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

 描述(申请人提供)：乳腺癌仍然是所有癌症中最常见的诊断之一，也是女性死亡的主要原因。因此，仍然迫切需要提高乳腺癌患者的治疗效果。移植物移植 自体脂肪组织是一种公认的修复肿块切除术后乳房形状缺陷的方法。我们独特的方法将利用自体脂肪组织作为药物储存库，通过预加载格列酮来移植，格列酮是FDA批准的治疗2型糖尿病的药物，具有强大的抗癌特性。格列酮会导致水肿、充血性心力衰竭和其他严重的副作用，这使得局部分娩特别有吸引力。这个 富含格列酮的脂肪会在局部产生脂联素，这是一种抗癌脂肪因子，也会起作用 通过对残留肿瘤细胞的作用来减少局部癌症复发。因此，自体脂肪将发挥两个关键作用：1)作为格列酮的缓释药库；2)作为生物反应器在肿瘤切除部位产生脂联素。通过这种方法，任何残留的肿瘤细胞都将通过格列酮和脂联素的联合抗肿瘤作用进行局部治疗。在本应用的目的1中，将确定在脂肪组织中预载的格列酮的浓度，该浓度可导致最大的脂联素和格列酮的释放以及对体外肿瘤细胞增殖的最大抑制。将进行格列酮加载到移植脂肪中的剂量递增研究，并测量随着时间的推移培养脂肪中脂联素和格列酮的释放。然后用载格列酮脂肪组织的培养液处理乳腺癌细胞，检测其对体外培养的乳腺癌细胞表型包括增殖、迁移/侵袭和凋亡率的影响。在目标2中，优化的格列酮负荷将被用于评估这种方法在使用患者来源的乳腺癌的小鼠模型中的有效性。这些肿瘤的优点是保持了患者肿瘤的异质性，以及对化疗的抵抗力。该方法将通过1)在肿瘤切除后移植格列酮脂肪库来评估该库抑制复发的效果，以及2)通过在肿瘤种植时移植格列酮脂肪库来评估其对肿瘤建立和转移的影响。主要结果包括肿瘤生长、细胞增殖、肿瘤细胞凋亡频率和转移。我们预计，治疗组的肿瘤较小，增殖减少，细胞凋亡增加，转移减少。这种局部治疗将在持续的一段时间内提供脂联素和格列酮的抗癌特性，总体目标是减少复发疾病的发生率。建议的局部治疗方法利用已有的技术(脂肪转移)和目前可用的治疗方法(格列酮)潜在地抑制肿瘤切除后的肿瘤复发。

 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.