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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 Patent Corporation Treaty Application No. PCT/US03/06905. We are seeking an industrial partner interested in its commercialization. (Ref: J190)


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