Ceramide Nanoliposomes in Combination with Focused Ultrasound for Treating Breast Cancer

神经酰胺纳米脂质体联合聚焦超声治疗乳腺癌

基本信息

批准号：
9750255
负责人：
MARK KESTER
金额：
$ 18.32万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9750255
关键词：
4T1 Adoptive Transfer Affect Animals Apoptosis Blood Blood Circulation CD8-Positive T-Lymphocytes Cancer Model Cardiac Cell Aging Cell Cycle Arrest Cell Death Cell Proliferation Cells Ceramides Cessation of life Chemistry Clinical Combined Modality Therapy Conduct Clinical Trials Data Dendritic Cells Development Dose Drug Delivery Systems Drug Targeting ERBB2 gene Enzymes Estrogen Receptors Evaluation Focused Ultrasound Focused Ultrasound Therapy Food and Drug Administration Drug Approval Formulation Foundations Future Gene Delivery Gene Expression Goals Growth Heating Hematology Hydrophobicity Hyperthermia Immunologic Markers Immunologics Immunosuppression Immunotherapeutic agent Individual Institution Intravenous Laboratories Light Lipids Liposomes Liver Lung Malignant - descriptor Malignant Neoplasms Mammary Neoplasms Mass Spectrum Analysis Measures Mediating Metabolism Modality Mus N-caproylsphingosine Nanotechnology Patients Phase I Clinical Trials Phase I/II Trial Physiological Pilot Projects Price Primary carcinoma of the liver cells Progesterone Receptors Publishing Refractory Regimen Relapse Research Project Grants Safety Second Messenger Systems Spleen System Testing Therapeutic Thermal Ablation Therapy Time Tissues Toxic effect Treatment Efficacy Tumor Immunity Tumor Tissue Ultrasonic Therapy Vaccination anti-tumor immune response base cancer subtypes expectation experience follow-up hormone therapy image guided image guided intervention image guided therapy improved in vivo insight lymph nodes malignant breast neoplasm nanoliposome outcome forecast patient population relating to nervous system synergism systems research targeted treatment triple-negative invasive breast carcinoma tumor tumor growth tumor microenvironment tumor progression uptake

项目摘要

Triple negative breast cancer poses a persistent clinical challenge given that it is refractory to most available endocrine or targeted therapies. Indeed, patient prognosis is dim in light of shorter median time to relapse and death compared to other breast cancer subtypes. Broadly speaking, our group is working to develop an improved therapy regimen for this patient population. We propose to achieve this by combining 2 separate treatment modalities [i.e. ceramide nanoliposomses (CNL) and image-guided focused ultrasound (FUS) ablation/heating] that we postulate will offer therapeutic synergy. Our expectation of synergy between CNL and FUS is based on evidence that (i) they are both capable of reducing, perhaps through distinct mechanisms, immunosuppression in the tumor microenvironment and (ii) the delivery of systemically administered liposomes is markedly enhanced in FUS-targeted tumors. The proposal consists of 2 specific aims. Aim 1 will be to determine which FUS regime (sub-ablative heating or partial thermal ablation) most effectively enhances the treatment efficacy of ceramide nanoliposomes against breast cancer. FUS will be applied to 4T1 (triple negative) breast tumors in combination with CNL administration. Determination of the most efficacious FUS regime will be made based upon tumor growth and animal survival data. Mass spectrometry of excised tumors will ascertain whether FUS enhances ceramide delivery. We will also perform comprehensive immunological analyses on tumor tissue, tumor draining lymph nodes (LNs), non-draining LN, spleen, and blood. Aim 2 will then be to investigate whether the most therapeutically efficacious combination of FUS and CNL is associated with toxicity. We will repeat the most efficacious FUS+CNL combination from Aim 1 and assess toxicity (liver and cardiac enzymes, cardio/neural and pulmonary physiological parameters, and hematological and immunological markers). Finally, we will perform ex-vivo studies to examine whether FUS application affects CNL chemistry. Going forward, note that Co-PI Kester has already successfully received an IND from the FDA (IND 109487) to initiate a phase 1 trial. If the proposed studies are successful, a follow-on phase 1/2 trial with CNL and FUS would ensue at our institution.

三阴性乳腺癌构成了持续的临床挑战，因为它对大多数人来说都是难治性的可用内分泌或靶向治疗。事实上，由于中位治疗时间较短，患者的预后很暗淡。与其他乳腺癌亚型相比，复发率和死亡率更高。从广义上讲，我们小组正在努力开发针对该患者群体的改进的治疗方案。我们建议通过结合 2 个独立的治疗方式[即神经酰胺纳米脂质体 (CNL) 和图像引导聚焦超声 (FUS) 我们假设消融/加热将提供治疗协同作用。我们对 CNL 和 CNL 之间协同效应的期望 FUS 基于以下证据：(i) 它们都能够通过不同的机制减少，肿瘤微环境中的免疫抑制和（ii）全身给药的脂质体的递送在 FUS 靶向肿瘤中显着增强。该提案包含 2 个具体目标。目标 1 是确定哪种 FUS 制度（亚烧蚀加热或部分热消融）最有效地增强神经酰胺纳米脂质体的治疗效果对抗乳腺癌。 FUS将与CNL联合应用于4T1（三阴性）乳腺肿瘤行政。将根据肿瘤生长和情况来确定最有效的 FUS 方案。动物生存数据。切除肿瘤的质谱分析将确定 FUS 是否增强神经酰胺送货。我们还将对肿瘤组织、肿瘤引流淋巴液进行全面的免疫学分析淋巴结 (LN)、非引流 LN、脾脏和血液。目标 2 将是调查是否最 FUS 和 CNL 的治疗有效组合与毒性相关。我们会重复最多的目标 1 中有效的 FUS+CNL 组合并评估毒性（肝脏和心肌酶、心脏/神经和肺部生理参数以及血液学和免疫学标志物）。最后我们将表演离体研究检查 FUS 应用是否影响 CNL 化学。展望未来，请注意 Co-PI Kester 已成功收到 FDA 的 IND (IND 109487) 以启动一期试验。如果如果拟议的研究取得成功，我们的机构将随后进行 CNL 和 FUS 的后续 1/2 期试验。