What therapy is used to correct epigenetic alterations?

Therapies to Correct Epigenetic Alterations

DNA methyltransferase inhibitors (DNMTIs) and histone deacetylase inhibitors (HDACIs) are the primary therapeutic approaches used to correct epigenetic alterations, with azacitidine being the most established FDA-approved epigenetic therapy for myelodysplastic syndromes. 1

Understanding Epigenetic Alterations

Epigenetic modifications refer to heritable changes in gene function that occur without altering the primary DNA sequence. These modifications include:

• DNA methylation
• Histone modifications (acetylation, methylation, phosphorylation)
• Non-coding RNAs (including microRNAs)
• Chromatin remodeling

Epigenetic alterations play crucial roles in various diseases, particularly cancer, where they can lead to silencing of tumor suppressor genes or activation of oncogenes 2, 3.

Established Epigenetic Therapies

1. DNA Methyltransferase Inhibitors (DNMTIs)

• Azacitidine (Vidaza): FDA-approved for myelodysplastic syndromes (MDS)

  • Mechanism: Incorporates into DNA and inhibits DNA methyltransferases
  • Dosing: Typically administered subcutaneously at 75 mg/m² daily for 7 days every 28 days
  • Clinical response: Achieves 15.7% overall response rate (complete + partial responses) in MDS patients 1
  • Survival benefit: Improves overall survival in higher-risk MDS

• Decitabine: Also approved for MDS

  • Similar mechanism to azacitidine but incorporates only into DNA

2. Histone Deacetylase Inhibitors (HDACIs)

• Vorinostat (Zolinza)

  • FDA-approved for cutaneous T-cell lymphoma
  • Mechanism: Inhibits histone deacetylases, leading to increased histone acetylation

• Romidepsin (Istodax)

  • Approved for cutaneous T-cell lymphoma and peripheral T-cell lymphoma
  • More potent HDACI than vorinostat

• Belinostat and Panobinostat

  • Newer generation HDACIs with approvals for specific hematologic malignancies

Emerging Epigenetic Therapeutic Approaches

1. EZH2 Inhibitors

EZH2 inhibitors have shown promise in SMARCA4-deficient cancers, as SWI/SNF complex loss leads to elevated PRC2 activity with increased H3K27me3 levels 4.

2. Combined Epigenetic Therapies

Combining DNMTIs with HDACIs has shown synergistic effects in preclinical studies and is being explored in clinical trials for various cancers 4.

3. MicroRNA-Based Therapies

Targeting aberrant miRNA expression is an emerging approach, as miRNAs function as post-transcriptional regulators of gene expression 4.

Disease-Specific Applications

Cancer

Epigenetic therapies have shown the most promise in hematologic malignancies, with established approvals for:

• Myelodysplastic syndromes
• Acute myeloid leukemia
• Certain lymphomas

For solid tumors, epigenetic therapies are still largely investigational, often used in combination with other treatment modalities 4.

Colorectal Cancer

Systems medicine approaches are being developed to identify rational combinations of targeted therapies based on individual epigenetic alterations 4.

Cardiovascular Disease

Epigenetic modifications have been implicated in ischemic heart disease, with potential therapeutic targets being explored 4.

Practical Considerations and Limitations

1. Response Assessment:

   • Response to epigenetic therapy may take longer than conventional chemotherapy
   • Regular monitoring of blood counts and bone marrow evaluations are necessary for hematologic conditions

2. Side Effects:

   • Myelosuppression is common with DNMTIs
   • Gastrointestinal symptoms, fatigue, and QT prolongation can occur with HDACIs

3. Treatment Duration:

   • Epigenetic therapies typically require multiple cycles before response is observed
   • For azacitidine, at least 4-6 cycles are recommended before assessing treatment failure 1

Future Directions

The field of epigenetic therapy is rapidly evolving with several promising approaches:

1. Development of more selective epigenetic modifiers with fewer off-target effects
2. Identification of biomarkers to predict response to epigenetic therapies
3. Combination strategies with immunotherapy, targeted agents, or conventional chemotherapy
4. Application to non-cancer conditions where epigenetic alterations play a role

As our understanding of epigenetic mechanisms in disease pathogenesis improves, more targeted and effective epigenetic therapies will likely emerge 4, 3.