A new method for enhancing L-ASP activity by combining it with antagonists of asparagine synthetase - such as siRNAs, antisense nucleotides, antibodies or small-molecule inhibitors

For the last several decades, L-asparaginase (L-ASP) has been widely used as a clinical treatment for leukemias.  Studies show that cancer cells that contain less asparagine synthetase (ASNS) are more susceptible to L-ASP.  The response to L-ASP therapy is often better when the expression of ASNS is limited.

The present invention describes a new method for enhancing L-ASP activity by combining it with antagonists of ASNS – such as siRNAs, antisense nucleotides, antibodies or small-molecule inhibitors – for treatment of cancers.  Reducing or suppressing the expression of ASNS potentiates the growth inhibitory activity of L-ASP.

Additionally, the invention discloses a novel biomarker screening tool to identify leukemia, ovarian, and other cancer patients that would be most likely to respond to L-ASP treatment.

Applications and Modality: 

·     A new method for improving the therapeutic efficacy of L-asparaginase.

·     ASNS antagonists such as siRNA, antibodies, antisense nucleotides, or small-molecule inhibitors can potentially be used in combination with L-ASP in the treatment of cancers.

·     ASNS gene or protein expression can serve as a therapeutic response biomarker for personalization of cancer therapy with the aforementioned combinations.

Market: 

·     There were more than 500,000 deaths from cancer in 2006. The current technology has the potential of being used in conjunction with L-ASP in treating cancer patients.

·     Oncaspar^TM, the PEG-derivitized L-ASP developed by Enzon Pharmaceuticals, registered annual sales of about $25 million in 2006, largely on the basis of treatment of acute lymphoblastic leukemia.  The present invention may make L-ASP applicable to treatment of types of cancers that are much more common.

Development Status: 

The technology is currently in the pre-clinical stage of development. With respect to L-ASP treatment of patients with solid tumors, Phase I clinical trials have been initiated (Principal Investigator Daniel D. Von Hoff, TGen, Inc.) at three institutions using L-ASP in combination with gemcitabine.

Publication: 

PL Lorenzi et al. Asparagine synthetase as a causal, predictive biomarker for L-asparaginase activity in ovarian cancer cells.  Mol Cancer Ther. Nov; 5(11):2613-2623. Epub 2006 Nov 6, doi 10.1158/1535-7163.MCT-06-0447.  [PubMed abs]

·     U.S. Provisional Application No. 60/779,143 filed 03 Mar 2006 (HHS Reference No. E-132-2006/0-US-01)

·     U.S. Provisional Application No. 60/833,027 filed 25 Jul 2006 (HHS Reference No. E-132-2006/1-US-02)

·     PCT Application No. PCT/US2007/005555 filed 02 Mar 2007, which published as WO 2007/103290 on 13 Sep 2007 (HHS Reference No. E-132-2006/2-PCT-01)

Inventors: 

Philip L. Lorenzi, John N. Weinstein and Natasha J. Caplen (NCI)

Licensing Status: 

Available for exclusive and non-exclusive licensing.

Collaborative Research Opportunity: 

The National Cancer Institute’s Genomics & Bioinformatics Group in the Laboratory of Molecular Pharmacology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the combination therapies described in this abstract.  Please contact John D. Hewes, Ph.D. at 301/435-3121 or hewesj@mail.nih.gov for more information.