Short non-coding protein regulatory rnas (sprrnas) and methods of use
Patent Number: WO2016065349
Executive Summary:
General Description:
Piwi-interacting RNAs (piRNAs), a newly identified class of small non-coding RNAs, direct the Piwi-dependent transposon silencing and heterochromatin modification in germ-line cells. Recently, several lines of evidence indicating that piRNAs may be dis-regulated and play crucial roles in tumorigenesis have emerged. piRNA could act as an oncogene or a tumor suppressor in carcinogenesis, and these piRNAs might be involved in regulating cancer cell activities.
Some piRNAs and piRNA-like RNAs can be defined as short non-coding protein regulatory RNAs (sprRNAs) and can be used as biomarkers of lung cancer. The sprRNAs, and their variants, fragments, and inhibitors are useful as therapeutic molecules. The inventors describe piRNA-L-163, which binds to and regulates phosphorylated ERM proteins (p-ERMs), a key cell cortex organizer; piRNA-L-138, which binds and stabilizes MDM2 oncogene upon treatment with chemotherapeutic agents; and a considerable number of other sncRNAs that can be co-precipitated with phosphorylated proteins from a lung cancer cell line, but not from a non-malignant cell line.
Their findings pave the way for a new class of cancer therapeutic targets.
Scientific Progress:
The inventors reported that piRNA-L-138 plays key roles in chemoresistance to cisplatin-based chemotherapy in lung squamous cell carcinoma (ref. 1). These observations were confirmed in a xenograft tumor model.
Future Directions:
Strengths:
Weaknesses:
Patent Status:
Publications:
1: Wang Y, Gable T, Ma MZ, Clark D, Zhao J, Zhang Y, Liu W, Mao L, Mei Y. A piRNA-like Small RNA Induces Chemoresistance to Cisplatin-Based Therapy by Inhibiting Apoptosis in Lung Squamous Cell Carcinoma. Mol Ther Nucleic Acids. 2017 Mar 17;6:269-278. doi: 10.1016/j.omtn.2017.01.003. Epub 2017 Jan 24. PubMed PMID: 28325293; PubMed Central PMCID: PMC5363509.
2: Mei Y, Wang Y, Kumari P, Shetty AC, Clark D, Gable T, MacKerell AD, Ma MZ, Weber DJ, Yang AJ, Edelman MJ, Mao L. A piRNA-like small RNA interacts with and modulates p-ERM proteins in human somatic cells. Nat Commun. 2015 Jun 22;6:7316. doi: 10.1038/ncomms8316. PubMed PMID: 26095918; PubMed Central PMCID: PMC4557300.
3: Mei Y, Clark D, Mao L. Novel dimensions of piRNAs in cancer. Cancer Lett. 2013 Aug 9;336(1):46-52. doi: 10.1016/j.canlet.2013.04.008. Epub 2013 Apr 16. Review. PubMed PMID: 23603435; PubMed Central PMCID: PMC3707114.
Inventor Bio: Li Mao
Li Mao received his M.D. degree from Nanjing University Medical School in China. After completing a Cancer Genetics Fellowship at John Hopkins University in Baltimore, Maryland in 1995, he held professor positions at the University of Texas M.D Anderson Cancer Research Center and was Department Chairman at the University of Maryland. Since 2016, Dr. Mao serves as Vice President and Head of Johnson & Johnson China Lung Cancer Center.
Executive Summary:
- Invention Type: Diagnostic/Therapeutic
- Patent Status: Application, patent pending
- Patent Link: https://patents.google.com/patent/WO2016065349
- Research Institute: University of Maryland - Baltimore
- Disease Focus: Cancer
- Basis of Invention: The invention is based on the surprising discovery of a novel class of short non-coding protein regulatory RNAs (sprRNAs), which emerge as integral components for the function of certain proteins in regulating cellular processes. Abnormal expression of sprRNAs can contribute to cancer development and progression
- How it works: Inhibitors, such as antibodies recognizing proteins binding sprRNAs or oligonucleotides hybridizing to sprRNAs, disrupt the protein-RNA interaction and thus inhibit cancer progression
- Lead Challenge Inventor: Li Mao
- Inventors: Li Mao, Yupin Mei
- Development Stage: Pre-clinical, in vitro data in cancer cell lines
- Novelty:
- sprRNAs and proteins they bind to are new therapeutic targets
- Clinical Applications:
- Treatment of cancers, including non-small-cell lung carcinoma
- Treatment of cisplastin-resistant lung cancer
- Diagnostics of various cancers
General Description:
Piwi-interacting RNAs (piRNAs), a newly identified class of small non-coding RNAs, direct the Piwi-dependent transposon silencing and heterochromatin modification in germ-line cells. Recently, several lines of evidence indicating that piRNAs may be dis-regulated and play crucial roles in tumorigenesis have emerged. piRNA could act as an oncogene or a tumor suppressor in carcinogenesis, and these piRNAs might be involved in regulating cancer cell activities.
Some piRNAs and piRNA-like RNAs can be defined as short non-coding protein regulatory RNAs (sprRNAs) and can be used as biomarkers of lung cancer. The sprRNAs, and their variants, fragments, and inhibitors are useful as therapeutic molecules. The inventors describe piRNA-L-163, which binds to and regulates phosphorylated ERM proteins (p-ERMs), a key cell cortex organizer; piRNA-L-138, which binds and stabilizes MDM2 oncogene upon treatment with chemotherapeutic agents; and a considerable number of other sncRNAs that can be co-precipitated with phosphorylated proteins from a lung cancer cell line, but not from a non-malignant cell line.
Their findings pave the way for a new class of cancer therapeutic targets.
Scientific Progress:
The inventors reported that piRNA-L-138 plays key roles in chemoresistance to cisplatin-based chemotherapy in lung squamous cell carcinoma (ref. 1). These observations were confirmed in a xenograft tumor model.
Future Directions:
- Understanding the mechanism of sprRNA action in somatic cells, including cancer cells
- Pre-clinical testing of various therapeutic agents targeting sprRNA
Strengths:
- sprRNAs represent a novel therapeutic target in lung cancer, the disease killing more than 150,000 Americans every year
Weaknesses:
- The research is still at very early stages
- The best therapeutic targets among multiple sprRNAs remain to be identified and validated
Patent Status:
- Application 2: WO2016065349A3 2016-07-14
- Application 3: WO2016065349A2 2016-04-28
- Filing date: 2015-10-24
- Publication date: 2016-11-10
Publications:
1: Wang Y, Gable T, Ma MZ, Clark D, Zhao J, Zhang Y, Liu W, Mao L, Mei Y. A piRNA-like Small RNA Induces Chemoresistance to Cisplatin-Based Therapy by Inhibiting Apoptosis in Lung Squamous Cell Carcinoma. Mol Ther Nucleic Acids. 2017 Mar 17;6:269-278. doi: 10.1016/j.omtn.2017.01.003. Epub 2017 Jan 24. PubMed PMID: 28325293; PubMed Central PMCID: PMC5363509.
2: Mei Y, Wang Y, Kumari P, Shetty AC, Clark D, Gable T, MacKerell AD, Ma MZ, Weber DJ, Yang AJ, Edelman MJ, Mao L. A piRNA-like small RNA interacts with and modulates p-ERM proteins in human somatic cells. Nat Commun. 2015 Jun 22;6:7316. doi: 10.1038/ncomms8316. PubMed PMID: 26095918; PubMed Central PMCID: PMC4557300.
3: Mei Y, Clark D, Mao L. Novel dimensions of piRNAs in cancer. Cancer Lett. 2013 Aug 9;336(1):46-52. doi: 10.1016/j.canlet.2013.04.008. Epub 2013 Apr 16. Review. PubMed PMID: 23603435; PubMed Central PMCID: PMC3707114.
Inventor Bio: Li Mao
Li Mao received his M.D. degree from Nanjing University Medical School in China. After completing a Cancer Genetics Fellowship at John Hopkins University in Baltimore, Maryland in 1995, he held professor positions at the University of Texas M.D Anderson Cancer Research Center and was Department Chairman at the University of Maryland. Since 2016, Dr. Mao serves as Vice President and Head of Johnson & Johnson China Lung Cancer Center.