NextGen RNAi Delivery to Breast Tumors for Selective mTORC2 Blockade

下一代 RNAi 递送至乳腺肿瘤以选择性阻断 mTORC2

基本信息

批准号：
10439746
负责人：
DANA M BRANTLEY-SIEDERS
金额：
$ 44.13万
依托单位：
VANDERBILT UNIVERSITY
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：
2018-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10439746
关键词：
Acute Allografting Automobile Driving Autophagocytosis Biological Biomedical Engineering Blood Vessels Breast Breast Cancer Model Breast Cancer Patient Breast Cancer Treatment Cell Survival Cells Characteristics Chemistry Chemoresistance Chemotherapy-Oncologic Procedure Clinical Complex DNA Sequence Alteration Data Development Diagnosis Disease Drug Combinations Drug Delivery Systems Drug Kinetics Drug resistance Drug usage Excision Experimental Models FRAP1 gene Failure Feedback Formulation Fostering Future Gene Silencing Goals Growth Human Cell Line Immune Immunocompetent Investigation Investigational Therapies Lead Lung Malignant Neoplasms Mammary Neoplasms Measures Molecular Molecular Target Nanotechnology Neoadjuvant Therapy Neoplasm Metastasis Operative Surgical Procedures Outcome Pathway interactions Patient-derived xenograft models of breast cancer Patients Pharmaceutical Preparations Pharmacotherapy Phenotype Phosphatidylinositols Phosphorylcholine Phosphotransferases Physiological Polymers Pre-Clinical Model Publishing RNA Interference Recurrence Research Personnel Residual Tumors Role Safety Signal Pathway Signal Transduction Small Interfering RNA Specimen Surface Technology Testing Therapeutic Therapeutic Index Transgenic Model Treatment Efficacy Work Xenograft procedure base cancer stem cell cancer subtypes chemotherapy clinically relevant cooking effective therapy efficacy study epithelial to mesenchymal transition experience improved in vivo inhibitor insight interest kinase inhibitor malignant breast neoplasm molecular targeted therapies mortality mouse model nanocarrier nanomedicine nanoparticle neoplastic cell next generation novel novel strategies novel therapeutics patient derived xenograft model stem-like cell success technology development therapeutic nanoparticles therapeutic target translational study treatment response treatment strategy triple-negative invasive breast carcinoma tumor tumor growth tumor microenvironment

项目摘要

Project Summary– Patients who receive the unfortunate diagnosis of triple negative breast cancer (TNBC) have very poor therapeutic options and suffer from a high rate of post-surgery recurrence, metastasis, and mortality due to this devastating disease. Recurrence occurs due chemotherapy-resistant cell survival after drug treatment and surgery. Recurrent TNBCs are lethal, and no molecularly targeted therapies are approved for these patients. Up to 40% of TNBC specimens collected from residual disease after chemotherapy have genomic alterations that cause activation of the phosphatidyl inositol-3 kinase (PI3K) / mechanistic target of rapamycin (mTOR) signaling axis, suggesting the crucial role of this pathway in TNBC chemotherapy resistance and recurrence. Based on published data and our own preliminary data, we are especially interested in therapeutic targeting of the mTOR kinase-containing complex mTORC2, which we believe is a key node in this pathway that drives cell survival and drug resistance in TNBCs. However, there are no existing drugs that selectively inhibit mTORC2, motivating the current proposal which his focused on development of the first highly selective and potent nanomedicine inhibitor of mTORC2 for treating patients with TNBC. Our central biological hypothesis (supported by our rigorous preliminary studies) is that selective mTORC2 inhibition, achieved in a way that spares mTORC1 signaling, will produce superior therapeutic response in TNBCs relative to existing drugs that can inhibit mTORC1 but not mTORC2 or that nonspecifically block both mTORC1 and mTORC2. The overall goal of this collaborative, multi-PI project is to optimize pharmacokinetics of nanoparticle technology for effective delivery of mTORC2-targeting RNAi to TNBC tumors. We specifically propose to test apply next generation nanocarrier surface chemistry and dual carrier/cargo hydrophobization principles to yield an optimized, enabling technology for development of a previously inaccessible mTORC2- selective therapeutic. The proposed project is uniquely accessible through the expertise of the multi-PI interdisciplinary team with bioengineering expertise in polymeric nanotechnologies for intracellular biologic drug delivery (Duvall), BC PI3K/mTOR signaling pathway therapeutics (Cook), and cutting edge preclinical models of BC, including highly clinically-relevant patient derived xenograft (PDX) models (Brantley-Seiders). The group’s interdisciplinary skillset will enable previously-inaccessible mTORC2 investigations and lead to more effective therapies for TNBC patients. This advance will foster unprecedented studies of mTORC2 while providing a novel strategy to treat PI3K/mTOR-driven TNBCs.

项目摘要 – 不幸诊断出三阴性乳腺癌 (TNBC) 的患者治疗选择非常差，并且术后复发、转移和复发率很高这种破坏性疾病的死亡率是由于化疗耐药细胞存活后发生的。药物治疗和手术是致命的，目前还没有批准分子靶向治疗。对于这些患者，从化疗后残留病灶中采集的 TNBC 标本中有高达 40% 导致磷脂酰肌醇 3 激酶 (PI3K) 激活的基因组改变/机制目标雷帕霉素 (mTOR) 信号轴，表明该通路在 TNBC 化疗中的关键作用根据已发表的数据和我们自己的初步数据，我们尤其如此。对包含 mTOR 激酶的复合物 mTORC2 的治疗靶向感兴趣，我们认为这是一个该途径中驱动 TNBC 细胞存活和耐药性的关键节点然而，目前尚不存在。选择性抑制 mTORC2 的药物，激发了当前的提议，他的重点是开发第一个高选择性和有效的 mTORC2 纳米药物抑制剂，用于治疗 TNBC 患者。中心生物学假设（得到我们严格的初步研究的支持）是选择性 mTORC2 以不影响 mTORC1 信号传导的方式实现的抑制将在以下方面产生优异的治疗反应： TNBC 与可抑制 mTORC1 但不能抑制 mTORC2 或非特异性阻断两者的现有药物相关 mTORC1 和 mTORC2 这个协作性多 PI 项目的总体目标是优化药代动力学。我们特别研究了将 mTORC2 靶向 RNAi 有效递送至 TNBC 肿瘤的纳米颗粒技术。建议测试应用下一代纳米载体表面化学和双载体/货物疏水化产生优化的技术的原则，用于开发以前无法访问的 mTORC2- 拟议的项目可以通过多位 PI 的专业知识来独特地实现。具有细胞内生物聚合物纳米技术生物工程专业知识的跨学科团队药物输送 (Duvall)、BC PI3K/mTOR 信号通路治疗 (Cook) 和尖端临床前 BC 模型，包括临床高度相关的患者衍生异种移植 (PDX) 模型 (Brantley-Seiders)。该小组的跨学科技能将使以前无法进行的 mTORC2 调查成为可能，并导致这一进展将促进 mTORC2 的研究，同时为 TNBC 患者提供更有效的治疗。提供了一种治疗 PI3K/mTOR 驱动的 TNBC 的新策略。