Novel Cancer Target Following HDAC Track: First Histone Demethylase offers opportunity in treating resistant cancers
Summary The invention encompasses a novel target representing a potential new avenue in the treatment of cancer and other diseases, based on interference with gene regulation. The target, LSD1 (lysine-sepcific demethylase 1), the first example of histone demethylase, is responsible for trimming methyl groups from histones. While previously it was thought that histone methylation was irreversible, the Shi group discovered both positive and negative regulators of LSD1.Histone demethylase is thought to play a crucial role in cancer pathology by modifying chromatin structure and regulating transcription of oncogenes. LSD1 is part of a larger complex that includes HDAC1/2, a target of great interest in cytostatic cancer therapy. HDAC 1/2 are thought to be operating upstream in the same system. Thus, inhibitors targeted at LSD1 or its essential co-factors may represent downstream therapeutic targets analogous to HDAC inhibitors. Like HDAC inhibitors, which are currently tested in a number of clinical trails for treatment against solid tumors and hematological cancers, histone demethylase inhibitors have the potential to produce therapies with efficacy and selectivity currently reserved for biologics and to be effective for refractory cancer because their mechanism of action differs from that of conventional anti-neoplastic agents.
Applications Modulation of LSD1 expression, and thus histone methylation, may lead to potent anti-cancer therapies. H3K4 methylation has been associated with colorectal cancer, liver cancer, prostate cancer, acute lymphoid leukemia, and myeloid leukemia. In a recent study, LSD1 was shown to interact with androgen receptors, regulating androgen-receptor induced transcription in both normal and tumor-characterized prostate tissue (Nature 437: 436-439, 2005). The androgen receptor has been known to play a critical role in the development of primary as well as advanced hormone-refractory prostate cancer, confirming the strong association between LSD1 regulation and oncogenesis.
Market Nearly 10 million people throughout the world are diagnosed with cancer each year resulting in over $180 billion spent on direct and indirect medical costs. In recent phase I and phase II clinical studies in human beings, the administration of HDAC inhibitors resulted in the partial or complete remission of human cancer. Targeting of histone demethylase, which is both part of the same complex and is responsible for similar cytostatic effects, represents an important complementary approach to treatment of resistant cancers.
Stage of Development Demethylase activity was confirmed using RNAi inhibition of LSD1, which led to an increase in H3K4 methylation and a de-repression of target genes. A rapid spectrophotometric assay, based on amine oxidation, is readily available for the discovery of modulators of LSD1 that dynamically regulate histone methylation.
Intellectual Property Multiple patents pending.
Publications Shi et al., Histone demethylation mediated by the nuclear amine oxidase homolog LSD1, Cell, 119:941-53.
Shi et al., Regulation of LSD1 histone demethylase activity by its associated factors, Molecular Cell, 19: 857-864.
Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases. Cell. 2006 May 5;125(3):467-81. Epub 2006 Apr 6.
Chen Z, Zang J, Whetstine J, Hong X, Davrazou F, Kutateladze TG, Simpson M, Mao Q, Pan CH, Dai S, Hagman J, Hansen K, Shi Y, Zhang G. Structural insights into histone demethylation by JMJD2 family members. Cell. 2006 May 19;125(4):691-702. Epub 2006 May 4. For Further Information Please Contact the Director of Business Development Michal Preminger Email: [email protected] Telephone: (617) 432-0920
Inventor(s): Shi, Yang
Type of Offer: Licensing
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