Blood Cancer

Epigenetic Therapy Cancer Treatment

Epigenetic drugs (Hypomethylating agents and HDAC inhibitors) in clinical use represent the initial agents that exploit epigenetic alterations to benefit patient outcome.

The very first indication for and the related drug approved in the field of epigenetics in cancer was Decitabine.( A derivative of Azacitadine).

Although 5-aza and decitabine have been used to treat numerous types of human tumors, they have been perhaps most successful against the hematologic malignancies, specifically MDS and AML. 5-aza was shown to have a significant response rate in patients with MDS, along with reduced risk of leukemic transformation and increased survival, which helped lead to its FDA approval in 2004 [Silverman et al. 2002]. A large-scale clinical study known as AZA-001 helped establish 5-aza as the preferred treatment for patients with high-risk MDS [Fenaux et al. 2009

After all, leukemias and lymphomas are treated durably with epigenetic therapies, which is in contrast to cytotoxic drugs that mainly stimulate cancer stem cells making the tumor recurrence almost always inevitable. This phenomenon is extremely important as durability of response is an issue with all successful therapies, even at best research platforms using most sophisticated technologies and targeted therapies.

Epigenetic drugs although for the longest time considered to be the holy grail in treatment of solid tumors, they have unfortunately failed in many studies to provide superior outcome to patients with solid tumors, that said in hematological cancer they still are being used and investigated to bring new hope, but even at best scenarios, the tumor generally becomes refractory as these agents are unselective when it comes to their mode of action at the DNA level. For example decitabine not only demethylates the oncosuppressor genes but also it does so on oncopromoters, such as S 100 B, which explains the carcinogenicity of the drug itself.

One of the foundation projects is clinical trials for the novel MTET therapy which appears to be unique in several folds, one is that the technology if optimized and approved, can selectively affect the oncosuppressor genes and not the cancer promoter genes. Therefore the cancer promoters genes will not be unleashed as is the case for traditional epigenetic drugs. Second it appears that components of MTET therapy is able to combine the histone desirable epigenetic effects with the DNA epigenetic desirable effect in combination, which is for the longest time a dream for any epigenetic product to accomplish, and finally there are potency issues that makes the MTET a flexible product on it’s effect on dynamic epigenetic platform of abberrancies.

More recent drugs in the market include EZH2 inhibitors. EZH2 mutations are found throughout the gene and their presence is associated with an adverse prognosis. While the role of EZH2 as an oncogene has been studied and documented extensively, in myeloid neoplasia EZH2 is also commonly altered by deletions and mutations that lead to the loss of EZH2 function, suggesting that this factor can have a possible role as a tumor suppressor. EZH2 mutations may affect other epigenetic mechanisms such as DNA methylation, given that EZH2 can directly interact with DNMTs and control their activity. Many hematopoietic tumors carry genetic alterations that lead to increased lysine 27 methylation and thus may be amenable to therapies with EZH2 inhibitors. Interestingly MTET also targets this important gene.

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