Fat transplant for glitazone delivery and adiponectin production to inhibit breast cancer

脂肪移植用于格列酮输送和脂联素生产以抑制乳腺癌

基本信息

批准号：
8958679
负责人：
Jayant Prasad Agarwal
金额：
$ 16.2万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8958679
关键词：
Address Adipocytes Adipose tissue Adverse effects Affect Apoptosis Apoptotic Autologous Autologous Transplantation Beds Bioreactors Breast Breast Cancer Cell Breast Cancer Patient Breast Cancer cell line Breast cancer metastasis CCL4 gene Cause of Death Cell Proliferation Cell Survival Cell Therapy Cells Clinic Clinical Clinical Data Conditioned Culture Media Congestive Heart Failure Data Defect Development Diabetes Mellitus Diagnosis Distant Dose Drug Delivery Systems Early treatment Edema Effectiveness Endocrine Excision FDA approved Fatty acid glycerol esters Frequencies Goals Growth Heterogeneity Human Implant In Vitro Incidence Inhibition of Cell Proliferation Left Localized Malignant Neoplasm Lung Malignant Neoplasms Mammary Neoplasms Mammary Tumorigenesis Measures Metastatic to Methods Modeling Monitor Mus Neoplasm Metastasis Operative Surgical Procedures Outcome Patients Pharmaceutical Preparations Phenotype Pioglitazone Production Property Proteins Radiation Radiation therapy Rattus Recurrence Recurrent disease Resected Residual Cancers Resistance Role Shapes Site Source Staging Systemic Therapy Techniques Testing Therapeutic Thiazolidinediones Time Toxic effect Translating Transplantation Treatment Efficacy Treatment Protocols Tumor-Associated Process Woman adiponectin breast lumpectomy cancer cell cancer recurrence cell motility chemotherapy improved in vivo innovation lipophilicity lymph nodes malignant breast neoplasm migration mouse model neoplastic cell novel therapeutic intervention pre-clinical prevent primary outcome public health relevance repaired research clinical testing rosiglitazone treatment strategy tumor tumor growth tumor initiation tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Breast cancer remains one of the most frequently diagnosed of all cancers, and a leading cause of death among women. As such, there is still a critical need to increase the efficacy of treatments for breast cancer patients. Transplantation of autologous adipose tissue is an accepted treatment to repair defects in breast shape after lumpectomy. Our unique approach will utilize the autologous adipose tissue as a drug reservoir by preloading the transplant with glitazones, FDA approved drugs for the treatment of diabetes-mellitus-2 that have potent anti-cancer properties. The glitazones can induce edema, congestive heart failure and other serious side effects making localized delivery particularly attractive. The glitazone-laden fat will locally produce adiponectin, an anti-cancer adipokine, which will also act to reduce local cancer recurrence through its actions on remnant tumor cells. Thus, the autologous fat will serve two key functions: 1) act as a sustained release drug depot for the glitazones and 2) act as a bioreactor to produce adiponectin at the site of tumor resection. With this approach, any remaining tumor cells will be treated locally by the combined anti-tumor actions of both the glitazone and adiponectin. In Aim 1 of this application the concentration of glitazone preloaded in adipose tissue that results in the greatest adiponectin and glitazone release and greatest inhibition of tumor cell proliferation in vitro will be determined. Dose escalation studies of glitazone loaded into explanted fat will be performed and the release of adiponectin and glitazone from the cultured fat measured over time. Breast cancer cells will then be treated with the media from the glitazone-loaded adipose tissue, and its effect on cultured breast cancer cell phenotype including proliferation, migration/invasion and incidence of apoptosis in vitro measured. In Aim 2, the optimized glitazone load will be utilized to evaluate the efficacy of this approach in a mouse model using patient-derived breast cancer tumors. These tumors have the advantage of maintaining the heterogeneity observed in patient tumors, as well as the resistance to chemotherapy. The approach will be tested 1) by transplanting glitazone-fat depots after tumor resection to assess the efficacy of the depot to inhibit recurrence, and 2) by transplanting glitazone-fat depots at time of tumor seeding, to assess its effect on tumor establishment and metastasis. Primary outcomes include tumor growth, cell proliferation, frequency of apoptotic tumor cells, and metastasis. We expect the treated group will have smaller tumors, reduced proliferation, increased apoptosis, and reduced metastasis. This localized treatment will deliver the anti-cancer properties of adiponectin and glitazone over a sustained period of time, with the overall goal of reducing the incidence of recurrent disease. The proposed localized treatment approach utilizes an established technique (fat transfer) and currently available therapeutics (glitazones) to potentially inhibit tumor recurrence following a lumpectomy.

描述（由适用提供）：乳腺癌仍然是所有癌症中最常诊断的乳腺癌之一，并且是女性中主要的死亡原因。因此，仍然需要提高乳腺癌患者治疗的效率。移植自体脂肪组织是一种公认的治疗方法，可修复乳房切除术后乳房形状的缺陷。我们独特的方法将通过用Glitazones预装移植，FDA批准的药物来治疗具有潜在抗癌特性的糖尿病 - 糖尿病 - 批准药物来利用自体脂肪组织作为药物库。 Glitazones可以诱导水肿，充血性心力衰竭和其他严重的副作用，使局部分娩特别有吸引力。丙酮脂肪将在本地产生脂联素，抗癌脂蛋白，也将作用通过对残留肿瘤细胞的作用来减少局部癌症复发。这是自体脂肪将发挥两个关键功能：1）充当glitazones的持续释放药物矿床，2）在肿瘤切除部位充当生物反应器，以产生脂联素。使用这种方法，任何剩余的肿瘤细胞都将通过glitazone和脂联素的抗肿瘤作用进行局部治疗。在本应用的目标1中，将确定将确定在脂肪组织中预加载的Glitazone浓度，从而确定将确定最大的脂联素和葡萄酮释放，并且将确定在体外对肿瘤细胞增殖的最大抑制作用。将进行装入外植物脂肪的葡萄球的剂量启发研究，并从随着时间的推移测量的培养脂肪中释放脂联素和glitazone。然后，将从负载的脂肪组织中用培养基处理乳腺癌细胞，以及其对培养的乳腺癌细胞表型的影响，包括在体外测量的体外测量中的增殖，迁移/侵袭和凋亡的发生率。在AIM 2中，将利用优化的亮酮负荷来评估使用患者衍生的乳腺癌肿瘤在小鼠模型中这种方法的效率。这些肿瘤的优点是保持在患者肿瘤中观察到的异质性以及对化学疗法的抗性。该方法将进行1）通过在肿瘤切除后移植glitazone-fat沉积物来评估沉积物对抑制复发的效率的效率，以及2）通过在肿瘤播种时移植Glitazone-Fat沉积物，以评估其对肿瘤的建立和转移的影响。主要结果包括肿瘤生长，细胞增殖，凋亡肿瘤细胞的频率和转移。我们预计，经过治疗的组将具有较小的肿瘤，减少增殖，凋亡增加和转移减少。这种局部治疗将在持续的时间内赋予脂联素和辉煌的抗癌特性，其总体目标是减少复发性疾病的事件。拟议的局部治疗方法利用已建立的技术（脂肪转移）和目前可用的治疗剂（Glitazone）来抑制肿瘤切除术后肿瘤复发。