What is Epigenetic Priming?

[Guest guest]

What is Epigenetic Priming?

The root cause of cancer is the mutations of key genes that cause the cell

to grow too fast or live too long. But it is not yet feasible to reverse

damage to DNA with drug therapy. So the standard approach is to force the

mutated tumor cells to self-destruct by exposing them to different

chemotherapy agents.

But there are non-genetic (epi-genetic) reasons for the malignant behavior

of tumor cells, which can be modified by other kinds of drugs - that may

help to overcome resistance to chemo agents.

Epigenetic factors can cause genes to behave (or " express themselves " )

differently -- like a car that's going too fast because the accelerator or

brake pedal is binding. Here we might gain control by smearing grease on

the affected parts. For grease to work, the part can't be physically broken

(mutated), just stuck.

Similarly, tumor cells can be resistant to chemotherapy when non-mutated

genes are stuck -- genes that would normally instruct the cell to die when

exposed to the chemo agents.

The concept (targeting epigenetics) seems similar to how we pre-wash

difficult stains before putting the clothes in the washer ... so that the

standard laundry soap can result in a clean wash.

Here's a study that's designed to see if an epigenetic drug given prior to

R-CHOP increases the sensitivity of the tumor cells to chemo.

(draft for lymphomation.org)

Phase I/II Trial of Azacytidine + R-CHOP in Diffuse Large B-Cell Lymphoma

http://bit.ly/ksAwY9 (Weil Cornell site)

" Significant progress has been made in treatment of diffuse large B-cell

lymphoma (DLBCL), but some patients are still not cured of their disease.

Recently, researchers have begun to understand how reversible changes in

expression of genes contribute to development of cancer and allow cancer

cells to become resistant to the effects of chemotherapy. These reversible

changes are termed " epigenetics " since they do not involve mutations in

genes themselves.

We are working to take advantage of the reversible nature of these changes

by pre-treating patients with azacitidine, a drug which reverses epigenetic

changes, before starting standard chemotherapy treatment. In this way, we

hope to improve the sensitivity of lymphoma cells to chemotherapy. "

All the best,

~ Karl

PS I suppose that such genes may be turned on or off by signals received

from by normal bystander cells in the microenvironment, by the types of

mutations within the cells, or both. Might affects on bystander cells

explain how lenalidomide sometimes works?

bcc: advisors