Diagnosing and Treating Cancer Using beta-Catenin Splice Variants
Description of Invention:
This application discloses and claims inventions which may be used alone or together. One group of inventions relates to early detection diagnostic, prognostic and patient monitoring methods (“Diagnostic Methods”). The other group of inventions relates to methods of treatment. Both groups of inventions have particular application with respect to esophageal squamous cell cancers (ESCC) or other types of adenocarcinomas and squamous cell carcinomas.
The Diagnostic Methods are useful in evaluating the status of preneoplastic lesions as well as tumor tissue. Because of this, the methods can be used to track the progression or regression of disease in many types of cell samples from normal to dysplasia to cancer.
The Diagnostic Methods involve measuring the level of one or more pairs of transcripts or the protein products of these pairs of transcripts or the cellular localization of the transcripts or proteins. The primary transcripts or protein products useful in this method are those of the beta-Catenin gene (CTNNB1). In particular, the levels of the 16A and 16B CTNNB1 transcripts or protein products are of importance in carrying out the methods of this patent application. Other gene transcripts or protein products that may be used in conjunction with CTNNB1 16A and 16B to provide additional information are WAF1 (p21) and cMYC.
The treatment methods include employing small interfering RNA molecules (siRNAs) as a means to alter the expression of one or more of these particular CTNNB1 transcripts. More specifically, preferred siRNA molecules can be used to alter the expression of the CTNNB1 transcripts 16A and/or 16B. These siRNA molecules may be single-stranded (ss) or double-stranded (ds) and may be delivered using a construct capable of producing the siRNA molecule upon delivery to the target cell.
Applications:
Diagnostic or prognostic methods for squamous cell cancers and adenocarcinomas
Monitoring therapeutic response during and after patient treatment
Development of cancer treatments
Basic research to further elucidate the role of beta catenin in signal transduction pathways and carcinogenesis
Development Stage:
The use of beta catenin transcripts to provide prognostic or diagnostic information remains the subject of research but early patient data is found in the article in Genes Chromosomes & Cancer listed below. Work related to the use of siRNA as a treatment strategy remains in its early stages of research and has not yet progressed to clinical trials.
Patent Status:
DHHS Reference No. E-018-2005/2 --
PCT/US2006/05032 filed 10 Feb 2006 and published as WO 2006/086772 on 17 Aug 2006, entitled “Method of Diagnosing and Treating Cancer Using Beta Catenin Splice Variants
U.S. Patent Application No. 11/883,694 filed 03 Aug 2007
DHHS Reference No. E-018-2005/1 --
U.S. Provisional Application No. 60/667,084 filed 30 Mar 2005, now abandoned
DHHS Reference No. E-018-2005/0 --
U.S. Provisional Application No. 60/652,154 filed 10 Feb 2005, now abandoned
Relevant Publication:
The patent application has been published as WO 2006/086772 A2 on 17 August 2006.
MJ Roth et al. beta-Catenin splice variants and downstream targets as markers for neoplastic progression of esophageal cancer. Genes Chromosomes Cancer. 2005 Dec;44(4):423-428. [PubMed abs]
SE Martin et al. Multiplexing siRNAs to compress RNAi-based screen size in human cells. Nucleic Acids Res. 2007 Mar 28; E published ahead of print, doi:10.1093/nar/gkm141. [PubMed abs]
A Thiele et al. AU-rich elements and alternative splicing in the beta-Catenin 3’ UTR can influence the human beta-Catenin mRNA stability. Exp Cell Res. 2006 Jul 15;312(12):2367-2378. [PubMed abs]
Licensing Status: This application is available for licensing on a non-exclusive or exclusive basis.
Biological Materials Availability:
Biological materials related to this technology are available and include those referred to in the following publications as well as a series of recently established aptamers capable of specific binding to the CTNNB1 protein.
MJ Roth et al. Cytologic detection of esophageal squamous cell carcinoma and precursor lesions using balloon and sponge samplers in asymptomatic adults in Linxian, China. Cancer. 1997 Dec 1;80(11):2047-2059. [PubMed abs]
Q-J Pan et al. Cytologic detection of esophageal squamous cell carcinoma and its precursor lesions using balloon samplers and liquid-based cytology in asymptomatic adults in Linxian, China. Acta Cytol. 2008 Jan-Feb;52(1):14-23. [PubMed abs]
MJ Roth et al. A study of beta-catenin splice variants and associated downstream targets as markers for neoplastic progression of squamous cell carcinoma of the esophagus. Genes Chromosomes Cancer. 2005 Dec;44(4):423-428. [PubMed abs]
PJ Limburg et al. Randomized, placebo-controlled esphogeal squamous cell cancer chemoprevention trial of selenomethionine and celecoxib. Gastroenterology. 2005 Sept;129(3):863-873. [PubMed abs]
Collaborative Research Opportunity:
The National Cancer Institute, Division of Cancer Epidemiology and Genetics, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize a method of diagnosing and treating cancer using beta-Catenin splice variants. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.
Portfolios: Cancer
Cancer -Diagnostics-In Vitro-DNA Based Cancer -Diagnostics-In Vitro-MAb Based Cancer -Diagnostics Cancer -Therapeutics
For Additional Information Please Contact: Susan S. Rucker J.D.
NIH Office of Technology Transfer
6011 Executive Blvd, Suite 325
Rockville, MD 20852-3804
Phone: (301) 435-4478
Email: ruckersu@mail.nih.gov
Fax: (301) 402-0220
