Epigenetic therapies have been suggested in treatment of all solid tumors, and extensively studied with variety of outcomes. Unfortunately as solo therapy they have shown minimum activity when it comes to improving patient survival at end stage disease.
The cancer epigenome is characterized by global DNA methylation and chromatin changes, such as the hypermethylation of specific CpG island promoters. Epigenetic agents like DNA methyltransferase or histone deacetylase inhibitors induce phenotype changes by reactivation of epigenetically silenced tumor suppressor genes. Despite initial promise in hematologic malignancies, epigenetic agents have not shown significant efficacy as monotherapy against solid tumors. Recent trials showed that epigenetic agents exert favorable modifier effects when combined with chemotherapy, hormonal therapy, or other epigenetic agents.
That said, there is good news!
The promising news is that cancer stem cells can be targeted by this modality. The effects of epigenetic therapies on cancer stem cells are shown in literature. Also it is well described in the literature that this class of therapies are able to enhance the response to chemo agents and significantly reduce the chances of cancer recurrence. Therefore epigenetic therapies are suggested as “ back bone” therapy for all other modalities of care, including surgery, radiation and chemotherapies.
One of the foundation projects is development of a protocol, called MTET, which has shown overwhelming preclinical data to support it’s activity in chemorefractory disease, and more importantly in advanced cancer.
One major development in current years of research is the perspective about tumor size and patient survival. For the longest time, it was thought that a larger tumor would cause shorter survival. Now we know that because of tumor ability to spread in smaller sizes ( when the tumor is more compact and hypoxic), the larger tumor does not mean the shorter survival. This change in paradigm of understanding the tumor cell biology caused a major shift in our care. Now we do not push for reduction of tumor size as we did before. For example the use of cytotoxic agents are now questioned in advanced stages of disease when survival of the patient is not simply dependent on the tumor size. Interestingly the RECIST criteria used to define response to any treatment unfortunately has not changed, meaning that a patient with smaller tumor post therapy is still considered a responder when the patient may not survive beyond expected without therapy!
Again the role of epigneteic therapies were more highlighted after such findings, as epigenetic therapies tend to target the cause of the disease, and cancer stem cells, and intend to differentiate the cancer stem cells to a lower plasticity phase where they commit to certain lineages of cells, with reduce capacity to reproduce and reengage in cell cycles. It is believed that this certainly can translate to a better outcome, and survival in many cases.