Blocking RNA for Treating Triple Negative Breast Cancer

In 2019, the US National Cancer Institute awarded Bound Therapeutics LLC, together with Thomas Jefferson University and Bio-Synthesis Inc., a Small Business Technology Transfer grant starting 15 June for their collaborative research project to develop a "microRNA-21 based Blockade of Triple-Negative Breast Cancer." 

Triple-negative breast cancer does not have receptors for estrogen, progesterone, or HER-2/neu hormones. Hence triple-negative breast cancer patients do not benefit from receptor-targeted treatments, such as tamoxifen and Herceptin, that are sometimes effective for treating hormone-receptor-positive cancers. 

“Triple-negative breast cancer strikes younger women, tragically killing half the patients within 4 years," said Dr. Yuan-Yuan Jin, Chief Operating Officer of Bound Therapeutics LLC. "Surgery, chemotherapy, and radiation are the current standard of care for triple-negative breast cancer."

"To provide effective molecular therapy that will keep patients alive with a good quality of life, we have designed a cancer cell-targeted drug that will block a tiny strand of ribonucleic acid, called microRNA-21," explained Dr. Eric Wickstrom, Professor of Biochemistry and Molecular Biology at Thomas Jefferson University, a partner in the award. “MicroRNA-21 drives cell division, and occurs at high levels in most triple negative breast cancer cells.”

Dr. Miguel Castro, President and CEO of Bio-Synthesis Inc., another research partner, said that "The drug candidates containing BNAs (bridged nucleic acid analogs) and peptide analogs that we are making to treat triple-negative breast cancer cells are extraordinarily specific and safe in mammalian models." 

Our clinical collaborator, Dr. Edith Mitchell, Clinical Professor of Medicine and Medical Oncology at Thomas Jefferson University, commented that "Patients with triple-negative disease have limited treatment options compared to patients with more common forms of breast cancer. There is an urgent need for targeted treatments in this area." Dr. Mitchell serves as the Director of the Jefferson Center to Eliminate Cancer Disparities in diagnosis, treatment, and survival of patients with different ancestries. She is a past President of the National Medical Association. 

The funds will enable Bound Therapeutics and its partners Bio-Synthesis Inc. and Thomas Jefferson University to test their drug design in a triple-negative breast cancer mouse model with a healthy immune system. Early results suggest that microRNA-21 blockade decloaks triple-negative breast cancer cells to enable attack by immune cells. 

Historically, drug development involved looking for functional sites or binding pockets in malfunctioning proteins that cause the disease, in order to find drugs for a treatment. However, not all diseases have faulty proteins that can be targeted by a drug binding to functional sites located on a protein. However, synthetic complementary RNA analogs can block pathogenic RNA molecules or speed up their degradation. RNA analogs are short sequences that bind or hybridize to RNA. RNA molecules such as messenger RNA (mRNA), microRNA (miRNA), long noncoding RNA (lncRNA) or ribosomal RNA (rRNA) are potential targets. To lengthen the lifetime of RNA-based drugs or to make them more specific, artificial RNA analogs such as BNAs can be incorporated. 

Bridged nucleic acids (BNAs) display (i) equal or higher binding affinity against an RNA complement with excellent single-mismatch discriminating power, (ii) much better RNA selective binding, (iii) stronger and more sequence selective triplex-forming characters, and (iv) high nuclease resistance, than regular DNAs or RNAs, or phosphorothioate analogs.