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 - 接受三重阴性乳腺癌（TNBC）的不幸诊断的患者（TNBC） 治疗选择差，遭受了较高的手术后复发率，转移和 由于这种毁灭性疾病而导致的死亡率。复发是由于化学疗法耐药性细胞存活而发生的 药物治疗和手术。复发性TNBC是致命的，没有分子靶向疗法被批准 对于这些患者。化学疗法后，多达40％从残留疾病收集的TNBC标本具有 引起磷脂酰肌醇-3激酶（PI3K） /机械靶标的基因组改变 雷帕霉素（MTOR）信号轴，表明该途径在TNBC化学疗法中的关键作用 阻力和复发。根据已发布的数据和我们自己的初步数据，我们尤其是 对含MTOR激酶的复合物MTORC2的治疗靶向感兴趣，我们认为这是一个 该途径中的关键节点驱动TNBC中的细胞存活和耐药性。但是，没有现有的 有选择地抑制MTORC2的药物，激发了当前的提议 MTORC2的第一个高度选择性和潜在的纳米医学抑制剂用于治疗TNBC患者。我们的 中央生物学假设（在我们严格的初步研究的支持下）是选择性MTORC2 抑制作用，以避免MTORC1信号传导的方式实现，将产生优越的治疗反应 TNBC相对于可能抑制MTORC1但不抑制MTORC2或未指定障碍的现有药物 MTORC1和MTORC2。这个合作，多PI项目的总体目标是优化药代动力学 纳米颗粒技术的有效输送MTORC2靶向RNAi到TNBC肿瘤。我们具体 测试的建议应用下一代纳米载体表面化学和双载体/货物疏水 原则是为了开发以前无法访问的MTORC2-的优化，有效的技术 选择性理论。通过Multi-Pi的专业知识，该提议的项目可以独特地访问 跨学科团队具有生物工程专业知识，用于细胞内生物学的聚合物纳米技术 药物输送（Duvall），BC PI3K/MTOR信号通路疗法（Cook）和尖端临床前 BC的模型，包括高度临床上的患者衍生型（PDX）模型（Brantley-seiders）。 该小组的跨学科技能集将实现以前无法访问的MTORC2调查，并导致 TNBC患者更有效的疗法。这一进步将促进对MTORC2的前所未有的研究 提供了一种治疗PI3K/MTOR驱动的TNBC的新型策略。