Exploiting a subtype-specific mitochondrial vulnerability for successful treatment of colorectal peritoneal metastases
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PROVIDER: PRJNA1014010 | ENA |
REPOSITORIES: ENA
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Project description:Peritoneal metastases (PM) in colorectal cancer (CRC) present a significant challenge due to limited treatment options and poor patient prognosis. While cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) offers curative potential for selected patients, its overall benefit remains limited compared to surgery alone. In this study we show that the majority of CRC-PM represent the CMS4-subtype. Despite CRS-HIPEC treatment, CMS4 patients had high rates of recurrent disease and mortality, indicating limited effectiveness of the treatment. To explore alternative treatment approaches, we queried large-scale compound screens and discovered the copper (Cu)-ionophore elesclomol (ES) as a highly effective agent against CMS4-specific disease models. ES exhibited rapid and selective cytotoxicity against CMS4 cells by targeting the oxidative phosphorylation machinery. CMS4 cells had reduced absolute mitochondrial content and lower expression of genes involved in oxidative phosphorylation, making them vulnerable to ES-induced cytotoxicity. Short exposures to ES combined with Cu (ES-Cu) resulted in near-complete growth inhibition of cancer cells, suggesting its potential for HIPEC-like intra-abdominal treatment procedures. Furthermore, ES-Cu demonstrated efficacy in preclinical models of PM, including CRC-PM and ovarian cancer organoids, and a HIPEC rat model of PM. These findings highlight ES-Cu as promising candidate for the local treatment of CRC-PM, with broader implications for other cancer types characterized by high incidence of PM.
2024-05-01 | GSE242676 | GEO
Project description:Exploiting the therapeutic vulnerability of IDH-mutant gliomas with zotiraciclib
| PRJNA1059002 | ENA
Project description:Prognostic Values of Immune Landscape in Ras-Mutant Colorectal Cancer Peritoneal Metastases
| PRJNA813588 | ENA
Project description:Jailkhani N, Clauser KR, Mak H, Rickelt S, Tian C, Whittaker CA, Tanabe KK, Purdy SR, Carr SA, and Hynes RO.2022.
Metastases are hard to detect and treat, and cause most cancer-related deaths. The relative lack of therapies targeting metastases represents a major unmet clinical need. The extracellular matrix or ECM forms a major component of the tumor microenvironment in both primary and metastatic tumors and certain ECM proteins can be selectively and abundantly expressed in such tumors. We propose that nanobodies against ECM proteins that show selective abundance in metastases can be used as vehicles for delivery of imaging and therapeutic cargoes. To gain a deeper understanding of the microenvironment of human metastases, we describe here an LC-MS/MS-based ECM signature shared by human TNBC and CRC metastases to different organs and provide evidence that this conserved set of ECM proteins is selectively elevated in other tumors. We also describe phage-display libraries of nanobodies raised against ECM-enriched preparations from human metastases from TNBC and CRC. As proof of concept, we developed selective and specific, high-affinity nanobodies against an example signature protein, Tenascin-C (TNC), known to be abundant in many tumor types and to play a role in metastases. We report that TNC is abundantly expressed in patient metastases and widely expressed across diverse metastatic sites originating from several primary tumor types. Using immuno-PET/CT we showed that anti-TNC nanobodies bind TNBC tumors and metastases with excellent specificity. We propose that such generic anti-tumor nanobodies are promising cancer-agnostic, in vivo tools for the delivery of therapeutics to tumor and metastatic ECM.
2022-03-28 | MSV000089136 | MassIVE
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
Project description:Exploiting a metabolic vulnerability in brain tumour stem cells using a brain-penetrant drug with safe profile
| PRJNA1065411 | ENA
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
Project description:A Novel Assessment of Metabolic Pathways in Peritoneal Metastases from Low-Grade Appendiceal Mucinous Neoplasms
| PRJNA1106805 | ENA
Project description:Our data suggest that neoadjuvant chemotherapy enhances anti-cancer responses of T cells in peritoneal metastases of patients with high-grade serous ovarian cancer but does not decrease levels of immune checkpoint molecules, providing a rationale for sequential chemo-immunotherapy.
2016-07-27 | GSE71340 | GEO
Project description:Isocitrate dehydrogenase (IDH)-mutant gliomas have distinctive metabolic and biological traits that may render them susceptible to targeted treatments. Here, by conducting a high-throughput drug screen, we pinpointed a specific susceptibility of IDH-mutant gliomas to zotiraciclib (ZTR). ZTR exhibited selective growth inhibition across multiple IDH-mutant glioma in vitro and in vivo models. Mechanistically, ZTR at low doses suppressed CDK9 and RNA Pol II phosphorylation in IDH-mutant cells, disrupting mitochondrial function and NAD+ production, causing oxidative stress.,. Integrated biochemical profiling of ZTR kinase targets and transcriptomics unveiled that ZTR-induced bioenergetic failure was linked to the suppression of PIM kinase activity. We posit that the combination of mitochondrial dysfunction and an inability to adapt to oxidative stress resulted in significant cell death upon ZTR treatment, ultimately increasing the therapeutic vulnerability of IDH-mutant gliomas. These findings prompted a clinical trial evaluating ZTR in IDH-mutant gliomas towards precision medicine (NCT05588141).
2024-12-31 | GSE252245 | GEO