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The Effects of the Proton Pump Inhibitor Esomeprazole on the Bioavailability of Regorafenib

ABSTRACT: Regorafenib is a novel oral multi-kinase inhibitor which targets angiogenic, stromal and oncogenic receptor tyrosine kinases. It is currently registered for GIST and mCRC. When regorafenib is co-administered with an acid suppressive agent, the intra-gastric pH increases, and as a result the equilibrium of ionized/non-ionized regorafenib may shift to the less soluble non-ionized form which reduces regorafenib bioavailability and exposure. Since proton pump inhibitors (PPIs) are often used during regorafenib therapy, this drug-drug interaction (DDI) confronts pharmacists and oncologists with challenges in clinical practice. In this study the investigators will therefore evaluate the impact of PPI-induced intra-gastric pH elevation on regorafenib pharmacokinetics in patients with GIST and mCRC.

DISEASE(S): Colorectal Neoplasms,Gastrointestinal Stromal Tumors

PROVIDER: 2217301 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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The effects of the proton pump inhibitor esomeprazole on the bioavailability of regorafenib

Project description:Primary objectives: To evaluate the area under the curve (AUC) of regorafenib compared to regorafenib concomitantly used with esomeprazole and to regorafenib used with esomeprazole 3 hours prior in patients with mCRC or GIST.

| 2535342 | ecrin-mdr-crc

Circulating microRNA analysis in a prospective co-clinical trial identifies biomarker of response and mechanisms of resistance to regorafenib in colorectal cancer

Project description:MicroRNA profiling was performed on baseline bloods using the NanoString nCounter platform in a serial liquid biopsies obtained at baseline in chemo-refractory mCRC patients treated with regorafenib in a phase II clinical trial (PROSPECT-R n=40; NCT03010722).

2024-01-25 | GSE248663 | GEO

Kinome Profiling of Gastrointestinal Stromal Tumors Using Multiplexed Inhibitor Beads and Mass Spectrometry Identifies Wee1 as a Candidate Therapeutic Target

Project description:Purpose: Management of gastrointestinal stromal tumor (GIST) has been revolutionized by the identification of activating mutations in KIT and PDGFRA and the clinical application of receptor tyrosine kinase (RTK) inhibitors in the advanced disease setting. Stratification of GIST into molecularly defined subsets provides insight into clinical behavior and response to approved targeted therapies. Although these RTK inhibitors are effective in the majority of GIST, resistance to these agents remains a significant clinical obstacle. Development of effective treatment strategies for refractory GIST requires identification of novel targets to provide additional therapeutic options. Global kinome profiling has the potential to identify critical signaling networks and reveal protein kinases that are essential in GIST. Experimental Design: Using Multiplexed Inhibitor Beads and Mass Spectrometry paired with a super-SILAC kinome standard, we explored the majority of the kinome in GIST specimens from three GIST subtypes (KIT-mutant, PDGFRA-mutant and succinate dehydrogenase-deficient GIST) to identify novel kinase targets. In vitro and in vivo studies were performed to evaluate the utility of targeting the identified kinases in GIST. Results: Kinome profiling revealed distinct signatures in three GIST subtypes. PDGFRA-mutant GIST had elevated tumor associated macrophage (TAM) kinases and immunohistochemical analysis confirmed increased TAMs present in these tumors. Kinome profiling with loss-of-function assays revealed a significant role for G2-M tyrosine kinase, Wee1, in GIST survival. In vitro and in vivo studies revealed significant efficacy of MK-1775 (Wee1 inhibitor) in combination with avapritinib in both KIT and PDGFRA-mutant GIST cell lines, as well as notable efficacy of MK-1775 as a single agent in the PDGFRA-mutant line. Conclusions: These studies provide strong preclinical justification for the use of MK-1775 in GIST.

2021-09-09 | PXD020720 | Pride

Transcript profiling of Arabidopsis plasma membrane proton pump mutants

2015-04-01 | GSE34202 | GEO

Transcript profiling of Arabidopsis plasma membrane proton pump mutants

Project description:Plasma membrane proton pump maintains proton electrochemical gradient and provides energy to secondary transporters. Arabidopsis mutant plants with reduced proton pump activity grow normal under ideal growth conditions; however their growth are reduced compared with wildtype plants when placed under the conditions that stress on protonmotive force (high external pH or high external potassium). Seedlings of wildtype, aha1, and aha2 mutant plants were grown under ideal growth condition. Total RNA from those seedlings were subjected to transcriptome analyses using Affymetrix Gene Chip.

2015-04-01 | E-GEOD-34202 | biostudies-arrayexpress

Gene expression profiles proton-induced in brest cell lines

Project description:Literature data report the helpful role of specific molecularly based signatures to predict response to treatment in cancer, including breast cancer (BC) disease. As known, BC is a heterogeneous disease presenting distinct subtypes with different clinical outcomes. Thus, the choice of a unique treatment plan for all BC patients, including radiation therapy (RT), may be not the best option. Technological advances in RT are evolving with the use of proton beams, which reduce the dose administered to the heart compared to conventional RT. However, limitate data regarding proton-induced molecular changes are currently available. The aim of this study was therefore to study gene expression profiles induced by proton irradiation with 0.5, 2 and 9 Gy of Ionizing radiation (IR) doses in breast cells. The great amount of data here collected, represent an useful tool to better understand the molecular mechanisms elicited by proton irradiation, thereby filling the existing lack of data in the literature.

2019-07-29 | GSE116325 | GEO

Murine model of gastrointestinal stromal tumors harboring a germline Kit K641E oncogenic mutant

Project description:Gastrointestinal stromal tumors (GIST) are thought to derive from the interstitial cells of Cajal (ICC) or an ICC precursor. Oncogenic mutations of the receptor tyrosine kinase KIT are present in most GIST. KIT K642E was originally identified in sporadic GIST and later found in the germ line of a familial GIST. A mouse model of harboring a germline Kit K641E mutant was created to model familial GIST. The expression profile was investigated in the gastric antrum in the knock-in Kit K641E murine GIST model by microarray.

2009-09-25 | GSE12931 | GEO

Distinct vascular genomic effects of proton and gamma radiation

Project description:We performed comparative RNA sequencing of the early (4 hrs) dose response (0.5 – 200 cGy whole body dose, 10 dose levels) of the mouse aorta to proton and gamma radiation. Total-body proton radiation of conscious animals was performed using a proton beam produced by a cyclotron system, while total-body gamma radiation of animals was performed using a Caesium-137 gamma source. A trend analysis identified genes that showed a dose response, using data permutation to estimate a false discovery rate (q-value) for each gene. We identified 29 and 194 genes (q-value ≤ 0.1) that were upregulated with increasing doses of proton and gamma radiation, respectively. No genes were down-regulated. While fewer genes were dose-responsive to proton radiation, the magnitude of the effect was greater than with gamma radiation. These highly responsive genes were enriched for pathways involved in the response to DNA damage, apoptosis, cellular stress and inflammation (p < 0.01). Gamma radiation responsive genes included the same pathways, but extended to genes in vasculature specific pathways. Genes responsive to both radiation types (19 genes at q-value ≤ 0.1) showed almost perfectly superimposable dose-response relationships. We observed the same superimposable dose response relationship of gamma and proton radiations in a subset of genes validated by quantitative PCR not only in the aorta but also in liver, lung, heart and kidney. Despite a relative similar relative biological effectiveness of protons and gamma photons and the activation of canonical radiation response pathways by both radiation types, we detected marked differences in the genomic response. It seems plausible that these genomic differences translate into differences in the biological processes leading to cardiovascular pathologies.

2019-01-25 | GSE105266 | GEO

Differences of miRNA expression profiling between GIST and leiomyoma tissue samples acquired by Tunneling Bloc Biopsy

Project description:miRNA expression profiling between GIST and leiomyoma specimens taken by Tunneling Bloc Biopsy Nine GIST patients and seven gastric leiomyoma patients underwent endoscopic biopsy called Tunnel Block Biopsy. MiRNAs were extracted from the tissues, then.

2016-01-04 | E-GEOD-63453 | biostudies-arrayexpress

Genes differentially expressed in primary and metastatic liver GISTs.

Project description:Although the main cause of gastrointestinal stromal tumor (GIST) is due to gain-of-function mutation of the c-kit gene in the interstitial cells of Cajal, concomitant genetic or epigenetic changes other than c-kit are thought to occur in the development of metastasis. We used microarrays to identify genes that were up-regulated and down-regulated in the metastatic liver GIST. Three primary gastric GISTs without synchronous or metachronous metastasis and five metastatic liver tumors originated from gastric GIST were utilized for RNA extraction and hybridization on Affymetrix microarrays. No patients had received imatinib therapy before surgery.

2010-04-13 | E-GEOD-21315 | biostudies-arrayexpress

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