Cancer Epigenetics and Targeted Therapies

The review by Drs. Boumber and Issa of epigenetic drugs that target human cancers nicely summarizes recent progress in this hot area and points out future lines of investigation. Salient points made by the authors include the advantages of using low-dose regimens for drugs that target DNA methylation (a major clinical advance that was pioneered by Issa and his colleagues at M.D. Anderson), the rationale for extending the use of these and other epigenetic agents to patients with solid tumors, and the recent development of drugs with pharmacologically desirable properties targeting the enzymes that catalyze histone modifications.

The question of which other classes of drugs will act synergistically with DNA methyltransferase inhibitors is an important one. The discovery of such combinations may tell us a lot about how DNA demethylation produces its anti-cancer effects. Cell-line screening with drug combinations and the use of carefully selected combinations in genetically modified mouse models of cancer will probably be the workhorse tools used to answer this question. However, there are obvious limitations to such approaches, mainly financial. As Boumber and Issa point out, there is also an exciting potential here for using unbiased and relatively inexpensive short hairpin RNA (shRNA) screens. The authors cite one nice example in their overview, and it will be interesting to see how generally useful such synthetic lethal screens will be.

Many laboratories have been asking whether specific mRNA or microRNA (miRNA) expression profiles or CpG methylation profiles in tumors might identify sensitivity to epigenetic drugs. Another topic that will be very interesting to pursue is the possible association between clinical responses to epigenetic drugs and tumor-associated somatic mutations in epigenetic pathway genes. As recently as 5 years ago it would have been difficult or impossible to ask this question; however, high-coverage targeted approaches and genome-wide sequencing approaches are uncovering a growing number of such mutations. Some examples include DNMT3A and TET2 mutations in acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) and other tumor types;[1-3] mutations in SWI/SNF family genes, not only in rare tumors such as malignant rhabdoid tumor, but now also in common malignancies such as ovarian carcinomas;[4,5] MLL2 and MLL3 histone methyltransferase gene mutations in medulloblastomas;[6] and EZH2 mutations in AML and lymphomas.[7,8] We already know that simple over- or under-expression of tyrosine kinase genes is usually not sufficient to confer high sensitivity of tumors to tyrosine kinase inhibitor drugs: gain-of-function somatic mutations are required to confer this sensitivity-presumably reflecting “oncogene addiction” only in the cancers with mutations. Will a similar scenario play out for epigenetic drugs and gain-of-function or loss-of-function mutations in epigenetic pathways?

Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

References:

1. Ley TJ, Ding L, Walter MJ, et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med. 2010;363:2424-33.

2. Delhommeau F, Dupont S, Della Valle V, et al. Mutation in TET2 in myeloid cancers. N Engl J Med. 2009;360:2289-301.

3. Langemeijer SM, Kuiper RP, Berends M, et al. Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat Genet. 2009;41:838-42.

4. Wiegand KC, Shah Sp, Al-Agha OM, et al. ARID1A mutations in endometriosis-associated ovarian carcinomas. N Engl J Med. 2010;363:1532-1543.

5. Jones S. Wang TL, Shih le M, et al. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science. 2010;330:228-31.

6. Parsons DW, Li M, Zhang X, et al. The genetic landscape of the childhood cancer medulloblastoma. Science. 2011;331:435-9.

7. Morin RD, Johnson NA, Severson TM, et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet. 2010;42:181-5.

8. Makishima H, Jankowska AM, Tiu RV, et al. Novel homo- and hemizygous mutations in EZH2 in myeloid malignancies. Leukemia. 2011;24:1799-804.