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.

Public Health Relevance

Late stage androgen-resistant, metastatic prostate cancer, termed castration-resistant prostate cancer, is a devastating disease that is a leading cause of cancer death in the United States. Androgen-resistant prostate cancer continues to signal through the Androgen Receptor, a transcription factor that is undruggable by small molecule therapeutics, but due to mutations, it no longer needs androgen for signaling. RNAi therapeutics have great potential to target the Androgen Receptor and this project will develop a self-delivering, prostate cancer targeted RNAi prodrug therapeutic.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA195191-01
Application #
8880847
Study Section
Special Emphasis Panel (ZCA1-RTRB-8 (J1))
Program Officer
Arya, Suresh
Project Start
2015-09-01
Project End
2017-08-31
Budget Start
2015-09-01
Budget End
2016-08-31
Support Year
1
Fiscal Year
2015
Total Cost
$202,275
Indirect Cost
$71,775
Name
University of California San Diego
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Hamil, Alexander S; Dowdy, Steven F (2016) Synthesis and Conjugation of Small Interfering Ribonucleic Neutral SiRNNs. Methods Mol Biol 1364:1-9