NextGen RNAi Delivery to Breast Tumors for Selective mTORC2 Blockade

项目总结-不幸被诊断为三阴性乳腺癌（TNBC）的患者 有非常差的治疗选择，并遭受术后复发，转移， 由于这种毁灭性的疾病。复发是由于化疗后耐药细胞存活所致。 药物治疗和手术。复发性TNBC是致命的，没有分子靶向治疗被批准 对于这些患者。从化疗后残留疾病中采集的TNBC标本中， 导致磷脂酰肌醇-3激酶（PI 3 K）激活的基因组改变/ 雷帕霉素（mTOR）信号轴，表明该途径在TNBC化疗中的关键作用 抵抗和复发。根据公布的数据和我们自己的初步数据，我们特别 对含有mTOR激酶的复合物mTORC 2的治疗靶向感兴趣，我们认为它是一种 这一途径中的关键节点驱动TNBC中的细胞存活和耐药性。然而，没有现有的 选择性抑制mTORC 2的药物，激发了目前的建议，他专注于开发 第一个高选择性和有效的mTORC 2纳米药物抑制剂，用于治疗TNBC患者。我们 中心生物学假设（由我们严格的初步研究支持）是选择性mTORC 2 以避免mTORC 1信号传导的方式实现的抑制将产生上级治疗反应， 相对于现有药物的TNBC，可以抑制mTORC 1但不能抑制mTORC 2或非特异性阻断两者 mTORC 1和mTORC 2。这个多PI合作项目的总体目标是优化药代动力学 纳米颗粒技术，用于将mTORC 2靶向RNAi有效递送至TNBC肿瘤。我们特别 建议测试应用下一代纳米载体表面化学和双重载体/货物疏水化 原则，以产生优化的，使技术的发展，以前无法访问mTORC 2- 选择性治疗拟议的项目是唯一通过多PI的专业知识访问 具有生物工程专业知识的跨学科团队，在用于细胞内生物学的聚合物纳米技术方面 药物递送（杜瓦尔）、BC PI 3 K/mTOR信号通路治疗（Cook）和尖端临床前 BC模型，包括高度临床相关的患者来源的异种移植物（PDX）模型（Brantley-Seiders）。 该小组的跨学科技能将使以前无法访问的mTORC 2调查，并导致 为TNBC患者提供更有效的治疗。这一进展将促进前所未有的mTORC 2研究， 提供了治疗PI 3 K/mTOR驱动的TNBC的新策略。

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.