In two of my earlier posts - on micro-RNAs and PARP inhibitors - I forgot to add what is really exciting about these developments.
Why is it that cancers are so dangerous? It is because they have lost a control mechanism that would normally prevent them from proliferating in this way. What these topics tell us is that the point of survival advantage is also their point of vulnerability.
Think of the cancer as the young man on a motor cycle. He abandons the rules of the road and races away at the lights. But his very lack of care is what causes him to have an accident. Thus in CLL with an ATM deletion there is a defect in DNA repair. This gives the CLL clone a survival advantage over other B cells, and allows it to develop further DNA damage, but it is only because it has the ATM deletion that it is vulnerable to PARP inhibitors. If you like it is like Judo - you use the cancer's strength against itself.
5 comments:
Ok, I am just trying to get a handle on this. Isn't it the over expression of Bcl-2 that actually flags a cell as being a CLL B-cell?
Since miR-15 and 16 are natural antitense Bcl-2 interactors could they not be used to produce apoptosis, and perhaps offer a control for CLL.
I am unclear how PARP is involved in the process other than it is cleved by miRNA's manipulation, thus lowering the levels of Bcl-2 and initiating apoptosis.
I guess my question is how is poly (ADP-ribose) polymerase involved in the process?
Chris Dwyer
PARP is involved in DNA repair. It has nothing to do with bcl-2. ATM is also involved in DNA repair - it is required to either kill a damaged cell or repair the damage. In its absence the cell does not repair the DNA damage and it does not die. Rather it lives on accumulating more and more damage. However, The PARP inhibitor kills the ATM depleted cell which requires PARP to stay alive. Non-ATM depleted cells do not need PARP to stay alive and are therefore not damaged by it.
The niR story that is similar relates not to miR15 and 16 but to the other miRs present on chromosome 5q, where Revlimid acts (see article on miRs)
Another example would be HSP-90 inhibitors, which according to an abstract last year by Dr. Tom Kipps, could be the Achilles heel of ZAP-70.
Kipps concluded: "Consequently, drugs that can inhibit activated Hsp90, such as 17-allyl-amino- demethoxy-geldanamycin (17-AAG), can cause selective degradation of ZAP-70, loss of effective Ig-signaling, and apoptosis of ZAP-70+ CLL cells at concentrations that have no apparent effect on normal T cells or ZAP-70-negative CLL cells. As such, CLL-cell expression of ZAP-70, an adverse prognosis marker, may actually become the Achilles heal of this CLL subtype, allowing for effective targeted- therapy of aggressive disease."
Targeted therapies are indeed exciting, but they take time to develop, though it is good to hear PARP inhibitor trials may start this year. As usual with us patients, it is a matter of beating the clock.
Remember that test-tube results are rarely duplicated in the real world.
Even the wonder drug Gleevic for CML isn't a cure. There is a resistance rate occuring in about 5% of patients per year, which means there's a maximum effectiveness of 20 years, and I suppose a median survival of 10 years.
Cancer is a very tough foe. It is now the number one killer of those under 85 in the US.
I wonder what I did wrong to get CLL in the first place? I've kept fit my whole life, I have no heart disease, no major illnesses, I rarely get sick (as opposed to others I know).
Yet I have a fatal illness that will kill me in a few years' time.
Is the trial at MDA "Combined Activation of PPAR-Gamma and RXR pathways by Rosiglitazone (Avandia) and Bexarotene (Targretin)in Hematological Malignancies" referring to a PARP inhibitor? If not, do you know where PARP trials will be offered - what location?
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