A New Approach to Cancer Therapy

By Klaus D. Linse on May 1, 2013 • ( 0 )

Poster 5319 presented by Dr. Masamitsu Konno reports a new way for a cancer therapy to treat Gastrointestinal Cancer

The title of the poster presented in the AACR 2013 Meeting poster session on Wednesday morning in the section “Non-Coding RNAs in Cancer Stem Cells, EMT, and metastasis” was

“Cancer reprogramming”

The picture of the poster is shown below.

Picture of poster #5319 about the use of BNA modified oligonucleotides for a cell reprogramming therapy.

During the recent AACR 2013 Meeting in Washington DC Dr. Masamitsu Konno together with Dr. Satoshi Obika’s group used synthetic oligonucleotides modified with bridged nucleic acids (BNAs) to study their potential in the use for the reprogramming of cells. The poster reported the successful reprogramming of mouse and human cells to pluripotency by direct transfection using mature double-stranded microRNAs. The miRNA hsa-mir369-3P was chosen as the target. This research aims to reprogram tumorigenic cells that are resistant to other drug treatment regiments by hopefully exterminating the cancer altogether.

The reported approach gives hope to usher in a new era of cancer treatments not presently available. It is hoped that approches like this will allow to interfere with the cancer development cycle at critical checkpoints to halt the development and spread of cancers altogether.

Picture of Drs. Konno and Castro in front of Dr. Konno’s poster.

Dr. Castro is the CEO and President of Biosynthesis Inc. Lewisville, Texas.

Biosynthesis is providing its third generation Bridged Nucleic Acids (BNA) also known as BNA3^TM to researchers in academia and industry to enhance their research.

This new technology is based on multi-functional synthetic RNA analogues that can be used in place of the first generation bridged nucleic acids known as Locked Nucleic Acids (LNA). These RNA analogues can be synthesized and spiked with DNA or RNA in order to modify the formation of nucleic acid helices. Also, when compared to Peptide Nucleic Acids (PNA), BNA3 allows for better base-pair stacking and a high stability of the resulting oligonucleotide complexes, making BNA based oligonucleotides an ideal solution for the detection of small or highly similar DNA or RNA targets.

Furthermore, Bio-Synthesis Inc. is now providing synthetic oligonucleotides containing BNA3 which are deprotected, desalted or HPLC purified. All oligonucleotides are quality checked by MALDI-TOF Mass Spectrometry.

Presentation Abstract:

Abstract Number:	5319

Presentation Title:	Cancer reprogramming

Presentation Time:	Wednesday, Apr 10, 2013, 8:00 AM -12:00 PM

Location:	Hall A-C, Poster Section 30

Poster Board Number:	2

Author Block:	Hisataka Ogawa, Hirofumi Yamamoto, Masamitsu Konno, Shin Kure, Susumu Miyazaki, Shinpei Nishikawa, Shinichiro Hasegawa, Katsuya Ohta, Yoshihiro Kano, Takahito Fukusumi, Atsushi Hamabe, Takeshi Yamamoto, Satoshi Obika, Taroh Satoh, Hidetoshi Eguchi, Hiroaki Nagano, Hidenori Inohara, Yuichirou Doki, Masaki Mori, Hideshi Ishii. Osaka University, Suita City, Japan

Abstract Body:	*Background: The 2012 Nobel Prize success (Gurdon and Yamanaka) gives boost to medical science. While the nuclear transplantation but also the gene transfer of defined factors can elicit cellular reprogramming efficiently in terminally differentiated somatic cells, we have been studied the effects of coding genes (oncogenes [OG], tumor suppressor genes [TSG], and ES-like genes) and non-coding ones (microRNA) on the gastrointestinal cancer cells (reviewed in JAMA, 2001; Cancer Sci, 2008). Compared with known tumor-related genes [OG/TSG], the retroviral-mediated gene transfer of induced pluripotent stem cells (iPSCs) factors, such as Oct4, Sox2, Klf4 and c-Myc resulted in radical modifications of cell lineages, more sensitization to anti-cancer reagents, and significant suppression of tumorigenesis in immunodeficient NOD/SCID mice (PNAS, 2010; BBRC, 2010; IJO, 2012). Given that the viral vectors have potential risks for genome insertion causing carcinogenesis, which would offend clinical application, our extensive screening of ES cell-specific microRNAs allowed the identification of a set of microRNAs (microRNA302 s, 200c and 369 s), which could execute full reprogramming from differentiated cells to iPSCs (Cell Stem Cell, 2011; Cancer Sci, 2011). Here we studied the effect of those microRNAs on gastrointestinal cancer cells in vitro* and in vivo. *Methods: To inactivate cancer cells, we screened a small set of microRNAs by in vitro* experiments, including cell growth, invasion, sphere formation, differentiation assay (three germs) and immunocytochemistry; and in vivo ones, such as chemo-sensitivity, teratoma assay and tumorigenesis. For in vivo assay, synthesized microRNAs were administered intravenously as conjugated forms with carbonate apatite, a novel microRNA delivery technology. The fluorescent labeled microRNAs monitored the efficiency in cancer tissue uptakes as well as the toxicity in normal tissues. *Result:* 1) Single microRNA302s were able to reprogram colorectal cancer HT29 cells in vitro, as shown by microscopic analysis and qRT-PCR: three germ line differentiation, reduced proliferation and suppressed invasion. 2) Cell fate analysis in vitro demonstrated that ~60% of HT29 cells reprogrammed, while remaining cells were subjected to apoptosis induction. The reprogrammed cells were sensitized to chemotherapy (fluorouracil). 3) In vivo study showed the microRNA302s effect on tumors, but not on normal tissues, to suppress tumorigenesis significantly in immunodeficient NOD/SCID mice. *Conclusion: In vitro* and in vivo assay demonstrated clearly that cancer-reprogramming therapy using synthesized microRNAs could modify the cancer cell malignancy, and that the combination with efficient DDS’s would facilitate the discovery of innovative cancer therapy. We study further the mechanism microRNA-mediated cancer reprogramming for the drug optimization.