Randomised Control Cross-over Trial to Test How Dietary Plant Sterols Modify Tumour Promoting Capabilities of Non-tumour Host Cells in Volunteers With Elevated LDL-C
试验速览
- 阶段
- 不适用
- 入组人数
- 50
- 试验地点
- 2
- 主要终点
- To change circulating oxysterols levels after phytosterols intervention.
研究概览
简要总结
Several types of human cells convert cholesterol into other molecules, including oxysterols. Oxysterols can promote breast cancer growth and help tumours to spread. Some breast cancer types recruit other cells (host cells) able to produce oxysterols within the local cancer environment.
How these other cells help breast tumours metastasize or resist chemotherapy is not well understood, but epidemiological and clinical studies suggest elevated LDL-C is associated with worse survival, poorer response to therapy and an increased propensity for disease relapse in breast cancer patients. In this trial the investigators will test how an LDL-C lowering dietary intervention (using commercially available phytosterol added food products), alters the ability of non-cancer cells (adipocytes, fibroblasts and macrophages) collected from high LDL-C volunteers to change chemotherapy response and metastatic process in breast cancer cells.
In this trial, volunteers with high LDL-C levels will be recruited by the University of Leeds, and divided randomly into two arms that cross over. The experimental period (yogurt drink enriched with phytosterols) and placebo period (non-enriched yogurt drink) will each last for 8 weeks, alternated with a 4 weeks of wash-out period. Samples will be collected 4 times (week-0, week-8, week-12, week-20) during the study and will include blood, white blood cells (macrophages), and fat tissue cells. Measurements will include oxysterol, LDL-C and phytosterol concentrations (volunteers' serum/plasma, media from the host cells/breast cancer experimental culture) and how the host cells alter the behaviour of cancer cells in the laboratory.
详细描述
Delivery of cholesterol to extra-hepatic tissues by LDL has a profound impact on different host cell types, many of which themselves have been implicated in BCa metastasis and chemoresistance.
Despite accumulating data, it is still unknown how host-cells help breast tumours metastasise or evade chemotherapy. The molecular link between cholesterol and metastasis may involve the enzymatic hydroxylation (an intermediate step in bile acid synthesis) of cholesterol. The synthesis and secretion of oxysterols into the tumour microenvironment and this is exacerbated in individuals with elevated LDL-cholesterol. This process, occurring largely in macrophages, adipocytes and fibroblasts, leads to biosynthesis and cellular export of oxysterols , which drive DNA mutations through oxidative stress, confer resistance to chemotherapy, enhance BCa growth and metastasis, and are elevated in serum of BCa patients at metastatic relapse. Our pilot data show non-cancer host-cells activate oxysterols signalling and drug resistance protein expression and confer chemotherapy resistance in adjacent cancer cells.
The investigators therefore propose to test the hypothesis that the reason epidemiological and clinical studies find elevated LDL-C and its co-morbidities associate with worse survival in BCa patients, is because the host-cells of these patients have enhanced cholesterol metabolic flux leading to increased oxysterols production and improved tolerance of chemotherapy and promotion of cancer metastatic pathways.
This trial is a multicentre cross-over double blind clinical trial in which volunteers with LDL-C ≥160mg/dL (4.1 mmol/L), recruited at the University of Leeds and/or identified through Horizon 2020 project PATHWAY-27, will be randomised into two arms of intervention, Group A (experimental arm) will be given an yoghurt drink enriched with PSS and Group B (placebo comparator) will be given yoghurt drink non-enriched with PSS. Each dietary intervention will last for 8 weeks, alternated with a 4 weeks of wash out period. This trial wants to highlight the superiority of the PSS (yoghurt drink enriched) to placebo (yoghurt drink non-enriched) intervention on the improvement of the serum/plasma and host cells (adipocytes and macrophages) LDL-C, oxysterols , PSS levels in high LDL-C levels volunteers and in respective conditioned media from the host cells/BCa cell lines co-culture, and superiority of the PSS to placebo intervention on the improvement of the cholesterol panel levels involved in BCa tolerance of chemotherapy and metastatic progression, according also to the molecular and genetical pathways.
Because of the unknown effect of PSS on the oxysterols metabolism and of its consequent chemotherapy and anti-metastatic proprieties, the trial will be divided in two phases (I and II):
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Prevention
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
盲法说明
All trial investigators will be blinded to the intervention, except for the CI. The CI will keep a record of interventions administrated. All trial participants and outcome assessors will be blinded to the intervention. Each food product has the same flavour and taste, as well as the same packaging to ensure blinding in maintained throughout study.
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 是
入选标准
- •Subjects capable of giving informed consent;
- •Non-pregnant, non-nursing female;
- •Age between 18-65 years old;
- •LDL-C ≥130mg/dL (3.4mmol/L) or TC/HDL ratio >4;
- •BMI ≥25 (kg/m2)
排除标准
- •Subjects who are under treatment with lipophilic statins;
- •Subjects under any other supplementation that improve cholesterol levels (i.e. monacolin, other PSS enriched products);
- •Subjects under any weight loss or lipid lowering dietary plan;
- •Present or past chronic diseases: CVDs, cancer, know positive hepatitis B virus surface antigen (HBsAg), hepatitis C (HCV) antibody or HIV, cirrhosis, gastrointestinal disorders (i.e. irritable bowel syndrome, Crohn's disease, celiac disease, bowel control problems), kidney diseases, autoimmune diseases, endocrine disorders, metabolic diseases (i.e. diabetes type I and type II, familiar hypercholesterolemia), neurological diseases;
- •Diagnosed eating disorders according to the Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5);
- •Past or planned within the trial period bariatric surgery;
- •Past or planned within the trial period gastrointestinal resections;
- •Corticosteroid and chronic inflammatory therapy;
- •Consumption within the preceding 8 weeks of other compounds capable of influencing cholesterol metabolism (bile acid-binding resins, ezetimibe, psyllium, fish oil supplements, soya lecithin, phytoestrogens and other PSS-fortified foods);
- •Females pregnant or females who are planning pregnancy;
- •Females breastfeeding;
- •Phytosterolemia diseases;
- •Participants with allergies to any of the substances presents in the yoghurt drink chosen for the trial: citric acid, anhydrous, sodium chloride, disodium edetate dehydrate, polysorbate 80, sodium hydroxide, Hypersensitivity to E. Coli derived proteins, nuts, peanuts, egg and soy proteins. Participants with a latex allergy are also not eligible as the inner needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex);
- •Participants with allergies to lidocaine;
- •Participation in other dietary or clinical trials.
结局指标
主要结局
To change circulating oxysterols levels after phytosterols intervention.
时间窗: Serum/plasma oxysterols concentrations will be measured during all the steps of the trial (baseline, 8th week, 12nd week, 20th week)
The changes of oxysterols content in serum/plasma after 8 weeks of phytosterols intervention compared to placebo. After the dietary intervention, we expect to observe a change of -20% in circulating 27-hydroxycholesterol content (marker of oxysterols systemic levels). Concentration of oxysterols using LC-MS/MS measurement of plasma in 50 subjects after placebo and after intervention.
次要结局
- Change intra-cellular adipocyte and macrophages oxysterols concentrations(Serum/plasma/medium oxysterols concentrations will be measured during all the steps of the trial (baseline, 8th week, 12nd week, 20th week))
- Study of adipocytes and macrophages interaction with breast cancer cell lines(Gene expression will be measured during all the steps of the trial (baseline, 8th week, 12nd week, 20th week))
- Study the effect of phytosterols on LDL-C(Serum/plasma phytosterols and lipid concentrations will be measured during all the steps of the trial (baseline, 8th week, 12nd week, 20th week))
- Study the effect of phytosterols on HDL-C(Serum/plasma phytosterols and lipid concentrations will be measured during all the steps of the trial (baseline, 8th week, 12nd week, 20th week))
- Study the effect of phytosterols on Total Cholesterol(Serum/plasma phytosterols and lipid concentrations will be measured during all the steps of the trial (baseline, 8th week, 12nd week, 20th week))
- Study the effect of phytosterols on Triglycerides(Serum/plasma phytosterols and lipid concentrations will be measured during all the steps of the trial (baseline, 8th week, 12nd week, 20th week))
- Study the effect of phytosterols on non-HDL-C(Serum/plasma phytosterols and lipid concentrations will be measured during all the steps of the trial (baseline, 8th week, 12nd week, 20th week))
- Quantify phytosterols in blood samples from volunteers.(Serum/plasma phytosterols and lipid concentrations will be measured during all the steps of the trial (baseline, 8th week, 12nd week, 20th week))
研究者
James Thorne
Chief Investigator
University of Leeds