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G-CSF in Preventing Neutropenia During First-Line Treatment With Chemotherapy and Bevacizumab in Patients With Metastatic Colorectal Cancer

ABSTRACT: RATIONALE: G-CSF may prevent or control neutropenia caused by first-line therapy in patients with metastatic colorectal cancer. PURPOSE: This phase II trial is studying how well G-CSF works in preventing neutropenia during first-line treatment with chemotherapy and bevacizumab in patients with metastatic colorectal cancer.

DISEASE(S): Traitement En 1ère Ligne Dans Le Cancer Colorectal Métastatique Chez Des Patients, Homozygotes Pour Le Polymorphisme Ugt1a1*28 Du Promoteur Du Gène Codant Pour L’enzyme Ugt1a1,Colorectal Cancer,Colorectal Neoplasms,Neutropenia

PROVIDER: 2045094 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Targeting gamma-glutamyltransferase 1 on myeloid-derived suppressor cells prevents tumor progression caused by G-CSF in neutropenic mouse model

Project description:Myeloid-derived suppressor cells (MDSCs) are one of the major immunosuppressive cells that accumulate in tumor-bearing hosts. Since MDSCs suppress anti-tumor immunity and promote tumor progression, they are promising targets for cancer immunotherapy. Granulocyte colony-stimulating factor (G-CSF) is an agent for the treatment of chemotherapy-induced febrile neutropenia in patients with cancer. However, several reports reveal that G-CSF would play crucial immune-related adverse roles in tumor progression through MDSCs. In this study, we showed that MDSCs differentiated in the presence of G-CSF in vitro exhibited the enhanced proliferation and immunosuppressive activity compared with those differentiated without G-CSF. RNA-seq analysis demonstrated that G-CSF enhanced the immunosuppressive function of MDSCs through the upregulation of gamma-glutamyltransferase (GGT) 1. Moreover, in the EL4 lymphoma-bearing neutropenic mouse model, the administration of recombinant G-CSF increased MDSCs and attenuated anti-cancer effect of chemotherapy. We showed that the combination of GGsTop, a GGT inhibitor, with G-CSF could prevent tumor growth caused by G-CSF, without affecting the promoting myelopoiesis by G-CSF. These results suggest that targeting GGT1 on MDSCs can eliminate the effect of G-CSF in promoting tumor growth. GGsTop could be an attractive combination agent when receiving G-CSF treatment for febrile neutropenia in patients with cancer.

2022-05-13 | GSE183066 | GEO

Genistein Protects Hematopoietic Stem Cells against G-CSF-Induced DNA Damage

Project description:Granulocyte colony-stimulating factor (G-CSF) has been utilized to treat neutropenia in various clinical settings. Although clearly beneficial, there are concerns that use of G-CSF in certain conditions increases the risk of myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML). The most striking example is in severe congenital neutropenia (SCN). SCN patients develop MDS/AML at a high rate that is directly correlated to the cumulative lifetime dosage of G-CSF. MDS and AML that arise in these settings are commonly associated with chromosomal deletions. We demonstrate that chronic G-CSF treatment in mice results in expansion of the hematopoietic stem cell population. Furthermore, primitive hematopoietic progenitors from G-CSF–treated mice show evidence of DNA damage as demonstrated by an increase in double strand breaks and recurrent chromosomal deletions. Concurrent treatment with genistein, a natural soy isoflavone, limits DNA damage in this population. The protective effect of genistein appears to be related to its preferential inhibition of G-CSF–induced proliferation of hematopoietic stem cells. Importantly, genistein does not impair G-CSF–induced proliferation of committed hematopoietic progenitors, nor diminish neutrophil production. The protective effect of genistein was accomplished with plasma levels that are easily attainable through dietary supplementation. aCGH was performed using NimbleGen

2014-02-07 | GSE54737 | GEO

Genistein Protects Hematopoietic Stem Cells against G-CSF-Induced DNA Damage

Project description:Granulocyte colony-stimulating factor (G-CSF) has been utilized to treat neutropenia in various clinical settings. Although clearly beneficial, there are concerns that use of G-CSF in certain conditions increases the risk of myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML). The most striking example is in severe congenital neutropenia (SCN). SCN patients develop MDS/AML at a high rate that is directly correlated to the cumulative lifetime dosage of G-CSF. MDS and AML that arise in these settings are commonly associated with chromosomal deletions. We demonstrate that chronic G-CSF treatment in mice results in expansion of the hematopoietic stem cell population. Furthermore, primitive hematopoietic progenitors from G-CSFM-bM-^@M-^Streated mice show evidence of DNA damage as demonstrated by an increase in double strand breaks and recurrent chromosomal deletions. Concurrent treatment with genistein, a natural soy isoflavone, limits DNA damage in this population. The protective effect of genistein appears to be related to its preferential inhibition of G-CSFM-bM-^@M-^Sinduced proliferation of hematopoietic stem cells. Importantly, genistein does not impair G-CSFM-bM-^@M-^Sinduced proliferation of committed hematopoietic progenitors, nor diminish neutrophil production. The protective effect of genistein was accomplished with plasma levels that are easily attainable through dietary supplementation. aCGH was performed using NimbleGen DNA was extracted from bone marrow samples from mice treated with G-CSF or diluent for 4 months and analyzed using NimbleGen 3x720K mouse copy number arrays

2014-02-07 | E-GEOD-54737 | biostudies-arrayexpress

Caspofungin Acetate Compared With Amphotericin B Liposomal in Treating Patients With Persistent Fever and Neutropenia Following Cancer Treatment

Project description:RATIONALE: Caspofungin acetate or amphotericin B liposomal may be effective in preventing or controlling fever and neutropenia caused by chemotherapy, bone marrow transplantation, or peripheral stem cell transplantation. It is not yet known whether caspofungin acetate or amphotericin B liposomal is more effective for treating these side effects. PURPOSE: Randomized phase III trial to compare the effectiveness of caspofungin acetate with that of amphotericin B liposomal in treating patients who have persistent fever and neutropenia after receiving anticancer therapy.

| 2005680 | ecrin-mdr-crc

CSF

Project description:CSF

| PRJEB14301 | ENA

Microglial homeostasis requires balanced CSF-1/CSF-2 receptor signaling

Project description:ALSP is a CSF1R-deficiency dementia associated with increased CSF2 expression Monoallelic deletion of Csf2 rescues most behavioral deficits and histopathological changes in Csf1r+/- mice by preventing microgliosis and eliminating most microglial transcriptomic alterations, including those indicative of oxidative stress and demyelination Elevation of Csf2 transcripts and of several CSF-2 downstream targets in the brains of ALSP patients demonstrates that the mechanisms identified in the mouse model are functional in man. Our data provide new insights into the mechanisms underlying ALSP and identify CSF-2 as a therapeutic target.

2020-01-17 | GSE143823 | GEO

Severe Chronic Neutropenia International Registry

Project description:Severe Chronic Neutropenia International Registry

| PRJNA771428 | ENA

csf

Project description:csf Raw sequence reads

| PRJNA1079012 | ENA

Colony Stimulating Factor 1 (CSF-1) responses in human monocyte derived macrophages

Project description:Although the role of macrophage colony stimulating factor (M-CSF/CSF-1) in homeostasis and disease processes has been studied extensively in mice, little is known of the impact of this cytokine on differentiated human macrophages. Here we show that, in contrast to its effects on mouse bone marrow-derived macrophages (BMM), CSF-1 did not induce expression of urokinase plasminogen activator mRNA, repress expression of apolipoprotein E mRNA, or prime LPS-induced TNF secretion in human monocyte-derived macrophages (HMDM) from several independent donors. Using expression profiling, we show that CSF-1 dynamically regulated the expression of several genes that encode chemokines and chemokine receptors (e.g. CXCL10/IP-10, CXCL2, CCL7, SDF2L1, CXCR4) in HMDM. CSF-1 also upregulated the expression of several genes encoding enzymes of the cholesterol biosynthetic pathway (HMGCR, MVD, IDI1, FDPS, SQLE, CYP51A1, EBP, NSDHL, DHCR7 and DHCR24), while expression of ABCG1, encoding a cholesterol efflux transporter, was repressed. Although the CSF-1/CSF-1R system has been proposed as a target for the treatment of inflammatory and metastatic disease based on studies in rodents, this is the first systematic analysis of the effects of CSF-1 on mature human macrophages. Our data demonstrates that CSF-1 represents a further link between inflammation and cardiovascular disease, inflammtion and immunity. Keywords: Stimulus response

2008-11-14 | GSE11061 | GEO

TAS-102, Irinotecan, and Bevacizumab in Pre-treated Metastatic Colorectal Cancer (TABAsCO), A Phase II Clinical Trial. ClinicalTrials.gov NCT04109924

Project description:Background: The efficacy of FOLFIRI plus an antiangiogenesis biologic agent as 2nd line therapy for metastatic colorectal adenocarcinoma is limited. TAS-102 is a novel oral antimetabolite with a distinct mechanism of action from fluoropyrimidines. We evaluated the antitumor efficacy of TAS-102, irinotecan and bevacizumab in patients with pre-treated, advanced colorectal adenocarcinoma in a multicenter, phase II, single-arm study. Methods: Patients with advanced colorectal adenocarcinoma who had progressed after oxaliplatin and fluoropyrimidine and were eligible for treatment with bevacizumab were treated with irinotecan, bevacizumab, and TAS-102 in 28-day cycles. The primary endpoint was progression-free survival (PFS). Results: We enrolled 35 evaluable patients. The study was positive. The median PFS was 7.9 (90% CI 6.2-11.8) months (vs. 6 months in historical control, p=0.018). The median overall survival was 16.5 (90% CI 9.8-17.5) months. Sixty-seven percent of patients experienced grade 3 or higher treatment-related adverse events. The most common toxicities were hematological (neutropenia) and gastrointestinal (diarrhea, nausea, and vomiting). Conclusions: Irinotecan, TAS-102 and bevacizumab is an active 2nd line therapy for patients with metastatic colorectal adenocarcinoma. Neutropenia is common and can affect dose density/intensity mandating use of G-CSF. A randomized study versus standard of care therapy is warranted.

2024-08-26 | GSE275628 | GEO

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