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Prolonging Survival in Melanoma Patients: Early Stage Diagnosis and Treatment by Detecting and Inhibiting NUAK2 Overexpression

Posted Jul 22 2010 5:00pm

Description of Invention:
Melanoma accounts for only ~4% of skin cancers, but is responsible for over 75% of skin cancer deaths worldwide. There are few treatment options available for melanoma and all current options show limited effectiveness. Melanoma is most treatable in its early stages, but most cases are not identified until the disease has progressed to the point where treatment is less effective. As normal melanocytes transform into melanoma tumor cells and metastasize, many changes occur in their gene expression patterns. Identifying genes whose expression levels impact melanoma patient survival is a key factor in developing better early detection tests and more effective treatment modalities for the disease.

NUAK2 is a stress-activated kinase and a member of the SNF-1/AMPK kinase family, a conserved family of serine/threonine kinases ubiquitous to all eukaryotes. This enzyme is normally involved in helping cells cope with glucose starvation, promoting cell-cell detachment for motility, and protecting cells from CD95-mediated apoptosis. SNF-1/AMPK kinases, such as NUAK2, also regulate cell cycle machinery by influencing the function of cyclin-dependent kinases (CDKs), such as CDK2. When deregulated, SNF-1/AMPK family members are known to contribute to cancer development and tumor progression in various cancers.

Scientists at the National Institutes of Health (NIH) have identified the NUAK2 gene (also known as SNARK) as a factor to predict the clinical outcome for melanoma patients. NUAK2 was selected as a gene of interest through extensive analysis of over 120 primary melanomas using a microarray-based comparative genomic hybridization approach which showed that genetic aberrations in NUAK2 correlated with disease. The most prominent discovery was that gain at the NUAK2 locus and deletion at the PTEN locus strongly correlated with more severe acral melanoma. Overexpression of phospho-Akt (p-Akt), caused by the PTEN deletion, combined with the overexpression of NUAK2 were found to be associated with rapid disease progression, poor patient survival, and increased tumor thickness, especially in acral melanoma models. The scientists are developing diagnostic tests for NUAK2 to better detect melanomas at an early stage when the disease is most treatable. They are also developing therapeutic small hairpin RNAs (shRNAs) to inhibit NUAK2 gene expression and thereby reduce melanoma tumor thickness and prevent aggressive disease progression. The shRNAs utilized to silence these target genes are incorporated into lentiviral vectors, which have the potential to be delivered into humans. These scientists also observed that NUAK2 overexpression correlated with increased expression of various CDKs. So, they are testing the effectiveness of CDK inhibitors in targeting melanomas that specifically exhibit genetic aberrations in NUAK2 and PTEN leading to NUAK2 and p-Akt overexpression. These new potential diagnostics and therapeutics centered on NUAK2 could provide important pharmaceutical tools to detect and treat melanoma at various stages of disease.

Applications:
  • Diagnostic tools and kits to identify melanoma at an early stage of disease where treatments are more effective and the mortality rate is reduced. Diagnostic tests for NUAK2 expression may be most useful in detecting acral melanoma, which is one of the most prominent forms of melanoma in Hispanic, Asian, and African-American populations.
  • Therapeutic nucleic acids to inhibit melanoma disease progression by targeting specific genes important in poor clinical outcomes, such as NUAK2 and PTEN.


Advantages:
  • Genetic aberrations in the NUAK2 and PTEN genes show a high correlation with poor clinical outcomes in melanoma patients. Diagnostic tests specifically directed at NUAK2 are anticipated to be highly predictive of the aggression level and course of disease in individual patients. Gaining information about melanoma before late-stage symptoms are observed should give clinicians more opportunity to treat patients before the cancer metastasizes out of control.
  • Few therapies exist for melanoma and the treatments utilized by clinicians are prone to toxic side effects. Targeted therapies, such as shRNAs directed against NUAK2 could combine more effective inhibition of melanoma with fewer harsh side effects.


Development Status:
This technology is in a preclinical stage of development.

Inventors:
Vincent J Hearing (NCI)
Takeshi Namiki (NCI)


Patent Status:
HHS, Reference No. E-281-2009/0
US, Application No. 61/321,136 filed 05 Apr 2010


Relevant Publication:
  1. T Namiki, et al. Genomic alterations in primary cutaneous melanomas detected by metaphase comparative genomic hybridization with laser capture or manual microdissection: 6p gains may predict poor outcome. Cancer Genet Cytogenet. 2005 Feb;157(1):1-11. [ PubMed: 15676140 ]
  2. JH Kim, et al. SNARK, a novel downstream molecule of EBV latent membrane protein 1, is associated with resistance to cancer cell death. Leuk Lymphoma. 2008 Jul;49(7):1392-1398. [ PubMed: 18452098 ]


Licensing Status:
Available for licensing.

Collaborative Research Opportunity:
The Center for Cancer Research, Laboratory of Cell Biology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Prolonging Survival in Melanoma Patients. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.


Portfolios:
Cancer - Diagnostics
Cancer - Therapeutics



For Additional Information Please Contact:
Samuel Bish Ph.D.
NIH Office of Technology Transfer
6011 Executive Blvd. Suite 325,
Rockville, MD 20852
United States
Email: bishse@mail.nih.gov
Phone: 301-435-5282
Fax: 301-402-0220


Ref No: 2140

Updated: 07/2010

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