Overcoming Breast Cancer Therapeutic Resistance by Multifunctional RNA Nanoparticles

通过多功能RNA纳米颗粒克服乳腺癌治疗耐药性

基本信息

批准号：
10600748
负责人：
Xiaoting Zhang
金额：
$ 40.65万
依托单位：
RNA NANOTHERAPEUTICS LLC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-07 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10600748
关键词：
Aftercare American Cancer Society Animals Antiestrogen Therapy Behavior Biological Products Body Weight Body Weight decreased Breast Cancer Cell Breast Cancer Patient Breast Cancer Treatment Breast Cancer cell line Breast Cancer therapy Cause of Death Cessation of life Clinical Clinical Trials Collaborations Data Development Diagnosis Disease Disease-Free Survival Doctor of Philosophy Dose ERBB2 gene Estrogen Antagonists Estrogen receptor positive Exhibits Fulvestrant Gene Expression Grant Heart Hematology Histology Human In Vitro Inflammatory Kidney Knowledge Lead Legal patent Letrozole Licensing Ligands Liver Malignant Neoplasms Mammary Neoplasms Measures Mediating Medicine Metastatic Neoplasm to the Lung Mission Molecular Monitor Mus Nanotechnology Neoplasm Metastasis Oligonucleotides Pathway interactions Patient Care Patient-derived xenograft models of breast cancer Persons Phase Physiological Pre-Clinical Model Private Sector Property Public Health RNA RNA vaccine RNA-targeting therapy Radiation therapy Refractory Research Resistance Safety Scientific Advances and Accomplishments Serum Small Business Technology Transfer Research Small Interfering RNA Tamoxifen Technology Testing Therapeutic Tissues Toxic effect Toxicokinetics Treatment Efficacy United States National Institutes of Health Universities Vertebral column Woman Work Xenograft procedure anticancer research aptamer base cancer stem cell commercialization effective therapy efficacy testing immunogenicity improved in vivo innovation malignant breast neoplasm mortality mouse model nanoparticle nanotherapeutic next generation novel novel therapeutics overexpression patient derived xenograft model resistance gene self assembly side effect small molecule success targeted treatment therapy resistant tumor tumor growth

项目摘要

Project Summary Breast cancer is one of the most frequent cancers and leading causes of death for women in the U.S. with an estimated 287,850 new diagnoses of invasive breast cancer and 43,250 deaths in 2022. The vast majority (75%) of breast cancer is estrogen receptor-positive (ER+) breast cancer but unfortunately, about 50% of them become resistant and fail to respond to the current anti-estrogen therapies. There are currently no effective treatment approaches available for these therapeutic resistant breast cancer and patients often rely on highly toxic chemo- and radiation therapies, etc. Thus, the development of new and improved targeted treatment to overcome resistance and minimize side effects is urgently needed. Recent work has established tissue-specific ER coactivator MED1 as a key anti-estrogen treatment resistance gene in breast cancer. Importantly, MED1 is overexpressed in about 50% of all breast cancers and clinical evidence indicates that MED1 expression highly correlates with poor disease-free survival of breast cancer patients. RNA Nanotherapeutics and its research partners at the University of Cincinnati have developed an innovative patented RNA nanotechnology-based approach to target MED1 in breast cancer cells to overcome treatment resistance. These highly stable multifunctional RNA nanoparticles have been successfully tested in in vitro and in vivo preclinical models and exhibited highly desirable tumor-specific targeting and treatment efficacy with no apparent toxicity. In this Phase I STTR, RNA Nanotherapeutics, in collaboration with its research partners at the University of Cincinnati and an oligonucleotide therapeutics CMC/strategy consultant, will carry out the following specific aims: 1) test the efficacy of the pRNA-HER2apt-siMED1 nanoparticles in vivo in breast cancer patient-derived xenograft (PDX) models; and 2) assess the safety and toxicity of the pRNA-HER2apt- siMED1 nanoparticles in vivo. We expect successful completion of these proposed studies will provide the results and data needed for our Phase II efforts and further engagement with private-sector investors to carry out IND enabling studies for clinical trials. With the recent increased FDA approvals and broad use of RNA- based vaccines and medicines, we fully anticipate that our RNA nanotechnology-based product represents a highly promising next-generation therapy to benefit breast cancer patient care and beyond.

项目概要乳腺癌是最常见的癌症之一，也是女性死亡的主要原因到 2022 年，美国预计将有 287,850 例新诊断浸润性乳腺癌，并有 43,250 例死亡。大多数 (75%) 乳腺癌是雌激素受体阳性 (ER+) 乳腺癌，但不幸的是，大约 50% 其中一些人对当前的抗雌激素疗法产生耐药性并且无法做出反应。目前没有对于这些耐药乳腺癌有有效的治疗方法，患者通常依赖因此，开发新的和改进的靶向药物迫切需要克服耐药性并尽量减少副作用的治疗。最近的工作有确定组织特异性 ER 共激活因子 MED1 作为乳腺中关键的抗雌激素治疗耐药基因癌症。重要的是，MED1 在大约 50% 的乳腺癌中过度表达，临床证据表明 MED1 表达与乳腺癌患者无病生存率差高度相关。核糖核酸 Nanotherapeutics 及其辛辛那提大学的研究合作伙伴开发了一种创新的基于专利RNA纳米技术的方法靶向乳腺癌细胞中的MED1以克服治疗反抗。这些高度稳定的多功能RNA纳米颗粒已成功通过体外和体外测试体内临床前模型，并表现出非常理想的肿瘤特异性靶向和治疗功效，且无需明显的毒性。在第一阶段 STTR 中，RNA Nanotherapeutics 与其研究合作伙伴合作辛辛那提大学和寡核苷酸治疗 CMC/策略顾问将开展以下具体目标：1）测试pRNA-HER2apt-siMED1纳米粒子在乳腺体内的功效癌症患者来源的异种移植（PDX）模型； 2) 评估 pRNA-HER2apt-的安全性和毒性体内的 siMED1 纳米颗粒。我们预计这些拟议研究的成功完成将提供我们第二阶段的努力以及与私营部门投资者的进一步接触所需的结果和数据 IND 使研究能够用于临床试验。随着最近 FDA 批准的增加和 RNA 的广泛使用基于疫苗和药物，我们完全预计我们基于 RNA 纳米技术的产品代表了非常有前途的下一代疗法，有利于乳腺癌患者的护理及其他方面。