Treating Prostate Cancer with RNAi Prodrugs

用 RNAi 前药治疗前列腺癌

基本信息

批准号：
8880847
负责人：
STEVEN F DOWDY
金额：
$ 20.23万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8880847
关键词：
American Androgen Receptor Androgens Biological Markers Cancer Etiology Cancer Patient Cause of Death Cell Survival Cell surface Cells Cessation of life Charge Chemistry DNA Sequence Alteration Development Disease Dose Early Diagnosis Enzymes Genes Genome Glutamate Carboxypeptidase II Growth Factor Image Liver Luc Gene Luciferases Malignant - descriptor Malignant neoplasm of prostate Medicine Metastatic Prostate Cancer Mutation Nuclear Receptors Oncogenic Pathway interactions Patients Pharmaceutical Preparations Plant Roots Prodrugs Prostate RNA Interference Radiation therapy Radical Prostatectomy Recurrent disease Resistance Schedule Signal Transduction Small Interfering RNA Staging Steroids Technology Testing Therapeutic Tissues United States Vertebral column Work Xenograft procedure anti-cancer therapeutic castration resistant prostate cancer cell growth chemical group falls in vivo inorganic phosphate men mouse model nanoparticle novel public health relevance response small molecule targeted delivery therapeutic target transcription factor tumor tumor DNA tumor progression

项目摘要

DESCRIPTION (provided by applicant): Prostate cancer is the second leading cause of death among American men. Early detection often results in promising treatment of local disease by Androgen blockade or radical prostatectomy combined with local radiation treatment. However, late stage Androgen-resistant metastatic prostate cancer, called castration-resistant prostate cancer, remains the leading cause of prostate cancer death due to the lack of treatments. Due to mutation, amplification and/or activation by growth factor pathways, Androgen Receptor, a transcription factor, becomes constitutively active in the absence of androgen to drive expression of cell growth and survival genes. Consequently, there is a great need to develop novel anticancer therapeutics that specifically target oncogenic Androgen Receptor, the root driver of prostate cancer progression and patient death. RNA Interference (RNAi) responses have great potential to target the entire "undruggable" genome, including targeting oncogenic Androgen Receptor. Unfortunately, despite its promising therapeutic features, due to their charged phosphate backbone, siRNAs have no ability to enter cells and require a delivery agent. While current siRNA delivery approaches are sufficient for delivery to the liver, unfortunately they fall far short of systemic delivery to all tissues in the body required to treat metastatic prostate cancer. Thus, for tissues outside the liver, RNAi delivery remains the technological problem to solve for development of RNAi therapeutics to treat prostate cancer. To tackle the RNAi delivery problem, we pioneered a self-delivery technology that radically shrinks RNAi therapeutics to the smallest possible size to induce RNAi responses, called siRiboNucleic Neutrals (siRNNs). siRNNs represent a "Prodrug" approach where the negative charge is directly neutralized by a bioreversible phosphotriester chemical group that allows for self-delivery of monomeric RNAi molecules into cells. Once inside cells, enzymes only present inside of cells, convert neutral siRNNs into charged siRNAs that induce RNAi responses. This R21 exploratory proposal represents a paradigm shift in the RNAi therapeutics field to test a monomeric self-delivering prostate cancer targeted siRNN therapeutic technology to knockdown Androgen Receptor, the key driver of prostate cancer fatalities. Aim 1: Targeting Androgen Receptor by siRNN RNAi Prodrugs in Prostate Cancer We will chemically optimize PSMA-targeted delivery and endosomal escape of siRNNs that knockdown Androgen Receptor in patient-derived androgen-resistant metastatic prostate cells in culture. Aim 2. PSMA Targeted DD-siRNNs in Patient-Derived Metastatic PCa Mouse Models Using patient-derived xenograft femoral metastatic mouse models of androgen-resistant prostate cancer, we will optimize PSMA-targeted siRNN delivery in vivo targeting the surrogate therapeutic target gene Luciferase that allows for rapid, quantitative in vivo RNAi analysis to optimize chemistry and dosing.

描述（由申请人提供）：前列腺癌是美国男性的第二大死亡原因，早期发现通常可以通过雄激素阻断或根治性前列腺切除术结合局部放射治疗来治疗局部疾病。前列腺癌，称为去势抵抗性前列腺癌，由于缺乏治疗，仍然是前列腺癌死亡的主要原因，这是由于生长因子途径、雄激素受体（一种转录因子）的突变、扩增和/或激活。在缺乏雄激素的情况下，雄激素会变得持续活跃，以驱动细胞生长和存活基因的表达，因此非常需要开发专门针对致癌雄激素受体（前列腺癌进展和患者死亡的根本驱动因素）的新型抗癌疗法。（RNAi）反应具有针对整个“不可成药”基因组的巨大潜力，包括针对致癌雄激素受体，不幸的是，尽管其具有带电荷的磷酸盐主链，但其治疗功能很有前景。 siRNA 无法进入细胞并需要递送剂，虽然目前的 siRNA 递送方法足以递送至肝脏，但不幸的是，它们远远不能全身递送至治疗所需的体内所有组织。因此，对于肝脏以外的组织，RNAi 递送仍然是开发治疗前列腺癌的 RNAi 疗法需要解决的技术问题。诱导 RNAi 反应的最小可能尺寸，称为 siRiboNucleic Neutrals (siRNN)，代表一种“前药”方法，其中负电荷直接被中和。生物可逆的磷酸三酯化学基团，允许单体 RNAi 分子自我递送到细胞内，酶仅存在于细胞内部，将中性 siRNN 转化为诱导 RNAi 反应的带电 siRNA。这一 R21 探索性提议代表了 RNAi 的范式转变。治疗领域测试单体自传递前列腺癌靶向 siRNN 治疗技术，以抑制雄激素受体，这是前列腺癌死亡的关键驱动因素。 1：前列腺癌中 siRNN RNAi 前药靶向雄激素受体我们将通过化学方法优化 siRNN 的 PSMA 靶向递送和内体逃逸，从而敲低培养物中患者来源的雄激素抗性转移性前列腺细胞中的雄激素受体。在患者衍生的转移性 PCa 小鼠模型中使用患者衍生的异种移植股骨转移小鼠模型对于雄激素抵抗性前列腺癌，我们将优化 PSMA 靶向 siRNN 体内递送，以替代治疗靶基因荧光素酶为目标，从而实现快速、定量的体内 RNAi 分析，以优化化学和剂量。