A major goal of translational cancer research is to develop targeted therapies that can specifically inhibit the expression or function of proteins that play an essential role in oncogenesis. There is considerable interest in using synthetic DNA or RNA oligonucleotides to achieve this goal because of their ability to recognize specified nucleic acid sequences or protein structures with high affinity. Several oligonucleotide-based strategies, including antisense, small interfering RNAs (siRNAs), protein-binding aptamers and immunostimulatory oligonucleotides, have produced potent anti-cancer effects in pre-clinical studies. However, clinical trials of therapeutic (antisense) oligonucleotides have been generally disappointing and this has been attributed, in part, to their inefficient uptake by cancer cells. The Principal Investigator and her collaborators have developed a novel antiproliferative oligonucleotide named AGRO100. This molecule has recently been tested in a clinical trial involving patients with advanced cancer and has demonstrated a remarkable lack of toxicity combined with promising clinical activity. Unlike most other oligonucleotides, AGRO100 is taken up efficiently and selectively by cancer cells in culture and in vivo. We hypothesize that these extraordinary properties are related to the unusual G-quadruplex structure of AGR0100 and its ability to bind specifically to a protein that is expressed at high levels on the surface of cancer cells. The long-term goal of this project is to develop oligonucleotides that are avidly and selectively taken up by cancers in vivo. Such tumor-targeting sequences could be incorporated into oligonucleotide-based therapeutics or conjugated to chemotherapy drugs in order to enhance their efficacy and reduce unpleasant side effects. In this application, we propose to elucidate the mechanism involved in the preferential uptake of AGRO100 by tumors and to identify sequence or structural motifs that lead to efficient oligonucleotide internalization by cancer cells. The first specific aim is to characterize the cellular internalization of AGRO100 and confirm the role of nucleolin in this process.
The second aim i s to use a SELEX approach to identify oligonucleotides (from combinatorial libraries) that have efficient and selective uptake by cancer cells.
The third aim i s to incorporate the optimal tumor-targeting sequences into antisense, siRNA and immunomodulatory oligonucleotides in order to determine if this leads to superior uptake and activity.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA122383-05
Application #
7906006
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Lees, Robert G
Project Start
2006-08-01
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2012-07-31
Support Year
5
Fiscal Year
2010
Total Cost
$255,082
Indirect Cost
Name
University of Louisville
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
Bates, Paula J; Reyes-Reyes, Elsa M; Malik, Mohammad T et al. (2017) G-quadruplex oligonucleotide AS1411 as a cancer-targeting agent: Uses and mechanisms. Biochim Biophys Acta Gen Subj 1861:1414-1428
Malik, Mohammad T; O'Toole, Martin G; Casson, Lavona K et al. (2015) AS1411-conjugated gold nanospheres and their potential for breast cancer therapy. Oncotarget 6:22270-81
Reyes-Reyes, E Merit; Šalipur, Francesca R; Shams, Mitra et al. (2015) Mechanistic studies of anticancer aptamer AS1411 reveal a novel role for nucleolin in regulating Rac1 activation. Mol Oncol 9:1392-405
Farin, Keren; Schokoroy, Sari; Haklai, Roni et al. (2011) Oncogenic synergism between ErbB1, nucleolin, and mutant Ras. Cancer Res 71:2140-51
Choi, Enid W; Nayak, Lalitha V; Bates, Paula J (2010) Cancer-selective antiproliferative activity is a general property of some G-rich oligodeoxynucleotides. Nucleic Acids Res 38:1623-35
Reyes-Reyes, E Merit; Teng, Yun; Bates, Paula J (2010) A new paradigm for aptamer therapeutic AS1411 action: uptake by macropinocytosis and its stimulation by a nucleolin-dependent mechanism. Cancer Res 70:8617-29
Bates, Paula J; Laber, Damian A; Miller, Donald M et al. (2009) Discovery and development of the G-rich oligonucleotide AS1411 as a novel treatment for cancer. Exp Mol Pathol 86:151-64