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

• 批准号: 10524103
• 负责人: DANA M BRANTLEY-SIEDERS
• 金额: $ 7.28万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 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/10524103
• 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

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-不幸被诊断为三阴性乳腺癌(TNBC)的患者 有非常糟糕的治疗选择，并遭受术后复发，转移，和 这种毁灭性疾病导致的死亡率。化疗耐药细胞存活后复发 药物治疗和手术。复发的TNBCs是致命的，没有分子靶向治疗被批准 对这些病人来说。从化疗后残留病变中收集的TNBC样本中，高达40%的人 导致磷脂酰肌醇-3激酶(PI3K)激活的基因组改变/机制靶点 雷帕霉素(MTOR)信号轴，提示该通路在TNBC化疗中的关键作用 耐药和复发。根据已公布的数据和我们自己的初步数据，我们特别 有兴趣治疗靶向的mTOR激酶复合体mTORC2，我们认为这是一种 该通路中的关键节点驱动TNBCs的细胞存活和耐药。然而，没有现有的 选择性抑制mTORC2的药物，激励他目前专注于开发的建议 第一个用于治疗TNBC患者的高度选择性和有效的mTORC2纳米药物抑制剂。我们的 中心生物学假说(由我们严格的初步研究支持)是选择性mTORC2 抑制，以一种省略mTORC1信号的方式实现，将产生卓越的治疗反应 TNBCs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、多PI项目的总体目标是优化药代动力学 纳米颗粒技术用于有效地将mTORC2靶向RNAi输送到TNBC肿瘤。我们特别指出 建议试验应用下一代纳米载体表面化学和双载体/货物疏水 为开发以前无法访问的mTORC2而产生优化、使能技术的原则- 选择性治疗。拟议的项目可以通过多个PI的专业知识独一无二地访问 在用于细胞内生物的聚合物纳米技术方面拥有生物工程专业知识的跨学科团队 药物传递(Duvall)、BC PI3K/mTOR信号通路疗法(COOK)和尖端临床前 BC的模型，包括高度临床相关的患者来源的异种移植(PDX)模型(Brantley-Seiders)。 该组织的跨学科技能将使以前无法接触到的mTORC2调查成为可能，并导致 对TNBC患者更有效的治疗。这一进展将促进对mTORC2的前所未有的研究，同时 为治疗PI3K/mTOR驱动的肿瘤提供了一种新的策略。