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Medium-throughput drug screening of patient-derived organoids from colorectal peritoneal metastases can be used to guide therapy

ABSTRACT: Medium-throughput drug screening of patient-derived organoids from colorectal peritoneal metastases can be used to guide therapy

PROVIDER: PRJNA629386 | ENA |

REPOSITORIES: ENA

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Medium-throughput drug screening of patient-derived organoids from colorectal peritoneal metastases can be used to guide therapy

Project description:Purpose: Colorectal cancer (CRC) patients with peritoneal metastases (CRPM) have limited treatment options and the lowest CRC survival rates. We aimed to determine whether organoid testing could help guide precision treatment for CRPM patients, as the clinical utility of prospective, functional drug screening including non-standard agents is unknown. Experimental Design: CRPM organoids (peritonoids) isolated from patients underwent parallel next-generation sequencing and medium-throughput drug panel testing ex vivo to identify specific drug sensitivities for each patient. We measured the utility of such a service including: success of peritonoid generation, time to cultivate peritonoids, reproducibility of the medium-throughput drug testing, and documented changes to clinical therapy as a result of the testing. Results: Peritonoids were successfully generated and validated from 68% (19/28) of patients undergoing standard care. Genomic and drug profiling was completed within 8 weeks and a formal report ranking drug sensitivities was provided to the medical oncology team upon failure of standard care treatment. This resulted in a treatment change for 2 patients, one of whom had a partial response despite previously progressing on multiple rounds of standard care chemotherapy. The barrier to implementing this technology in Australia is the need for drug access and funding for off-label indications. Conclusions: Our approach is feasible, reproducible and can guide novel therapeutic choices in this poor prognosis cohort, where new treatment options are urgently needed. This platform is relevant to many solid organ malignancies.

2020-05-31 | GSE147971 | GEO

Medium-throughput drug screening of patient-derived organoids from colorectal peritoneal metastases can be used to guide therapy

Project description:Medium-throughput drug screening of patient-derived organoids from colorectal peritoneal metastases can be used to guide therapy

| PRJNA622682 | ENA

Medium-throughput drug screening of patient-derived organoids from colorectal peritoneal metastases can be used to guide therapy

Project description:Medium-throughput drug screening of patient-derived organoids from colorectal peritoneal metastases can be used to guide therapy

| PRJNA629387 | ENA

Expression data of peritoneal macrophages from Wild-type mouse cultured in control or serine/glycine-depleted medium.

Project description:Activation of signaling pathways downstream of Toll-like receptor 4 upregulate expression of genes related to serine metabolism. We cultured peritoneal macrophages in control or serine/glycine-depleted medium for 24 hr, stimulated them with LPS (10 ng/ml) for 6 or 12 hr, and collected them to compare the gene expression. Microarray analysis revealed that serine/glycine-depletion in peritoneal macrophages upregulates gene expression of enzymes for serine biosynthesis.

2021-03-31 | GSE156325 | GEO

Prognostic Values of Immune Landscape in Ras-Mutant Colorectal Cancer Peritoneal Metastases

Project description:Prognostic Values of Immune Landscape in Ras-Mutant Colorectal Cancer Peritoneal Metastases

| PRJNA813588 | ENA

Medium-throughput Drug Screening of Patient-derived Organoids from Colorectal Peritoneal Metastases to Direct Personalized Therapy.

Project description:PurposePatients with colorectal cancer with peritoneal metastases (CRPMs) have limited treatment options and the lowest colorectal cancer survival rates. We aimed to determine whether organoid testing could help guide precision treatment for patients with CRPMs, as the clinical utility of prospective, functional drug screening including nonstandard agents is unknown.Experimental designCRPM organoids (peritonoids) isolated from patients underwent parallel next-generation sequencing and medium-throughput drug panel testing ex vivo to identify specific drug sensitivities for each patient. We measured the utility of such a service including: success of peritonoid generation, time to cultivate peritonoids, reproducibility of the medium-throughput drug testing, and documented changes to clinical therapy as a result of the testing.ResultsPeritonoids were successfully generated and validated from 68% (19/28) of patients undergoing standard care. Genomic and drug profiling was completed within 8 weeks and a formal report ranking drug sensitivities was provided to the medical oncology team upon failure of standard care treatment. This resulted in a treatment change for two patients, one of whom had a partial response despite previously progressing on multiple rounds of standard care chemotherapy. The barrier to implementing this technology in Australia is the need for drug access and funding for off-label indications.ConclusionsOur approach is feasible, reproducible, and can guide novel therapeutic choices in this poor prognosis cohort, where new treatment options are urgently needed. This platform is relevant to many solid organ malignancies.

| S-EPMC8366292 | biostudies-literature

Tailoring heated intra-peritoneal Mitomycin C for peritoneal metastases originating from colorectal carcinoma – A translational approach to improve survival

Project description:Patients with peritoneal metastases (PM) originating from colorectal carcinoma (CRC) are curatively treated by cytoreductive surgery (CRS) and hyperthermic intra-peritoneal chemotherapy (HIPEC) with Mitomycin C (MMC). We aim to improve patient selection and personalize treatment for patients treated with HIPEC by predicting MMC sensitivity. MMC sensitivity was determined for 12 CRC cell lines using two separate assays. Thirty-seven genes related to the FA-BRCA pathway, ATM-ATR pathway and enzymatic activation of MMC were correlated on expression array platform to MMC sensitivity. Low sensitivity correlated with a decrease in BLM (p=0.01) and BRCA2 (p=0.02) on mRNA expression level. Both genes are part of the Fanconi Anaemia-BRCA (FA-BRCA) pathway and therefore, functionality of the FA-BRCA pathway in cell lines was determined using chromosomal breakage assay and Western Blot for key protein FANCD2. However, FA-BRCA pathway functionality showed no correlation to MMC sensitivity. BLM was further analysed by staining for the corresponding protein with immunohistochemistry (IHC) on both CRC cell lines and patient material. In cell lines, weak intensity staining by IHC correlated to high sensitivity (p=0.04) to MMC. High BLM protein expression was significantly correlated to a decreased survival in patients after CRS and HIPEC (p=0.04). We are the first to have found a possible predictive biomarker for PM with CRC.

2015-12-01 | GSE50494 | GEO

Exploiting a subtype-specific mitochondrial vulnerability for successful treatment of colorectal peritoneal metastases

Project description:Exploiting a subtype-specific mitochondrial vulnerability for successful treatment of colorectal peritoneal metastases

| PRJNA1014010 | ENA

A Novel Assessment of Metabolic Pathways in Peritoneal Metastases from Low-Grade Appendiceal Mucinous Neoplasms

Project description:Background: There is a paucity of targeted therapies for patients with pseudomyxoma peritonei (PMP) secondary to low-grade appendiceal mucinous neoplasms (LAMNs). Dysregulated metabolism has emerged as a hallmark of cancer, and the relationship of metabolomics and cancer is an area of active scientific exploration. We sought to characterize phenotypic differences found in peritoneal metastases (PM) derived from LAMN versus adenocarcinoma. Methods: Tumors were washed with phosphate-buffered saline (PBS), microdissected, then dissociated in ice-cold methanol dried and reconstituted in pyridine. Samples were derivatized in tert-butyldimethylsilyl (TBDMS) and subjected to gas chromatography-coupled mass spectrometry. Metabolites were assessed based on a standard library. RNA sequencing was performed, with pathway and network analyses on differentially expressed genes.Results: Eight peritoneal tumor samples were obtained and analyzed: LAMNs (4), and moderate to poorly differentiated adenocarcinoma (colon [1], appendix [3]). Decreases in pyroglutamate, fumarate, and cysteine in PM from LAMNs were found compared with adenocarcinoma. Analyses showed the differential gene expression was dominated by the prevalence of metabolic pathways, particularly lipid metabolism. The gene retinol saturase (RETSAT), downregulated by LAMN, was involved in the multiple metabolic pathways that involve lipids. Using network mapping, we found IL1B signaling to be a potential top-level modulation candidate. Conclusions: Distinct metabolic signatures may exist for PM from LAMN versus adenocarcinoma. A multitude of genes are differentially regulated, many of which are involved in metabolic pathways. Additional research is needed to identify the significance and applicability of targeting metabolic pathways in the potential development of novel therapeutics for these challenging tumors.

2024-05-01 | GSE266352 | GEO

A Novel Assessment of Metabolic Pathways in Peritoneal Metastases from Low-Grade Appendiceal Mucinous Neoplasms

Project description:A Novel Assessment of Metabolic Pathways in Peritoneal Metastases from Low-Grade Appendiceal Mucinous Neoplasms

| PRJNA1106805 | ENA