News in Ovarian Cancer Research

M. D. Anderson Cancer Center

Cancer Newsline Audio Podcast Series

Date: March 02, 2009

Duration: 0 / 13:53

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Lisa Garvin:

 

Welcome to Cancer Newsline, a weekly podcast series from the University of Texas M.D. Anderson Cancer Center. Cancer Newsline helps you stay current with the news on cancer research, diagnosis, treatment and prevention, providing the latest information on reducing your family's cancer risk. I'm your host Lisa Garvin. Today we are talking with Dr. Anil Sood, a professor in M.D. Anderson's Department of Gynecology. His research, to be published in the December New England Journal of Medicine found that two proteins have a significant impact on the survival of women with ovarian cancer. The two proteins Dicer and Drosha are vital to a cell's machinery that silences genes. Sood's team found that the presence of these proteins in the tumor also affects survival in breast and lung cancer patients. Welcome Dr. Sood. Can you describe your findings with ovarian cancer, regarding ovarian cancer?

 

Dr. Anil Sood:

 

Sure. In this particular project we looked at these two enzymes, Dicer and Drosha that play a critical role in cells in terms of how genes are regulated. The Dicer and Drosha are known to play a critical role in normal cells, however, interestingly we found that about half of the human ovarian cancers tend to have either low or absent levels of these particular proteins. When both of these proteins are low or absent, we found that patients tend to live for a substantially shorter length of time, such that when both of these proteins are low, patients on average survived for about 2.6 years who had ovarian cancer compared to those patients who had tumors with normal or high levels of Dicer and Drosha. In those patients the average survival was more than 11 years, so there was quite a bit of difference. So, we wanted to make sure that these findings validated, so we looked at a separate cohort of ovarian cancer patients and again the findings validated even in that setting. Then we also looked at cell lines and found that even in cancer cells that are derived from human patients in these cell lines about half of them tend to have low or absent levels of these proteins. And when that occurs there are alterations in how the cells can process longer fragments of RNA called shRNA. They are still able to process the short interfering RNA without any problem.

 

Lisa Garvin:

 

Now, explain how Dicer and Drosha actually work.

 

Sood:

 

Okay, the enzyme Drosha actually functions within the nucleus of a cell, so that it processes longer fragments of RNA and it cuts them into shorter fragments. These fragments are then transported out of the nucleus into the cytoplasm where they are further processed by the enzyme called Dicer into even shorter fragments that then go on to result in silencing or shutting off of specific genes or pathways.

 

Garvin:

 

Now, is this RNA acting as a messenger? I know sometimes RNA can act as a messenger or it can do its own thing. What is it doing in this case?

 

Sood:

 

In this case, these shorter fragments, either the short interfering RNA or once the miRNA is cleaved these fragments actually guide other proteins to actually shut off a specific gene. Now, many of these genes can be cancer promoting genes, but there are some thought that some of these miRNAs may actually play a role in regulating genes that actually control tumor growth.

 

Garvin:

 

How do these findings apply to other types of cancer? I mean, you were studying ovarian cancer in particular, but it seems like it might have impacts in other types.

 

Sood:

 

Sure and to ask that question, we started to look at even breast cancer as well as lung cancers and found that especially the Dicer protein was associated with very, very similar findings in that when the levels of Dicer gene were low either in breast or in lung cancer, the patients tended to survive for a much shorter time period. So, we do feel that these findings extend beyond ovarian cancer to other cancer types as well.

 

Garvin:

 

Now, how did you latch on to Dicer and Drosha, what prompted you to study these particular proteins?

 

Sood:

 

For the last several years we have been working on developing newer therapy strategies using short interfering RNA, which is a new way of shutting off of the genes, but there are many options for doing that. You can use either short interfering RNA or you can use longer fragments. So, as a part of this area of research, we wanted to figure out that are there alterations in the actual machinery that regulates or processes some of these RNA fragments. That's how we got started into this line of research and found that actually the longer fragments can't be processed in many cancer cells.

 

Garvin:

 

Where do you go from here? I mean, I know we are pretty far from the bedside at this point, but what would be your next step now that you've found this?

 

Sood:

 

Well, there are many next steps. One is that this so far indeed appears to be a promising prognostic factor in terms of differentiating those patients who will tend to do better compare to worse. Could there be therapies that are tailored toward individuals who have low Dicer and Drosha levels. These are some of the questions that we are trying to tackle. The other element is that as RNA interference based therapy strategies get closer and closer to the clinic as we are now, these kinds of findings help us determine which type of fragments specifically to use for therapeutic purposes. So, these will guide our development of therapies as well.

 

Garvin:

 

From what I have read, it seems like it was an "a-ha!" moment for RNA and the fact that it did have other functions than just being a messenger, so is this kind of a new frontier maybe in targeted therapies and are prognostic tools tumor markers?

 

Sood:

 

Well, I think all of those applications are very feasible. One is the prognostic applications and then of course for therapy. If the siRNA-based therapies indeed come out to be promising as they hold promise for, then that would open up a lot of avenues for targeting genes or proteins that simply cannot be targeted by other methods.

 

Garvin:

 

Is there any other…is there something that we've missed or is there something else that other implications or other avenues that you might be exploring based on your research?

 

Sood:

 

I think these are the major avenues. The other avenues we understanding is what you alluded to earlier is the other roles for RNA in regulation of genes and cancer cells. And again, that's an evolving area of research and there is still a lot to be done over the next several years.

 

Garvin:

 

And this is probably good news for ovarian cancer as well. I mean, we've had limited success with CA-125 and other prognostic factors. It's still known as the silent killer. Do you think that this really might be a new way to kind of detect ovarian cancer at earlier stages when it is more treatable?

 

Sood:

 

For detection, this may be harder to do because we were looking at more at outcome of cancer patients. Could there be opportunities for detection downstream of these enzymes or proteins in terms looking at RNA alterations, we're certainly exploring those kind of avenues, but we always try to take a cautious, but systematic approach in terms of developing these kind of biomarkers for both diagnostic and prognostic applications.

 

Garvin:

 

So, as far as the survival rates that you saw in your research, that's pretty significant in the world of survival rates in research, isn't not?

 

Sood:

 

Yes, absolutely and it really the most dramatic difference occurred when you take into account both of the proteins. The differences in survival were smaller when you look at each individual protein and again to me the even more impressive finding was that, yes, there was difference in survival, but it was validated in separate cohort and it extended to even other malignancies, such as breast and lung cancer. To me that's quite remarkable that this finding may have applications even for other malignancies.

 

Garvin:

 

Thank you, Dr. Sood for talking with us today. If you have questions about anything you've heard today on Cancer Newsline, contact ASK M.D. Anderson at 1-877-MDA-6789 or online at www.mdanderson.org/ask. Thank you for listening to this episode of Cancer Newsline. Tune in next week for the next episode in our series.

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