Harnessing the potential of epigenetic therapy to target solid tumors

Abstract

Epigenetic therapies may play a prominent role in the future management of solid tumors. This possibility is based on the clinical efficacy of existing drugs in treating defined hematopoietic neoplasms, paired with promising new data from preclinical and clinical studies that examined these agents in solid tumors. We suggest that current drugs may represent a targeted therapeutic approach for reprogramming solid tumor cells, a strategy that must be pursued in concert with the explosion in knowledge about the molecular underpinnings of normal and cancer epigenomes. We hypothesize that understanding targeted proteins in the context of their enzymatic and scaffolding functions and in terms of their interactions in complexes with proteins that are targets of new drugs under development defines the future of epigenetic therapies for cancer. IntroductionThe last decade has witnessed an explosion in our understanding of epigenetic modifications in cancer, including a growing appreciation of its complexity and plasticity (1-4). These developments have poised us for an exciting time to translate this knowledge into the concept of "epigenetic therapy" for cancer. To date, such therapies have gained traction largely within the sphere of hematopoietic malignancies; however, an improved understanding of the determinants of sensitivity to existing drugs, both in laboratory and early clinical trial paradigms, suggests true potential for solid tumors (5, 6). Moreover, recent studies may pave the way for newly emerging drugs and novel drug combinations in solid tumor treatment.

DNA Methylation in Cancer and Aging

“…Because it is these exact same sites that undergo de novo methylation in cancer, it is not surprising that these genes are already repressed in the normal tissue prior to transformation. This modification may also inhibit upregulation of genes that would normally combat the tumor phenotype through processes like DNA repair or apoptosis, many of which are already classified as tumor repressors (27). It thus appears that cancer-associated de novo DNA methylation, rather than bringing about repression of active genes, is occurring mostly on silent genes, and if it has any influence at all, it would have to be in preventing their activation (28).…”

Genome-wide DNA methylation profiling of recurrent and non-recurrent chordomas

“…In addition, epigenetic therapy is being actively pursued for haematological malignancies and more recently has been targeted towards solid tumors. 15,16 Especially, DNA hypermethylation of CpG rich regions in the promoter region of tumor suppressor genes has been established as an alternative mechanism for silencing of tumor suppressor genes in many cancer types. RASSF1A and HIC1 tumor suppressor genes are among the most significantly hypermethylated genes in human cancer.…”

CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer

“…With recent findings in epigenetics research, it is now clear that DNA methylation and histone modification are reversible processes that can be targeted for therapeutic intervention using small-molecule inhibitors of the epigenetic writers (methyltransferases, acetyltransferases, kinases), readers (bromodomain-or chromodomain-containing genes), and erasers (demethylases, deacetylases, phosphatases) (28)(29)(30)(31). For example, the histone acetyl-lysine reader BRD4 can be targeted for inhibition using drugs that disrupt bromodomain binding to acetylated histones (32,33).…”