ExperimentBank || Let's cure leukemia - oncolytic virus at action again

Experiment Bank - The site for free exchange, review, and discussion of novel scientific experiments

Front Page ? Everything ? News ? Wish list ? Help ? FAQ

?Let's cure leukemia - oncolytic virus at action again
By schun, Section Biology Posted on Thu Apr 29th, 2010 at 08:22:42 AM PST

Chronic myeloid leukemia (CML) accounts for 9% of all leukemia in Canada. CML is characterized by Philadelphia translocation between chromosome 9 and 22. The translocation creates a fusion protein Bcr-Abl. Bcr-abl protein is a tyrosine kinase that causes overexpression of abl kinase. It is also responsible for anti-apoptotic activity of CML (kang 2000)Many therapeutic drugs are developed to target bcr-abl. Some drugs inhibit the tyrosine kinase activity of Bcr-Abl, some blocks oligomierization of Bcr-Abl, some destabilize Bcr-AblBlocking bcr-abl's function should treat CML since it is the main cause for CML. However, most treatment fails in the end and relapse is often seen in CML patients due to resistance. Oncovirotherapy uses selective targeting of tumour based on its defect. Oncolytic viruses are replicating microorganisms that target tumour in both its wild-type form and recombinant form. These viruses infect, replicate, lead the cells to cytolysis, and spread among the neighbouring tumor cells and leave the normal cells unharmed (Stojdl 2000). For example, wild-type Vesicular Stomatits Virus (wtVSV) induces primary anti-viral response by triggering interferon response factor 3 (IRF-3) phosphorylation and its subsequent transcription of a co-hort of genes that are responsible for viral response (Stojdl 2003).

I propose generating a recombinant VSV that expresses Crk7 protein. Crk7 plays a role in inhibiting ERK/MAPK pathway (Iornes 2009).
K562 is CML cell line that is being used to study CML in many labs. Recent study has shown K562 undergo apoptosis from inhibition of ERK/MAPK pathway.
Preliminary data from ex vivo experiment has shown that wtVSV can replicate very well in K562 but it is not efficient at killing the cells.
So, by generating VSV-Crk7, we will be able to see a dual effect: Killing of tumor cell by viral infection and inhibition of ERK/MAPK by Crk7 to cause apoptosis.

< Finding the Weaknesses of Cancer (2 comments) | TE evolution (12 comments) >

Let's cure leukemia - oncolytic virus at action again | 8 comments (8 topical, 0 editorial)

[new] Resistance (none / 0) (#1)
by KP on Tue Apr 27th, 2010 at 07:02:09 PM PST
(User Info)

So i know that individuals become resistant to therapies such as Gleevec because of mutations in downstream effects. Is it possible that resistance is can be acquired using the oncolytic virus therapy you suggested?

[new] oncolytic virus resistance (none / 0) (#2)
by fishes on Tue Apr 27th, 2010 at 07:57:12 PM PST
(User Info)

Interesting question. I am curious about this too. From thinking about it, it seems that the oncolytic viral cells would most likely divide/propagate more quickly than even a cancer cell. Therefore, the cancer cells would hopefully all be dead by the time and sort of 'resistance' could have a chance to develop. Correct me if I'm wrong schun ;)

[ Parent ]

[new] RE: Resistance (none / 0) (#3)
by Bioinfkat on Wed Apr 28th, 2010 at 01:43:16 PM PST
(User Info)

I don't know much about the use of viruses in cancer therapy but in the case of resistance to other type of therapies, it has been proposed that some cells gain resistance to the treatment as a result of evolution however some cells are intrinsically resistant to the treatment even before it is administered. I'm not sure if this could also cause a problem when using viruses?

[ Parent ]

[new] Resistance (none / 0) (#4)
by SarahLepage on Wed Apr 28th, 2010 at 02:46:58 PM PST
(User Info)

I'm sure that intrinsic resistance will be found in a small number of individuals, such as a particular defect in the apoptosis pathway (which may have contributed to the cancer in the first place). This is another area in which personalized medicine would greatly benefit patients...screening for resistance-generating mutations in the cancer cells can dictate whether this would be an effective therapy.

I'd be most worried about the oncolytic virus acquiring mutations as it replicated...this could result in potentially disastrous consequences for the host, if the virus starts to infect normal cells. Do you have any ideas for diminishing this issue?

[ Parent ]

[new] Hot topic! (none / 0) (#6)
by schun on Thu Apr 29th, 2010 at 04:33:22 AM PST
(User Info)

man, I wasn't expecting people to reply to one another before I got there.

So, I'm gonna agree with fishes with potential viral resistance. Virus particles will propagate quickly than the cancer cell. And studies has shown that as tumor disappears, so does the virus because virus no longer has a host to live and propagate in.

The only resistance to viral particle that I can think of is through anti-viral response through interferon production. But most tumor have defective pathway for interferon production.

So the some of the things that I know that cause resistance is lets for mutation specific target drugs. So for instance, some drugs are targeted for Bcr-Abl. But if there's a new mutation in Bcr-Abl and the drugs can't interact with Bcr-Abl, it is now considered as resistance. However, with viruses, whether there's a new mutation or not, the cancer cell is defective in its apotosis/proliferation pathway and the general sense that it is defected will allow virus to infect.

So, regarding evolution of virus and becoming disasterous consequence for the host is something everyone does worry about. However, the viruses that are chosen is known not to be pathogenic to human. So then, there is a chance that virus may mutate and can now infect human (i.e avian flu). Well, to potential prevent this with VSV, they would remove the M-protein (which prevents Interferon production),so that interferon would be produced to increase its safety. Since, tumor has defective pathway in interferon production, removal of M protein wouldn't affect it.

I hope I covered everyone's question!
let me know if I didn't!

[ Parent ]

[new] Viral resistance - immune system (none / 0) (#8)
by schun on Thu Apr 29th, 2010 at 06:07:36 AM PST
(User Info)

I do remember reading about viral resistance, but it's not due to tumor cell's mechanism but more of our immune system that will produce antibodies against it, so the 2nd and 3rd boost of virus has less effect. So I think oncolytic virus labs are trying to work around this issue.

[ Parent ]

[new] CRK7 (none / 0) (#5)
by smile on Wed Apr 28th, 2010 at 10:25:41 PM PST
(User Info)

May I know how exactly Crk7 works in inhibiting ERK/MAPK pathway? Cancers cells have accumulated many mutation, is this Crk7's target proteins also one of the mutation hot spot that always developed in cancer? If this is the case, the over-expression of Crk7 might not be able to kill the cancer cells successfully.

[new] Crk7 - unknown (none / 0) (#7)
by schun on Thu Apr 29th, 2010 at 04:40:13 AM PST
(User Info)

Crk7 is a novel protein and they found out that Crk7 inhibit ERK/MAPK pathway(Iornes 2009) but the exact mechanism is unknown. What we do know about Crk7 is that it localizes in the nucleus, and it seems to have a role in splicing and transcription. This new finding may suggest a few role in Crk7 or some sort of downstream effect.

So the study has shown that in breast cancer, tamoxifen is one of the common drugs for ER-alpha. However, resistance arises and they found out that with distribution with tamoxifen, Crk7 has significant change in its transcript level. (Iornes 2008). So all we know is that, in breast cancer, Crk7 is overexpressed along with Her2(which SHOULD cause apoptosis due to high Crk7), and when Crk7 is silenced, it activates ERK/MAPK. So, I don't think Crk7 itself is sufficient to kill tumor and that's why I'm suggesting the dual effect: viral effect + Crk7 effect.

[ Parent ]

Let's cure leukemia - oncolytic virus at action again | 8 comments (8 topical, 0 editorial)

?+?Menu

? create account
? faq
? search

?+?Login

Make a new account

Username:

Password:

?+?Related Links

? More on cellular and molecular biology
? Also by schun

All trademarks and copyrights on this page are owned by their respective companies. Comments are owned by the Poster. The Rest ? 1999 The Management

create account | faq | search