug concentrations within tumor tissue and biological mechanisms of response and resistance. Both 120 mg and 240 mg daily dosing achieved a pharmacodynamic impact, but patient relapse was observed. Sequencing of three recurrent tumors revealed an absence of TP53-inactivating mutations, indicating alternative mechanisms of resistance. To understand the mechanisms of response and resistance associated with navtemadlin, we conducted functional and spatial analyses of human tissue and patient-derived glioblastoma (GBM) models. Navtemadlin induced partial tumor cell death as monotherapy, but combination with temozolomide enhanced apoptosis while sparing normal bone marrow cells in vitro. We additionally report upregulation of oligodendrocyte differentiation genes as an unexplored mechanism of navtemadlin tolerance in GBM. Overall, these results indicate that clinically achievable doses of navtemadlin exert pharmacodynamic effects and suggest that combined treatment with standard-of-care DNA damaging chemotherapy may be a route to more durable survival benefits.
2025-01-22 | GSE280951 | GEO
Project description:To investigate the effectiveness of p53 reactivation in treating glioblastoma, we conducted a surgical window-of-opportunity trial (NCT03107780) of the MDM2 inhibitor navtemadlin (KRT-232) on 21 patients and determined achievable drug concentrations within tumor tissue and biological mechanisms of response and resistance. Both 120 mg and 240 mg daily dosing achieved a pharmacodynamic impact, but patient relapse was observed. Sequencing of three recurrent tumors revealed an absence of TP53-inactivating mutations, indicating alternative mechanisms of resistance. To understand the mechanisms of response and resistance associated with navtemadlin, we conducted functional and spatial analyses of human tissue and patient-derived glioblastoma (GBM) models. Navtemadlin induced partial tumor cell death as monotherapy, but combination with temozolomide enhanced apoptosis while sparing normal bone marrow cells in vitro. We additionally report upregulation of oligodendrocyte differentiation genes as an unexplored mechanism of navtemadlin tolerance in GBM. Overall, these results indicate that clinically achievable doses of navtemadlin exert pharmacodynamic effects and suggest that combined treatment with standard-of-care DNA damaging chemotherapy may be a route to more durable survival benefits.
2025-01-22 | GSE280891 | GEO
Project description:This is a window of opportunity translational study investigating the use of pre-operative pembrolizumab and chemotherapy or chemoradiotherapy in non-metastatic colorectal cancer.
| 2308212 | ecrin-mdr-crc
Project description:Afatinib is a pan-HER inhibitor that improved progression-free-survival (PFS) in recurrent HNSCC versus methotrexate: median PFS 2.6 versus 1.7 months (LUX H&N 1 trial). This study is a translational research linked to EORTC 90111 afatinib trial, an open-label, randomized, multicenter, phase II window of opportunity trial. Treatment-naïve HNSCC patients selected for primary curative surgery were randomized (5:1 ratio) to receive Afatinib during 14 days (day -15 until day -1) before surgery (day 0) or no treatment. Tumour biopsies, FDG/PET, and MRI were performed at diagnosis and at surgery. The primary end point was metabolic FDG-PET/CT response, defined according to EORTC guidelines.
2019-01-23 | GSE101491 | GEO
Project description:Gene expression profiling in EORTC 90111 study, a window of opportunity trial with afatinib in HNSCC
| PRJNA791613 | ENA
Project description:In the EORTC 90111, open-label, randomised, multicentre, phase II trial, patients were treated with afatinib for 14 days (day 15 until day 1) before surgery (day 0). Tumour biopsies, 2-[fluorine-18]-fluoro-2-deoxy-d-glucose positron emission tomography (18-FDG PET) and magnetic resonance imaging (MRI) were performed at diagnosis and just before surgery. The main aim of the study was to identify predictive biomarkers among treatment-naive patients in this curative setting.
2023-12-21 | GSE192464 | GEO
Project description:The results from the randomized phase II BELOB trial provided evidence for a potential benefit of bevacizumab (beva; a humanized monoclonal antibody against circulating VEGF-A) when added to CCNU chemotherapy in recurrent GBM patients. In this study, we have performed gene expression profiling (DASL and RNA-seq) on formalin fixed, paraffin embedded (FFPE) tumor material from patients treated within the BELOB trial to identify recurrent GBM patients who benefit most from combined beva/CCNU treatment. We first extensively validate the use of FFPE tissues for expression profiling on both DASL and RNA-seq. Our data show that tumors assigned to IGS-18 or ‘classical’ GBMs show a significant benefit in progression free survival (PFS) and a trend towards benefit in overall survival (OS) from beva+CCNU treatment; other subtypes do not show such benefit. In particular, expression of FMO4 and OSBPL3 were associated with treatment response. All molecular glioma subtypes are evenly distributed along the different study arms and the improved outcome in the beva/CCNU arm therefore is not explained by an uneven distribution of prognostically favorable subtypes. Analysis of RNA-seq data highlighted genetic changes, including mutations, gene fusions (and identification of the exact genomic breakpoint), and copy number changes (albeit with limited resolution) within this well-defined cohort of tumors. When validated in an independent dataset, the predictive markers identified in this study will allow selection of recurrent GBM patients that benefit from beva+CCNU treatment.
2016-01-19 | GSE72951 | GEO
Project description:This study sought to determine whether an endometrial gland specific transcriptome and splicing profile are altered in the window of implantation (days 21-23 of the menstrual cycle) in women with recurrent pregnancy loss. Our data provide a comprehensive catalogue of gene isoforms and relative exon usage in endometrial glands. The endometrial gland targets identified in this study could be used to identify a perturbed endometrium, isolate causes of recurrent pregnancy loss and develop targeted therapies in personalised medicine.
2021-09-23 | GSE183555 | GEO
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