Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Early downmodulation of tumor glycolysis predicts response to fasting-mimicking diet in triple-negative breast cancer patients

ABSTRACT: In preclinical experiments, cyclic fasting-mimicking diets (FMDs) showed broad anticancer effects in combination with chemotherapy. Among different tumor types, triple-negative breast cancer (TNBC) is exquisitely sensitive to FMD. However, the antitumor activity and efficacy of cyclic FMD in TNBC patients remain unclear. Here, we show that a severely calorie-restricted, triweekly, 5-day FMD regimen results in excellent pathologic complete response (pCR) rates (primary endpoint) and long-term clinical outcomes (secondary endpoints) when combined with preoperative chemotherapy in 30 patients with early-stage TNBC enrolled in the phase II trial BREAKFAST. Bulk and single-cell RNA-sequencing analysis revealed that highly glycolytic cancer cells, myeloid cells and pericytes from tumors achieving pCR undergo a significant, early downmodulation of pathways related to glycolysis and pyruvate metabolism. Our findings pave the wave for conducting larger clinical trials to investigate the efficacy of cyclic FMD in early-stage TNBC patients, and to validate early changes of intratumor glycolysis as a predictor of clinical benefit from nutrient restriction. ClinicalTrials.gov Identifier: NCT04248998

ORGANISM(S): Homo sapiens

PROVIDER: GSE279219 | GEO | 2024/10/15

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Fasting Mimicking Diet blocks breast cancer and cancer stem cells escape

Project description:Metastatic tumors remain lethal due to primary/acquired resistance to therapy or cancer stem cell (CSC)-mediated repopulation. We show that a fasting-mimicking diet (FMD) activates starvation escape pathways in triple negative breast cancer (TNBC) cells, which can be identified and targeted by drugs. In CSCs, FMD cycles lower glucose-dependent protein kinase A signaling and stemness markers to reduce cell number and increase mouse survival. Accordingly, metastatic TNBC patients with lower glycemia survive longer than those with higher baseline glycemia. By contrast, in differentiated cancer cells, FMD cycles activate PI3K-AKT, mTOR and CDK4/6 as survival/growth pathways, which can be targeted by drugs to promote tumor regression. FMD cycles also prevent hyperglycemia and other toxicities caused by these drugs. These data indicate that FMD has wide and differential effects on normal, cancer and cancer stem cells, allowing the rapid identification and targeting of starvation escape pathways and providing a method potentially applicable to many malignancies.

2022-01-26 | GSE184452 | GEO

Systemic and transcriptional response to intermittent fasting and fasting-mimicking diet in mice

Project description:Dietary restriction (DR) has multiple beneficial effects on health and longevity and can also improve the efficacy of certain therapies. Diets used to instigate DR are diverse and the corresponding response is not uniformly measured. We compared the systemic and liver-specific transcriptional response to intermittent fasting (IF) and commercially available fasting-mimicking diet (FMD) after short and long-term use in C57BL/6J mice. We show that neither DR regimen causes observable adverse effects in mice. The weight loss was limited to 20% and was quickly compensated during refeeding days. The slightly higher weight loss upon FMD versus IF correlated with stronger fasting response assessed by lower glucose levels and higher ketone body, free fatty acids, and especially FGF21 concentrations in blood. RNA sequencing demonstrated similar transcriptional programs in the liver after both regimens, with PPARα signalling as top enriched pathway, while on individual gene level FMD more potently increased gluconeogenesis-related, and PPARα and p53 target gene expression compared to IF. Repeated IF induced similar transcriptional responses as acute IF. However, repeated cycles of FMD resulted in blunted expression of genes involved in ketogenesis and fatty acid oxidation. Short-term FMD causes more pronounced changes in blood parameters and slightly higher weight loss than IF, while both activate similar pathways (particularly PPARα signalling) in the liver. On individual gene level FMD induces a stronger transcriptional response, whereas cyclic application blunts transcriptional upregulation of fatty acid oxidation and ketogenesis only in FMD. Hence, our comparative characterization of IF and FMD protocols renders both as effective DR regimens and serves as resource in the fasting research field.

2024-10-23 | GSE279842 | GEO

Fasting-mimicking diet reshapes antitumor immunity in cancer patients

Project description:To investigate whether the fasting-mimicking diet (FMD) affects intratumor immunity, we assessed the impact of one FMD cycle before surgery in matched tumor tissue specimens from 22 early-stage breast cancer patients. At the tumor level, FMD activated antitumor immune programs in early-stage breast cancer patients.

| EGAS00001004944 | EGA

Fasting Mimicking Diet cycles prevent effects of a high fat diet on cardiometabolic risk factors and lifespan

Project description:Diet-induced obesity is the central cause of diabetes, cardiovascular disease as well as metabolic syndrome. Here, we have studied the efficacy of cycles of a 4-5 day fasting mimicking diet (FMD) in inhibiting high-fat, high calorie diet (HFCD) -induced obesity in mature female C57BL/6 mice. We show that a monthly 5-day cycle of FMD inhibit HFCD-mediated obesity by causing a reduction in calorie intake and accumulation of visceral and subcutaneous fat depots without lean body mass loss. FMD cycles also increase cardiac vascularity, function and stress resistance, and reverse the hypercholesterolemia caused by the HFCD. The sustained activation of adipocyte genes associated with mitochondrial metabolism and biogenesis and the sustained ketogenesis in the HFCD-fed mice subjected to monthly cycles of FMD indicate a reprogramming of fat cell metabolism that is likely to be at the center of obesity reversal. All these improvements could explain the protection from early mortality elicited by the high-fat, high calorie diet.

2021-08-19 | GSE163060 | GEO

Marizomib eradicates primary and metastatic triple-negative breast cancer via proteasome and oxidative phosphorylation inhibition

Project description:Lacking effective targeted therapies, triple-negative breast cancer (TNBCs) is highly aggressive, metastatic, and clinically challenging breast cancer subtype with worst prognosis. Despite survival dependency on the proteasome pathway genes, the FDA-approved proteasome inhibitors induced minimal clinical response in TNBC patients due to weaker proteasome inhibition. Here, we show that a novel proteasome inhibitor Marizomib (Mzb), inhibited multiple proteasome catalytic activities and induced better anti-tumor response in TNBC cell line and patient-derived xenografts alone and in combination with a standard-of-care chemotherapy, doxorubicin. Mechanistically, Mzb inhibits oxidative phosphorylation (OXPHOS) via PGC-1α suppression in conjunction with proteasome inhibition in TNBC cells. Development of metastatic disease, especially brain metastasis, remains a reason for a greater mortality rate amongst TNBC patients. Mzb reduces lung and brain metastasis in vivo by reducing circulating tumor cells and the expression of multiple epithelial-to-mesenchymal genes. We also demonstrate that Mzb-induced OXPHOS inhibition upregulates glycolysis to fulfill the metabolic demand of TNBC cells and hence, combined inhibition of glycolysis with Mzb leads to a synergistic anti-cancer activity in vivo. Collectively, our data provide a strong rationale for the clinical evaluation of Mzb in primary and metastatic TNBC patients.

2020-05-27 | PXD015141 | Pride

Novel inhibition of central carbon metabolism pathways by Rac and Cdc42 inhibitorMBQ-167 and paclitaxel

Project description:Triple negative breast cancer (TNBC) represents a therapeutic challenge where standard chemotherapy is limited to paclitaxel. MBQ-167, a clinical stage small molecule inhibitor that targets Rac and Cdc42, inhibits tumor growth and metastasis in mouse models of TNBC. Herein, we investigated the efficacy of MBQ-167 in combination with paclitaxel in TNBC pre-clinical models, as a prelude to safety trials of this combination in advanced breast cancer patients. Individual MBQ-167 or combination therapy with paclitaxel was more effective at reducing TNBC cell viability and increasing apoptosis compared to paclitaxel alone. In orthotopic mouse models of human TNBC (MDA-MB-231 and MDA-MB-468), individual MBQ-167, paclitaxel, or the combination reduced mammary tumor growth with similar efficacy, with no apparent liver toxicity. However, paclitaxel single agent treatment significantly increased lung metastasis, while MBQ-167, single or combined, reduced lung metastasis. In the syngeneic 4T1/BALB/c model, combined MBQ-167 and paclitaxel decreased established lung metastases by ~80%. To determine the molecular basis for the improved efficacy of the combined treatment on metastasis, 4T1 tumor extracts from BALB/c mice treated with MBQ-167, paclitaxel, or the combination were subjected to transcriptomic analysis. Gene set enrichment identified specific downregulation of central carbon metabolic pathways by the combination of MBQ-167 and Paclitaxel but not individual compounds. Biochemical validation, by immunoblotting and metabolic Seahorse analysis, shows that combined MBQ-167 and paclitaxel reduces glycolysis. This study provides a strong rationale for the clinical testing of MBQ-167 in combination with paclitaxel as a potential therapeutic for TNBC and identifies a unique mechanism of action.

2024-08-05 | GSE272653 | GEO

Identification of Prognosis-Relevant Subgroups in Patients with Chemoresistant Triple Negative Breast Cancer

Project description:Triple-negative breast cancer (TNBC) patients with residual disease after neoadjuvant chemotherapy generally have worse outcome; however, some patients with residual tumor after neoadjuvant chemotherapy do not relapse. We hypothesize that there are subgroups of chemoresistant TNBC patients with different prognosis. In this study, 25 chemoresistant samples from 47 neoadjuvant chemotherapy-treated TNBC (The Methodist Hospital) are chosen for study We used gene expression data of TNBC patients with residual disease and different prognosis to molecularly define the clinically relevant subgroups, and developed a 7-gene prognostic signature for chemoresistant TNBCs

2013-01-15 | E-GEOD-43502 | biostudies-arrayexpress

Fasting Mimic Diet Inhibits Tumor Progression by Targeting IgA+ Cells in Colorectal Cancer

Project description:Globally, colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the third leading cause of cancer death. Evidence based on epidemiological, animal, and human studies strongly support the influence of dietary factors on CRC risk. Numerous prospective clinical trials have shown that fasting mimicking diets (FMD) exerts a wide range of antitumor effects. FMD as an adjunct to cancer treatment can reinforce tumor immunity and, therefore, boost the efficacy of chemo- and immunotherapy. Thus, it makes systematic analysis of key targets and molecular mechanisms of FMD in the immunomodulation important clinical significance in the prevention and treatment of CRC. In this study, we used single cell RNA sequencing (scRNA-seq) to analyze changes in tumor immune microenvironment of CRC after FMD treatment.

2023-08-14 | GSE212911 | GEO

Copanlisib Microarray Data

Project description:Chemotherapy is the mainstay treatment stragety for triple negative breast cancer (TNBC). However resistance to chemotherapy is common, leading to disease progression and death. Strategies that improve chemotherapy efficacy has the potential to reduce TNBC mortality. In this research, we demonstrated that the pan-PI3K inhibitor copanlisib, which is already in clinic to treat hematologic malignancies, enhanced the cytotoxicity of eribulin, a common chemotherapy used to treat taxane-resistant TNBC, in a panel of TNBC patient-derived xenograft (PDX) models. The improved tumor growth inhibition was irrespective of PI3K pathway alteration and was corroborated by the enhanced apoptotic induction observed in PDX tumors post combination therapy compared to each drug alone. The combination therapy inhibited eribulin-induced PI3K pathway activation, providing an underlying mechanism of action for its enhanced anti-tumor effect. Based on these results, a Phase I/II trial of this combination in patients with metastatic TNBC was initiated and is ongoing.

2024-04-26 | GSE243865 | GEO

Identification of Prognosis-Relevant Subgroups in Patients with Chemoresistant Triple Negative Breast Cancer

2013-01-15 | GSE43502 | GEO