Treating Prostate Cancer with RNAi Prodrugs

用 RNAi 前药治疗前列腺癌

• 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
• 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

 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死亡的第二大原因。早期发现往往导致有希望的治疗局部疾病的雄激素阻断或根治性子宫切除术结合局部放射治疗。然而，晚期雄激素抵抗性转移性前列腺癌，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。由于生长因子途径的突变、扩增和/或激活，雄激素受体（一种转录因子）在雄激素不存在的情况下变得组成型活性，以驱动细胞生长和存活基因的表达。因此，非常需要开发特异性靶向致癌雄激素受体（前列腺癌进展和患者死亡的根本驱动因素）的新型抗癌治疗剂。RNA干扰（RNAi）反应具有靶向整个“非药物性”基因组的巨大潜力，包括靶向致癌雄激素受体。不幸的是，尽管其具有有希望的治疗特征，但由于其带电的磷酸骨架，siRNA没有进入细胞的能力，并且需要递送剂。虽然目前的siRNA递送方法足以递送至肝脏，但不幸的是，它们远不能全身递送至治疗肿瘤所需的体内所有组织。 转移性前列腺癌因此，对于肝外的组织，RNAi递送仍然是开发RNAi治疗剂以治疗前列腺癌所要解决的技术问题。为了解决RNAi递送问题，我们开创了一种自我递送技术，该技术将RNAi疗法从根本上缩小到尽可能小的尺寸以诱导RNAi反应，称为siRiboNucleic Neutrals（siRNNs）。siRNN代表了一种“前药”方法，其中负电荷被生物可逆的磷酸三酯化学基团直接中和，这允许单体RNAi分子自我递送到细胞中。一旦进入细胞内，仅存在于细胞内的酶将中性siRNN转化为诱导RNAi反应的带电siRNA。这项R21探索性提案代表了RNAi治疗领域的范式转变，以测试单体自我递送前列腺癌靶向siRNN治疗技术，以敲低雄激素受体，这是前列腺癌死亡的关键驱动因素。目标1：我们将在化学上优化siRNA靶向的递送和内体逃逸，其在培养的患者来源的雄激素抗性转移性前列腺细胞中敲低雄激素受体。目标2.使用雄激素抵抗性前列腺癌的患者来源的异种移植股骨转移小鼠模型，我们将优化靶向替代治疗靶基因荧光素酶的体内靶向PSMA的siRNN递送，其允许快速、定量的体内RNAi分析以优化化学和给药。