Epigenetic therapies in haematological malignancies: searching for true targets
Lucia Altucci1, Saverio Minucci2
1Dipartimento di Patologia Generale, Seconda Università degli Studi di Napoli, Vico L. De Crecchio 7, 80138 Napoli, Italy.
Abstract:
Epigenetic alterations complement genetic mutations as a molecular mechanism leading to cell transformation, and maintenance of the cancer phenotype. Of note, they are reversible by pharmacological manipulation of the enzymes responsible for chromatin modification: indeed, epigenetic drugs (histone deacetylase inhibitors and DNA demethylating agents) are currently on the market, inducing proliferative arrest and death of tumor cells. These drugs, however, have been effective only in a few tumor types: the lack of consistent clinical results is mainly due to their use in a poorly targeted approach, since the epigenetic alterations present in cancer cells are mostly unknown. In a few cases (notably, leukemias expressing RAR and MLL fusion proteins), the molecular mechanisms underlying tumor-selective and tumor-specific epigenetic alterations have started to be deciphered. These studies are revealing a dazzling complexity in the mechanisms leading to alterations of the epigenome, and the need of combination therapies targeting different chromatin modifiers to reach an effective reversion of epigenetic alterations.
Insights
Epigenetic alterations drive cancer and can be reversed by epigenetic drugs. However, their limited effectiveness stems from unknown cancer-specific epigenetic changes, necessitating targeted combination therapies.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Epigenetic alterations are crucial in cancer development and maintenance.
- Epigenetic drugs targeting chromatin modification enzymes are available but show limited clinical efficacy.
- Current challenges include a lack of understanding of cancer-specific epigenetic alterations.
Purpose of the Study:
- To investigate the molecular mechanisms of tumor-specific epigenetic alterations.
- To understand the complexity of epigenome modifications in cancer.
- To identify strategies for effective epigenetic reversion in cancer therapy.
Main Methods:
- Analysis of epigenetic alterations in cancer cells.
- Pharmacological manipulation of chromatin-modifying enzymes.
- Deciphering molecular mechanisms in specific cancer types (e.g., leukemias with RAR and MLL fusion proteins).
Main Results:
- Epigenetic drugs can induce cancer cell death and proliferation arrest.
- Limited clinical success is attributed to poorly targeted approaches and unknown epigenetic landscapes.
- Studies reveal complex mechanisms underlying epigenome alterations in specific cancers.
Conclusions:
- Effective cancer treatment requires understanding and targeting tumor-specific epigenetic alterations.
- Combination therapies targeting multiple chromatin modifiers are needed for effective epigenetic reversion.
- Further research into cancer epigenetics is essential for developing novel therapeutic strategies.
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