Engineering Biomaterials to Modulate the Bone Marrow Microenvironment in Multiple Myeloma

工程生物材料调节多发性骨髓瘤的骨髓微环境

基本信息

批准号：
10744373
负责人：
Christian Gabriel FIGUEROA-ESPADA
金额：
$ 4.92万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-09 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10744373
关键词：
ATAC-seq Adhesions Antineoplastic Agents Antitumor Response Architecture Big Data Binding Biocompatible Materials Bioinformatics Biomedical Engineering Blood Circulation Bone Marrow Bortezomib Cancer Biology Cell Adhesion Cell Communication Cells Cessation of life Chemistry Clinic Clinical Complex Custom Cyclophilin A Development Disease Drug Delivery Systems Drug resistance E-Selectin Encapsulated Endothelial Cells Endothelium Engineering Formulation Funding Gene Silencing Genetic Transcription Goals Hematologic Neoplasms Histology Homing Hybrids In Vitro Knowledge Laboratories Laboratory Research Libraries Ligands Lipids Malignant Bone Marrow Neoplasm Malignant Neoplasms Mechanics Membrane Mentors Messenger RNA Methods Microfluidics Migration Assay Modality Modeling Multiple Myeloma Mus Nanotechnology Neoplasm Metastasis Nucleic Acids Patients Pennsylvania Phase Plasma Cells Polyethylene Glycols Polymers Postdoctoral Fellow Property Proteasome Inhibitor RNA Interference Therapy RNA Sequences RNA delivery Research Research Project Grants Resistance Resistance development Small Interfering RNA Specificity Surface Technology Testing Therapeutic Tissue Engineering Training Translating Tumor Biology Tumor Burden United States United States National Institutes of Health Universities Work Xenograft Model adhesion receptor aptamer cancer drug resistance cancer therapy clinical translation design dosage effective therapy high dimensionality improved in vitro Assay in vivo innovation migration nanoparticle new therapeutic target novel nucleic acid delivery post-doctoral training pre-doctoral programs screening skills small molecule targeted delivery therapeutic RNA therapeutic nanoparticles therapeutic target three-dimensional modeling transcriptome sequencing tumor tumor microenvironment tumor progression tumor-immune system interactions virtual whole body imaging

项目摘要

PROJECT SUMMARY Multiple myeloma (MM) accounts for ~23% of all hematologic malignancies with a 2.1% of cancer-related deaths in the United States in 2022. Despite tremendous efforts to develop effective therapies, MM remains largely incurable, and virtually all patients develop resistance to current therapies. Thus, there is an urgent clinical need for innovative and improved MM therapeutics. It has been demonstrated that bone marrow endothelium is critical to MM cell homing, progression, survival, and drug resistance. Specifically, cyclophilin A and E-selectin, a homing factor and adhesion receptor, respectively, expressed by bone marrow endothelial cells, are critical to MM survival. Thus, inhibition of cyclophilin A and E-selectin provides a potential therapeutic strategy to abolish MM dissemination and resistance. However, direct- and specific-inhibition of cyclophilin A and E-selectin by small molecules has been elusive. Thus, cyclophilin A and E-selectin are promising candidates for combination RNA interference (RNAi) therapy, which inhibits traditionally undruggable targets by directly reducing their messenger RNA (mRNA) expression. The challenge of utilizing small-interfering RNA (siRNA) is the need for safe and effective delivery methods, as siRNA degrades in the bloodstream and does not readily cross membranes. During my predoctoral studies, I have engineered a library of polymer-lipid hybrid biomaterials, that in combination with polyethylene glycol (PEG)-lipid conjugates and siRNA, assembled into nanoparticles (NPs) via microfluidic mixing. Through high-throughput in vivo screening, I identified a NP formulation with potent gene silencing in bone marrow endothelial cells in vivo. This formulation was used to encapsulate cyclophilin A siRNA, and showed inhibition of MM progression in vivo, and sensitized MM cells to the proteasome inhibitor bortezomib, a current therapeutic modality to treat MM. During the F99 phase, I will improve our NP design by incorporating bone marrow endothelial-targeting ligands on the NP’s surface to enhance their specificity to bone marrow endothelium, minimizing off-target effects. I will use our targeted NP to co-encapsulate cyclophilin A and E- selectin siRNA sequences, and evaluate their inhibition in vitro through adhesion and transendothelial migration assays, to determine the invasive abilities of MM cells. Further, I will test our co-delivery siRNA nanotechnology through a survival study in a validated mouse xenograft model of MM and quantify its effects either alone or in combination with bortezomib. This technology is expected to provide with a broadly enabling platform to target other bone marrow-homing cancers. For the K00 phase, I will identify a renowned cancer biology laboratory to study cell-cell interactions in the bone marrow immune microenvironment utilizing high-dimensional single-cell approaches and tissue-engineered models, with the aim to determine mechanisms that drive cancer progression and drug resistance. Completion of this project will successfully prepare me to launch an NIH-funded research laboratory that focuses on drug delivery targeting the tumor microenvironment as means of cancer therapy.

项目摘要多发性骨髓瘤（MM）占所有血液系统恶性肿瘤的约23％，占癌症相关的2.1％在2022年美国，尽管为开发有效的疗法做出了巨大努力，MM仍在很大程度上仍然无法治愈，几乎所有患者都会对当前疗法产生抗药性。那是紧迫的临床需求用于创新和改进的MM治疗。已经证明骨髓内皮很关键 MM细胞归巢，进展，存活和耐药性。具体而言，环磷脂A和E-选择素，A 由骨髓内皮细胞表达的分别表达的归因因子和粘合受体对 MM生存。那抑制环肽A和E-选择素提供了一种潜在的治疗策略来消除 MM传播和抵抗力。但是，通过直接和特异性抑制环磷脂A和E-选择蛋白小分子难以捉摸。那就是，环蛋白A和E-选择素是合并的候选者 RNA干扰（RNAi）疗法，该疗法通过直接降低其抑制了传统上不可能的靶标的信使RNA（mRNA）表达。使用小型互换RNA（siRNA）的挑战是需要安全有效的递送方法，因为siRNA在血液中降解，并且不容易交叉膜。在我的研究期间，我设计了一个聚合物 - 脂质混合材料的库，结合聚乙烯乙二醇（PEG） - 脂质结合物和siRNA，组装成纳米颗粒（NPS）通过微流体混合。通过体内筛选高通量，我确定了具有潜在基因的NP公式在体内沉默骨髓内皮细胞。该公式用于封装环磷脂siRNA，并显示体内MM进展的抑制作用，以及对蛋白酶体抑制剂硼替佐米的敏感MM细胞，当前的热模态以治疗MM。在F99阶段，我将通过编码来改善我们的NP设计 NP表面上的骨髓内皮靶向配体，以增强其对骨髓的特异性内皮，最小化脱靶效应。我将使用我们的靶向NP共同服用环粒蛋白A和E- 选择素siRNA序列，并通过粘合剂和跨内皮迁移评估其体外抑制作用测定，以确定MM细胞的侵入性能力。此外，我将测试我们的共递送siRNA纳米技术通过在经过验证的MM的小鼠Xenographic模型中进行的生存研究，并单独或在与硼替佐米结合。预计该技术将为目标提供广泛的平台其他骨髓癌。对于K00阶段，我将确定一个著名的癌症生物学实验室利用高维单细胞的骨髓免疫环境中的研究细胞 - 细胞相互作用方法和组织工程模型，目的是确定驱动癌症进展的机制和耐药性。该项目的完成将成功地为我启动NIH资助的研究做好准备专注于针对肿瘤微环境作为癌症治疗的药物的实验室。