Phase I/II study of prevention of Colorectal Cancer CRC with Allopurinol in High-Risk Subjects
Ontology highlight
ABSTRACT:
DISEASE(S): Colon Adenoma,Chemoprevention Of Colorectal Cancer
PROVIDER: 2519335 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Antigen Ki-67 is a nuclear protein expressed in proliferating mammalian cells. It is widely used in cancer histopathology but its functions remain unclear. Here, we show that Ki-67 controls heterochromatin organisation. Altering Ki-67 expression levels did not significantly affect cell proliferation in vivo. Ki-67 mutant mice developed normally and cells lacking Ki-67 proliferated efficiently. Conversely, upregulation of Ki-67 expression in differentiated tissues did not inhibit cell cycle arrest. Ki-67 interactors included proteins involved in nucleolar processes and chromatin regulators. Ki-67 depletion disrupted nucleologenesis but did not inhibit pre-rRNA processing. In contrast, it altered gene expression. Ki-67 silencing also had wide-ranging effects on chromatin organisation, disrupting heterochromatin compaction and long-range genomic interactions. Trimethylation of histone H3K9 and H4K20 at heterochromatin was strongly reduced. Overexpression of human or Xenopus Ki-67 induced ectopic heterochromatin formation. Altogether, our results suggest that Ki-67 expression in proliferating cells spatially organises heterochromatin, thereby controlling gene expression.
2018-10-26 | PXD003551 | Pride
Project description:Ki-67 molecular functions and properties have remained quite obscure for a long time, despite its importance as a major proliferation marker in clinic. Only recently it has been shown that Ki-67 has a major role in the formation of the mitotic chromosome periphery compartment, and it is a protein phosphatase 1 (PP1) binding protein. Understanding Ki-67 functions at different stages of the cell cycle has been so far hindered by the fact that the different phenotypes observed in cells upon Ki-67 depletion could be the outcome of secondary effects. Here, by using Auxin-inducible-degron (AID) system, we show that Ki-67 degradation at the G1/S boundary causes the disassembly of the replication machinery and leads to DNA damage. This triggers the interferon response and causes replication delay. Our results support the model whereby Ki-67 contributes to replication forks protection, and it is important for timely DNA replication and genome maintenance.
2024-04-13 | PXD037513 | Pride
Project description:Purpose: Valproic acid(VPA) has anti-cancer activity attributed to histone deacetylase inhibition(HDACi). We published the Genomically–Derived Sensitivity Signature for VPA(GDSS-VPA), a gene expression biomarker predicting breast cancer sensitivity to VPA in vitro and in vivo. We conducted a window-of-opportunity study examining the tolerability of VPA and the ability of the GDSS-VPA to predict biologic changes in breast tumors from VPA. Methods: Eligible women had untreated breast cancer with breast tumors over 1.5 cm. After a biopsy, women took VPA for 7-12 days, increasing from 30mg/kg/day PO divided BID to a maximum of 50mg/kg/day. After VPA treatment, serum VPA level was measured followed by breast surgery or a biopsy. Tumor proliferation was assessed by Ki-67 immunohistochemistry. Peripheral blood mononuclear cells(PBMCs) histone acetylation was assessed by Western blot. Results: Thirty women were evaluable. The median age was 54(range 31-73). 52% of women tolerated 50mg/kg/day, but 10% missed more than two doses due to adverse events(AEs). Grade 3 AEs included one patient with vomiting and diarrhea and one with fatigue. The end serum VPA level correlated with change in PBMC histone acetylation(rho=0.451, p=0.024). 50% of women with triple-negative breast cancer(TNBC) had a Ki-67 reduction of at least 10%, compared with 17% of other women. GDSS-VPA correlated with a Ki-67 decrease of at least 10%(AUC 0.66). Conclusions: Most women tolerate VPA. VPA treatment caused a decrease in proliferation of breast tumors. The genomic biomarker correlated with decreased proliferation. HDACi is a valid strategy for drug development in TNBC using gene expression biomarkers.
2016-12-17 | GSE83530 | GEO
Project description:Protein inhibitor of activated STAT (PIAS) are E3 SUMO ligases playing important roles in protein stability and signaling transduction pathways. PIAS proteins are overexpressed in the triple-negative breast cancer cell line MDA-MB-231, and PIAS knockout (KO) results in a reduction in cell proliferation and cell arrest in S phase. However, the molecular mechanisms underlying PIAS functions in cell proliferation and cell cycle remain largely unknown. Here, we used quantitative SUMO proteomics to explore the regulatory role of PIAS SUMO E3 ligases upon CRISPR/Cas9 KO of individual PIAS. A total of 1422 sites were identified, and around 10% of SUMO sites were regulated following KO of one or more PIAS genes. We identified protein substrates that were either specific to individual PIAS ligase or regulated by several PIAS ligases. Ki-67 and TOP2A, which are involved in cell proliferation and epithelial-to-mesenchymal transition, are SUMOylated at several lysine residues by all PIAS ligases, suggesting a level of redundancy between these proteins. Confocal microscopy and biochemical experiments revealed that SUMOylation regulated TOP2A protein stability, while this modification is involved in the recruitment of Ki-67 nucleolar proteins containing SUMO interacting motif. These results provide novel insights into both the redundant and specific regulatory mechanisms of cell proliferation and cell cycle mediated by PIAS SUMO E3 ligases.
2023-02-02 | PXD023841 | Pride
Project description:Transcriptional profiling of isogenic human cervical cancer cell line HCT-116, comparing cells treated with control shRNA or with Ki-67 shRNA, grown either in vitro or as tumours in nude mice. The aim was to assess effects of loss of Ki-67 on gene expression during exponential cell growth and in tumours
2021-02-18 | GSE162365 | GEO
Project description:Ki-67 is highly expressed in proliferating cells, characteristic that made the protein a very important marker widely used in the clinic. However, its molecular functions and properties have remained quite obscure for a long time. Only recently important discoveries have shed some light on Ki-67 function and shown that Ki-67 has a major role in the formation of mitotic chromosome periphery compartment, it is associated with protein phosphatase one (PP1) and regulates chromatin structure in both interphase and mitosis. However, it is still difficult to understand the specific molecular function of this protein since the different phenotypes could be the outcome of secondary effects. In fact, the studies so far conducted have used either RNAi or knock-out cells: the former could lead to phenotypes which are the sum of a cascade of complex events while the latter could be the outcome of compensatory mechanisms taking place. To address these problems, we have generated a cell line system for the rapid manipulation of Ki-67 by introducing an Auxin-inducible-degron (AID) tag in both alleles of the endogenous Ki-67 gene in HCT116 cells. This AID system allows rapid protein depletion by the addition of Auxin.
2024-04-07 | E-MTAB-12279 | biostudies-arrayexpress
Project description:<p>The biological determinants of sensitivity and resistance to immune checkpoint inhibitors are not completely understood. To elucidate the role of intratumoral T-cells and its association with the tumor genomic landscape, we perform paired whole exome DNA sequencing and multiplexed quantitative immunofluorescence (QIF) in pre-treatment samples from non-small cell lung carcinoma patients treated with PD-1 axis blockers. QIF was used to simultaneously measure the level of CD3+ tumor infiltrating lymphocytes (TILs), in situ T-cell proliferation (Ki-67 in CD3) and effector capacity (Granzyme-B in CD3). Whole exome sequencing reported in the number/type of mutations and predicted class I and class II mutant neoantigens.</p>
| phs001618 | dbGaP
Project description:Endocrine therapy in patients with breast cancer can be limited by the problem of resistance. Preclinical studies suggest that complete blockade of the estrogen receptor (ER) combined with inhibition of the epidermal growth factor receptor (EGFR) can overcome endocrine resistance. We tested this hypothesis in a phase II neoadjuvant trial of anastrozole and fulvestrant combined with gefitinib in postmenopausal women with newly diagnosed ER-positive breast cancer. After a baseline tumor core biopsy, patients were randomized to receive anastrozole and fulvestrant (AF) or anastrozole, fulvestrant, and gefitinib (AFG) for 3 weeks. After a second biopsy at 3 weeks, all patients received AFG for 4 months and surgery was done if the tumor was operable. The primary endpoint was best clinical response by RECIST criteria and secondary endpoints were toxicity and change in biomarkers. The study closed after 15 patients were enrolled because of slow accrual. Median patient age was 67 years and median clinical tumor size was 7 cm. Four patients had metastatic disease present. Three patients withdrew before response was assessed. In the remaining twelve patients, there were two complete clinical responses (17%), three partial responses (25%), five had stable disease (41%), and two (17%) had progressive disease. Most common adverse events were rash in four patients, diarrhea in four, joint symptoms in three, and abnormal liver function tests in three. There were no grade 4 toxicities and all toxicities were reversible. At 3 weeks, cell proliferation as measured by Ki-67 was significantly reduced in the AFG group (p value= 0.01) with a parallel reduction in the expression of the Cyclin D1 (p value=0.02). RNA microarray data showed a corresponding decrease in the expression of cell cycle genes. These results suggest that AFG was an effective neoadjuvant therapy and consistently reduced proliferation in ER-positive tumors.
2011-12-20 | GSE33658 | GEO
Project description:In-depth clinical proteomic analysis of laser-microdissected HOT lesions of five luminal B breast cancer Ki-67 high subtype.
2020-10-12 | PXD021912 | JPOST Repository
Project description:Colonic adenomatous polyps are pre cancer lesions and are used as intermediate markers for testing agents with potential cancer prevention.
Meriva© is a bioavailable form of curcumin, a polyphenolic compound obtained from turmeric (Curcuma longa L.) endowed with anti-inflammatory, antioxidant and antitumor effects. In vivo data indicate that curcumin formulated with phosphatidylcholine furnishes higher blood levels of parent agent than natural curcumin.
Mirtoselect©, an anthocyanin mixture from bilberry containing isolated cyanidin-3-glucoside (C3G), the most abundant anthocyanin in diet, prevents intestinal adenoma formation in the Apc(Min) mouse model.
The investigators hypothesize that the combination of both agents will decrease the expression of proteins involved in colon tumorigenesis relative to placebo.
The change of biomarker expression between pre-treatment biopsy and post-treatment endoscopic resection in the target adenoma and the normal rectal mucosa will be the response measures.
The primary response measure is the change of immunohistochemical (IHC) expression of β-catenin in adenomatous tissue and normal rectal mucosa. Secondary response measures are the changes of IHC Nuclear Factor-Kβ (NFKβ), cell proliferation by Ki-67 Labeling Index and apoptosis by P53 in adenomatous and adjacent normal mucosa.
The study design is a phase II, randomized, double blind, placebo controlled, window of opportunity trial of the combination of Mirtoselect 1 gr/day+Meriva 1 gr/day or placebo. Subjects with histological confirmation of colorectal adenomatous polyps >1 cm not suitable to immediate complete removal will be enrolled in a 4-week intervention trial before endoscopic polypectomy.
The demonstration of a biological activity of the two agent combination may provide the rationale for a phase III trial aimed at reducing the risk of colon cancer in high risk subjects.
| 2152076 | ecrin-mdr-crc