RNA molecules are secreted in extracellular spaces (exRNAs) and act as endocrine signals altering the phenotypes of cancer cells. In this application we will focus on the class of small non-codingRNAs named microRNAs. We propose an innovative therapeutic concept: the depletion of oncogenic microRNAs from malignant cells by enhancing their secretion as exRNAs or blocking suppressor microRNAs'delivery in extracellular space by blocking secretion mechanisms. Our main goal is to develop new strategies using combined miRNA and siRNA to maximize therapeutic benefit by affecting the production of exRNAs. Our proposal centers on the identification and targeting of specific tumor-derived exRNA and exosomes leading to novel therapies and improved therapeutic outcomes. In UH2 phase of the grant, using ovarian cancer (OC) cell lines and cells derived from OC patient tumors, we will identify novel exRNA-based cancer therapeutic lead candidates by siRNA library genome-wide screening based on secretion measurements, by small RNA deep sequencing in "paired" samples from tumors, plasma and ascites from the same patient, and by functional studies for the lead exRNA candidates. In the UH3 phase, we will achieve pre-clinical optimization by testing the exRNA lead(s) identified in the UH2 for antitumor efficacy in well-established OC murine orthotopic models and their safety using well-established preclinical protocols.
The aims i n exploratory UH2 phase are designed to identify and validate the function of novel exRNA therapeutic candidates for pre- clinical studies. In UH3 phase, we will formulate the methods for the validation of the assays to determine the activity, pharmacology in tissue and plasma to establish dosage schedules in animal models for the design of rational anti-tumor approaches. Using our nanoliposomal delivery technology, we will also conduct target modulation and efficacy studies to generate clear evidence regarding the safety of exRNA-based therapeutic candidates in the proposed dose range. Our approach, by using a new category of regulatory exRNAs- miRNAs, could substantially enhance therapeutic efficacy for cancer treatment. We will also demonstrate, for the first time, the use of nanoliposome-siRNA-exRNA targeting to generate a synergistic boosting effect for treatment of cancers. While we are focusing on OC due to the high mortality associated with this malignancy, our findings have applications for any type of cancer. This proposal brings synergistic capabilities of scientists working for over a decade in the fields of miRNA (Dr. Calin), siRNA (Dr. Sood), nanoparticle delivery (Dr. Lopez-Berestein), and exosome biology (Dr. O'Halloran). The team has the expertise and synergistic drive to achieve novel exRNA therapeutic development by performing highly innovative research, and has developed RNA-based therapies in the past.

Public Health Relevance

We propose to develop an innovative cancer therapeutic approach based on the modulation of exogenous RNA release or uptake. In the UH2 phase, we will identify and establish functional validity of novel exRNA cancer therapeutic lead candidates. In UH3 phase we will achieve pre-clinical optimization including the establishment of Standard Operating Procedures for all procedures, antitumor activity testing in orthotopic murine models of ovarian cancer and safety and pharmacokinetics in murine models and if necessary in a second species.

Agency
National Institute of Health (NIH)
Institute
National Center for Advancing Translational Sciences (NCATS)
Type
Exploratory/Developmental Cooperative Agreement Phase I (UH2)
Project #
5UH2TR000943-02
Application #
8711594
Study Section
Special Emphasis Panel (ZRG1-OBT-Z (50))
Program Officer
Tagle, Danilo A
Project Start
2013-08-01
Project End
2015-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
2
Fiscal Year
2014
Total Cost
$500,000
Indirect Cost
$140,625
Name
University of Texas MD Anderson Cancer Center
Department
Other Health Professions
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Ling, Hui; Pickard, Karen; Ivan, Cristina et al. (2016) The clinical and biological significance of MIR-224 expression in colorectal cancer metastasis. Gut 65:977-89
Van Roosbroeck, Katrien; Fanini, Francesca; Setoyama, Tetsuro et al. (2016) Combining anti-miR-155 with chemotherapy for the treatment of lung cancers. Clin Cancer Res :
Paladini, Laura; Fabris, Linda; Bottai, Giulia et al. (2016) Targeting microRNAs as key modulators of tumor immune response. J Exp Clin Cancer Res 35:103
Rytelewski, Mateusz; Maleki Vareki, Saman; Mangala, Lingegowda S et al. (2016) Reciprocal positive selection for weakness - preventing olaparib resistance by inhibiting BRCA2. Oncotarget 7:20825-39
Nagaraja, A S; Dorniak, P L; Sadaoui, N C et al. (2016) Sustained adrenergic signaling leads to increased metastasis in ovarian cancer via increased PGE2 synthesis. Oncogene 35:2390-7
Sun, Yan; Liu, Yuexin; Cogdell, David et al. (2016) Examining plasma microRNA markers for colorectal cancer at different stages. Oncotarget 7:11434-49
Almeida, Maria Inês; Calin, George Adrian (2016) The miR-143/miR-145 cluster and the tumor microenvironment: unexpected roles. Genome Med 8:29
Fabris, Linda; Ceder, Yvonne; Chinnaiyan, Arul M et al. (2016) The Potential of MicroRNAs as Prostate Cancer Biomarkers. Eur Urol 70:312-22
Redis, Roxana S; Vela, Luz E; Lu, Weiqin et al. (2016) Allele-Specific Reprogramming of Cancer Metabolism by the Long Non-coding RNA CCAT2. Mol Cell 61:520-34
Wu, Sherry Y; Rupaimoole, Rajesha; Shen, Fangrong et al. (2016) A miR-192-EGR1-HOXB9 regulatory network controls the angiogenic switch in cancer. Nat Commun 7:11169

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