Romidepsin an epigentic therapy - news / trials / background

[Guest guest]

First to a News item, based on an ASH report:

Romidepsin Induces Responses (some complete) in Peripheral T-Cell Lymphoma

http://bit.ly/fUANBl

Comment:

Romidepsin is one of a new class of lymphoma drugs that can induce tumor

cells to die by silencing or restoring the expression of genes involved in

the aberrant behavior of the malignant cells. A mouthful.

These appear to work by " reprogramming " the cells - turning ON

(up-regulating) built-in gene-based programs that suppress tumor growth/

survival,

.. OR by turning OFF (down-regulating) the genes that cause the cells to

divide too fast or resist dying.

The field is called epigenetic therapy - how drugs can target the enzymes

that control gene expression - hyper- OR hypo- methylation, and acetylation.

==

Here are Romidepsin Trials for lymphoma / CLL: http://bit.ly/eLeAPo - a way

to perhaps utilize this agent today in one of the clinical trials.

==

Technical background:

Epigenetic Modulation and Therapy of Lymphoid Malignancies

" The FDA has approved four epigenetic therapies for oncology: VidazaT

(azacitidine, 2004), DacogenR (decitabine, 5-aza-2'-deoxycytidine, 2006),

ZolinzaT (vorinostat, 2006), and IstodaxR (romidepsin, 2009); and many more

are in clinical and preclinical development. "

While we know the enzymatic targets of these agents, we still do not fully

understand the true mechanism of action of these agents. Ostensibly, both

classes of agents work to inhibit enzymes that silence genes with tumor

suppressor function: DNA methyltransferases (DNMTs) and histone deacetylases

(HDACs).

Reduction of hypermethylation has been documented following inhibition of

DNMT by 5-aza-2-deoxycytidine and 5-azacytidine. Significant clinical

activity including durable responses and improvement in survival initially

led to approval of these agents in myelodysplastic syndrome (MDS).

Although demethylation has been confirmed following treatment with these

agents, particularly in the low dose, chronic schedule developed for MDS,

the extent of demethylation does not correlate with response, suggesting

other factors are important. The genes critical for response are still under

study - several known to be hypermethylated in MDS have been intensively

studied, including the p15INK4B and the fragile histidine triad (FHIT)

genes.

There are many parallels for the HDAC inhibitors, which also inhibit enzyme

activity and promote gene transcription.

FDA approvals for vorinostat and romidepsin are based on clinical activity

in cutaneous T-cell lymphoma (CTCL) including durable and complete

responses.

Activity in peripheral T-cell lymphomas has also been observed in clinical

trials with romidepsin and other HDAC inhibitors.

Increased global histone acetylation has been noted in clinical samples;

however, there is no correlation of this marker with response to vorinostat.

Romidepsin, on the other hand, requires activation and our clinical data

have suggested a correlation between persistent histone acetylation and

clinical response.

The gene alterations critical for clinical activity still require

definition. Although HDAC inhibitors reliably induce the CDK inhibitor p21,

overall about 5% of genes assayed are upregulated by HDAC inhibitors in

array studies, and an equal number downregulated.

Notably, multiple cellular proteins are also affected by acetylation; some

of them potentially responsible for the activity of the HDAC inhibitors.

This may depend upon cellular context but in some cell types is likely to be

as important if not more important than their effects on gene transcription.

T-cell lymphomas in more than one-third of patients show sensitivity to the

HDAC inhibitors, and it is not known which of the myriad activities is

critical for the activity in the T-cell lymphomas.

What we do know is that in a subset of patients, responses can be very good,

and of very long duration. Critical needs for epigenetic therapies include a

more precise determination of mechanisms of action, so that we may identify

the subsets of patients who will have disease response.

We need to define mechanisms of resistance that emerge after treatment fails

if we hope to prevent that outcome.

We need effective combinations with epigenetic therapies to increase their

activity in the diseases currently known to be susceptible, but also to

extend their range of activity.

Epigenetic therapies - originally identified as differentiating agents - are

unique among anticancer therapies in having the potential to actually reset

(reprogram) the oncogenic (genes involved in growth and survival) phenotype

(characteristics of the cell). A significant research effort is needed to

harness this potential. "

==

E. Bates, MD

Medical Oncology Branch, National Cancer Institute, National Institutes of

Health, Bethesda, MD

http://ash.confex.com/ash/2010/webprogram/Paper25827.html

All the best,

~ Karl

Patients Against Lymphoma

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