MBD2 inhibition identified as a selective strategy for reducing tumor growth

The cancer market is attracting heavy R&D investment and to date over one thousand innovative compounds have entered clinical development, many of which are now reaching, or are about to reach the market (for a complete evaluation of oncology R&D click here). Substantial unmet needs still however exist in the cancer market and the high incidence of disease is leaving pharmaceutical companies striving to improve the efficacy of treatments. Much activity surrounds the identification of novel targets and pathways involved in chromatin plasticity represent an area receiving current interest.

The concept that chromatin structure is plastic and that this represents a key mechanism in the regulation of transcriptional control is now generally accepted. This plasticity is regulated by histone (de)acetylation (Click here to access "Histone deacetylase inhibitors: Redefining pharmaceutical approaches to the treatment of cancer") and methylation. Correspondingly, defects in acetylation and/or methylation have been proposed to play a central role in cancer, while on the other hand therapeutics that modulate histone deacetylase or methylase activity hold considerable potential for the treatment of cancer. CpG island hypermethylation is known to be associated with gene silencing in cancer, and these silenced genes can be reactivated by 5-aza-2'-deoxycytidine (5-Aza-CdR), a potent inhibitor of DNA methylation.

Methylated DNA binding proteins (MBDs) constitute a family of proteins that recognize methylated DNA and are responsible for creating, maintaining, and interacting with the epigenome. One of the methylated binding proteins, MBD2, has been described as both a transcriptional repressor. Although the exact role of MBD2 in gene expression is still unclear, there is strong evidence suggesting that MBD2 is critical for tumorigenesis. Evidence of increased MBD2 expression in tumors and cancer cells has been observed and its expression in mammary tumors correlates with tumor size. Although MBD2 deficiency rendered mice resistant to tumorigenesis, whether inhibition of MBD2 would inhibit established tumors or whether MBD2 was required just for initiating the tumorigenic state but not for maintenance of tumorigenicity has been the subject of debate.

Moshe Szyf’s group at McGill University is one group involved in the study of MDB2 and they have made the important observation that knock down of MDB2 inhibited anchorage independent growth of human cancer cells and MBD2 deficient mice were shown to be resistant to intestinal tumorigenesis. MBD2 is therefore an attractive anticancer target, even more so since MBD2 deficient mice were previously shown to be viable and fertile and knock down of MBD2 was reported to have no effect on cellular growth parameters of nontransformed cells.

In their recent Carcinogenesis paper, the McGill group extend their earlier findings testing the hypothesis that pharmacological inhibition of MBD2 inhibits cancer growth in vivo. In particular, antisense inhibitors of MBD2 inhibited anchorage-independent growth of human lung (A549) and colorectal (HCT116) cancer cell lines in vitro and tumorigenic growth of human cancer cell xenografts in vivo. This was related to an inhibition of the early stages of tumor implantation as well as the progression of implanted tumors. MBD2 antisense oligonucleotide does not inhibit the growth of normal or transformed cell lines, alter cell cycle parameters in vitro or exhibit overt toxicity in vivo. Instead the authors speculate that MDB2 is critical for the interaction of tumors with surrounding tissue under conditions of non-anchorage growth or growth within a non-cognate environment. Such a function would mean that blocking MDB2 results in the inhibition of tumor growth but not under conditions of normal tissue growth.

These data provide a proof of principle that MBD2 is a new anticancer target and that pharmacological inhibition of MBD2 by agents such as the antisense inhibitors described in this paper are potential new anticancer therapeutics, which in contrast to the vast majority of current approaches do not target the normal progression of the cell cycle.


Entry date Sunday, April 18, 2004

Adapted from Campbell et al, Carcinogenesis. 2004 Apr;25(4):499-507.
 

LeadDiscovery and BioPortfolio aims to provide reliable, insightful analysis on the biotechnology industry. However, this information is provided "as is" and no representations or warranties either express or implied of completeness, accuracy, or of any other nature are made with respect to this information. This information is neither an offer to sell nor a solicitation to buy the securities of any company. This information contains forward-looking statements, which involve risks and uncertainties which may not be listed. The biotechnology industry is an emerging industry and the securities of the companies mentioned in this report have a very high degree of risk and volatility. For this reason, this information is supplied on the condition that the reader will make his or her own determination as to its suitability for any purpose prior to any use of this information. The employees and officers of LeadDiscovery and BioPortfolio may hold positions in some or all of the stocks discussed in this report.

This abstract has been produced by LeadDiscovery Ltd. Founded by life scientists for life scientists we aim to help industry identify cutting edge drug discovery options and academic/biotech institutions maximize the potential of their research. Abstracts strictly reflect the opinion of LeadDiscovery's editorial panel. While all reasonable efforts are made to ensure the accuracy of information provided LeadDiscovery and the publisher BioPortfolio, takes no responsibility for incorrect or misleading information. LeadDiscovery is designed for educational and drug development purposes only and is not intended or designed to offer medical advice or advice of any sort, and must not be used for such purpose. The information provided through LeadDiscovery and BioPortfolio should not be used for diagnosing or treating a health problem or a disease and no reliance should be placed on any information contained in this abstract or elsewhere on LeadDiscovery's and BioPortfolio's website. It is not intended to be a substitute for professional care. If you have or suspect you may have a health problem, you should consult your physician or other health care provider.