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

• 批准号: 10771651
• 负责人: Xiaoting Zhang
• 金额: $ 5.5万
• 依托单位: RNA NANOTHERAPEUTICS LLC
• 依托单位国家: 美国
• 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/10771651
• 关键词: Antiestrogen Therapy; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Treatment; Breast Cancer therapy; Cause of Death; Cessation of life; Clinical; Clinical Trials; Collaborations; Data; Development; Disease-Free Survival; Estrogen Antagonists; Estrogen receptor positive; Exhibits; Human; In Vitro; Knowledge; Lead; Legal patent; Malignant Neoplasms; Medicine; Mission; Nanotechnology; Newly Diagnosed; Oligonucleotides; Patient Care; Patient-derived xenograft models of breast cancer; Patients; Persons; Phase; Pre-Clinical Model; Private Sector; Public Health; RNA; RNA vaccine; Radiation therapy; Research; Resistance; Scientific Advances and Accomplishments; Small Business Technology Transfer Research; Testing; Therapeutic; Tissues; Toxic effect; Treatment Efficacy; United States National Institutes of Health; Universities; Untranslated RNA; Woman; Work; anticancer research; chemotherapy; effective therapy; efficacy testing; improved; in vivo; innovation; malignant breast neoplasm; nanoparticle; nanotherapeutic; next generation; overexpression; resistance gene; safety assessment; side effect; targeted treatment; therapy resistant; tumor

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.

项目摘要 乳腺癌是世界上最常见的癌症之一，也是妇女死亡的主要原因。 据估计，2022年美国新增浸润性乳腺癌诊断病例287,850例，死亡43,250例。浩瀚无边 大多数乳腺癌(75%)是雌激素受体阳性(ER+)乳腺癌，但不幸的是，约50% 他们中的一些人对目前的抗雌激素疗法产生了抵抗力，并且没有反应。目前没有 对于这些治疗耐药的乳腺癌，可用的有效治疗方法和患者经常依赖 关于高毒性的化疗和放射治疗等。因此，开发新的和改进的有针对性的 迫切需要克服耐药性和最大限度减少副作用的治疗。最近的工作有 建立组织特异性ER辅活化子MED1作为乳腺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的表达与乳腺癌患者较差的无病生存率高度相关。核糖核酸 辛辛那提大学的纳米疗法及其研究伙伴开发了一种创新的 基于专利RNA纳米技术的靶向MED1的乳腺癌细胞治疗方法 抵抗。这些高度稳定的多功能RNA纳米颗粒已经在体外和 体内临床前模型，并显示出非常理想的肿瘤特异性靶向和治疗效果 明显的毒性。在这个第一阶段，RNA纳米疗法与它的研究伙伴合作，在 辛辛那提大学和一位寡核苷酸疗法CMC/战略顾问将开展 具体目标如下：1)检测PRNA-HER2apt-siMED1纳米粒在乳房的体内疗效 2)评估PRNA-HER2apt的安全性和毒性。 SiMED_1纳米粒在体内。我们预期这些建议研究的成功完成，将可提供 我们的第二阶段工作和与私营部门投资者的进一步接触所需的结果和数据 OUT IND为临床试验启用研究。随着最近FDA批准的增加和RNA的广泛使用- 基于疫苗和药物，我们完全期待我们基于RNA纳米技术的产品代表着一种 非常有希望的下一代疗法，有利于乳腺癌患者的护理和更远的地方。