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Compositions and Methods for Preventing and Treating Cancer Via Modulating UBE1L and/or ISG15

Individuals with acute promyelocytic leukemia (APL)(FAB M3) express oncogenic promyelocytic leukemia (PML)/retinoic acid receptora (RARa). All-trans-retinoic acid (RA) treatment causes complete remission of APL through induction of leukemic cell differentiation. A hallmark of the RA response in APL is PML/RARa degradation that reverses PML/RARa oncogenic effects. Proteasomal inhibitors prevent PML/RARa proteolysis, despite RA treatment, which is indicative of a proteasome-dependent pathway in this degradation. PML/RARa expression results in dominant-negative transcriptional repression. This repression is antagonized by pharmacological RA doses that overcome inhibitory effects on transcription of the N-Cor/SMRT co-repressor complex having histone deacetylase activity. RA treatment recruits a co-activator complex that stimulates transcription, resulting in activation of target genes.

Dartmouth researchers have now found that UBE1L is a retinoid target gene in APL. UBE1L antagonizes PML/RARa oncogenic effects by triggering PML/RARa degradation. The consequence of this action is the promotion of apoptosis resulting in anti-oncogenic effects of UBE1L in APL and potentially in other neoplastic or pre-neoplastic cell contexts. Accordingly, compositions which target UBE1L or other proteins related thereto, such as the ubiquitin-like protein ISG15, are expected to be useful in preventing and treating cancer.

This technology is claimed in the published United States Patent Application No. 12,262,337 and the published Japanese Patent Application No. 2003-574120. We are seeking an industrial partner interested in its commercialization. (Ref: J190)

Last Updated: 7/24/12