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（由适用提供）：前列腺癌是美国男性死亡的第二大原因。早期检测通常会导致雄激素阻断或从根治性前后切除术与局部辐射治疗相结合对局部疾病的治疗。然而，由于缺乏治疗而导致前列腺癌死亡的主要原因，耐晚期的抗雄激素转移性前列腺癌仍然是前列腺癌死亡的主要原因。由于突变，通过生长因子途径的扩增和/或激活，在没有雄激素的情况下，雄激素受体（一种转录因子）始终如一地活跃以驱动细胞生长和存活基因的表达。因此，非常需要开发新颖的抗癌疗法，该治疗专门针对致癌雄激素受体，雄激素受体是前列腺癌进展和患者死亡的根驱动因素。 RNA干扰（RNAi）反应具有巨大的靶向整个“不难”基因组的潜力，包括靶向致癌雄激素受体。不幸的是，由于其带电的磷酸骨架，其承诺的治疗特征，siRNA无法进入细胞并需要递送剂。虽然当前的siRNA输送方法足以传递到肝脏，但不幸的是，它们远远远远远远没有进行治疗所需的身体的所有时间转移性前列腺癌。对于肝脏以外的组织，RNAi的递送仍然是解决RNAi治疗以治疗前列腺癌的技术问题。为了解决RNAi递送问题，我们开创了一种自我交付的技术，该技术从根本上缩小RNAi疗法的尺寸最小，以诱导RNAi反应，称为Siribonucleic中性（SIRNNS）。 SIRNNS代表了一种“前药”方法，其中负电荷被生物可爱的磷光化学基团直接中和，该基团可以将单体RNAi分子自传递到细胞中。一旦在细胞内部，仅存在于细胞内部的酶，将中性siRNNS转化为影响RNAi反应的带电siRNA。该R21探索性建议代表了RNAi治疗领域的范式转移，以测试单体自我抑制的前列腺癌针对SIRNN治疗技术，以敲除前列腺癌死亡的主要驱动因素。 AIM 1：Sirnn RNAi前药靶向雄激素受体，在前列腺癌中，我们将化学优化siRNNS的PSMA靶向递送和内体逃生，这些siRNNS在培养中敲低雄激素受体的抑制雄激素受体。 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.