Thursday, April 4, 2013

Why did Mirna Therapeutics choose miR-34 for your lead development program?

Recently, we sat down with TIDES speaker Dr. David Brown, the Director of Discovery at Mirna Therapeutics.  He discussed at length Mi-RNAs and pre-clinical development programming.  Today's featured question is:

Why did Mirna Therapeutics choose miR-34 for your lead development program?

David's response: miR-34 was one of about 15 or 20 microRNAs that we identified in studies about 10 years ago that functioned as tumor suppressors. So, we had done work at a company that I was working for to identify microRNAs that played roles in human health. We were doing a collection of studies looking at microRNA expression in cancer patients. We identified a number of microRNAs that were either down-regulated or up-regulated consistently in tumors in cancer patients. We were also, at the same time, doing studies trying to understand the functional roles of microRNAs. For those studies we were introducing microRNA mimics into cancer cells or inhibiting microRNA function in specific cells. Those studies led us to this 15 or 20 microRNAs that were commonly down-regulated in cancer patient tumors that also had the capacity to affect apoptosis or reduce cell proliferation or viability or affect cell cycle progression in cancer cells. miR-34 was one of those micro RNAs and it turns out that as we began to study the role and function of miR-34 and its biological activity, we noted that miR-34 was a microRNA that probably had the broadest range of activity. That is, it had the capacity to induce apoptosis and reduce cell proliferation and cell viability in a very broad range of cancer cells. That led us to study it further. 
Among the most interesting features of miR-34 was the capacity to actually cause the complete loss of viable cancer cells. If you gave cancer cells several doses of miR-34 in culture, you’d essentially wipe out all viable cancer cells. There is also some work that we did with cancer stem cells. We noted that the down-regulation of miR-34 was vital for the development of cancer stem cell characteristics. In fact, if you introduced miR-34 back into cancer stem cell populations, they lost their stem-like characteristics and qualities. It also significantly reduced their capacity to form tumors in mice. So that, for us, was pretty compelling evidence that miR-34 was a very strong tumor suppressor. 
However, when we started studying it in animal models of cancer is really where we got very excited. We noted that among the microRNAs that we were testing for therapeutic development that miR-34 had this amazing capacity to inhibit tumor growth. We were using models of lung cancer and prostate cancer and multiple myeloma and leukemia. In all cases we saw that an introduction of a mimic of miR-34 had the ability to significantly inhibit tumor development. We then went on and married the miR-34 mimic, to a delivery technology that was developed originally by a company called Novosom and then ultimately purchased by a company called Marina Biotech. We’ve noted that the combination of a mimic of miR-34 with this delivery technology provided us with a very strong accumulation of miR-34 in solid tumors, especially those solid tumors that were in the liver. In two different models of liver cancer we noted that miR-34 that had been formulated with this delivery technology caused complete tumor regression. So, for us, this is pretty compelling evidence that miR-34 functions as a tumor suppressor and has the ability to cause a therapeutic response. 
At this point we’ve continued to study miR-34 and its ability to affect tumor growth and, in fact, cause tumor regression. What we’ve noted is that the introduction of miR-34 into liver cancer cells has effects on the genes within the beta catenin pathway and wnt pathway. It has the ability to affect genes in the c-Met pathway, the MYC pathway, the MAP kinase pathway, and the vegf pathway. It also stimulates expression of genes, tumor suppressor genes within the p53 pathway. So, you begin to get this understanding of the fact that this single microRNA functions as a tumor suppressor based on its ability to co-regulate many oncogenes and tumor suppressors. This kind of power provides a potency that we are able to observe in these animal models and we certainly hope that is going to now translate as we move into the clinic.

Listen to David's full podcast here.
Read the full transcript here.

You can find out more from David at the TIDES Summit, taking place May 12-15, 2013 in Boston, MA. He will be presenting Efficacy, PK and Tox Data Supporting the Move to IND for Mirna Therapeutics on Wednesday, May 15. For more information on this session and the rest of the program, download the agenda. If you'd like to join David in Boston, as a reader of this blog when you register to join us and mention the code TIDES13JP, you'll save 20% off the standard rate! Stay tuned for more excerpts from David's podcast.

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