Thursday, October 8, 2009

MicroRNA-26 yet another Small RNA in the Fight against Liver Cancer

When you combine the fact that current systemic small RNA delivery technologies should work best for the liver and solid cancers, that RNAi opens up many of the well validated, but hitherto un-druggable cancer targets, and that endogenous small RNA regulatory pathways (microRNAs in particular) turn out to play central roles in cancer biology, then it should not come as a surprise that various Small RNA Therapeutics approaches are poised to greatly advance the care of liver cancer patients. Surgical resection is the most common treatment, while the pleiotropic small molecule inhibitor Sorafenib that has been shown to increase median survival from 7.9 to 10.7 months is the most advanced drug for this treatment. Clearly, in light of this and the over 600,000 deaths from primary hepatocellular carcinoma (HCC) alone each year, many of them in East Asia (HBV-related), and many more deaths from the metastatic spread of other cancers to the liver, the unmet medical need is significant.

This potential has not been lost on the RNAi Therapeutics industry. There are now a number of RNAi Therapeutics liver cancer programs already in or approaching the clinic, most prominently Alnylam’s VSP-02, but also others such as one by mdRNA. At the same time, there is increased validation for microRNA-based therapeutics for liver cancer both of the antagonist type (e.g. Rosetta-Regulus collaboration) and the agonist type. In the case of the latter, two recent high-profile papers in Cell (Kota et al., 2009: Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model) and the New England Journal of Medicine (Ji et al., 2009: MicroRNA Expression, Survival, and Response to Interferon in Liver Cancer) suggest that microRNA-26 mimicry is a serious contender.

Kota and colleagues got started after making the observation that miR-26a is strongly down-regulated in a mouse model of liver cancer driven by the myc oncogene. Importantly, miR-26a levels were subsequently found to be also reduced by about 50% in liver cancer samples compared to the matched healthy liver tissue. While global down-regulation of microRNAs is a well known general property of cancer, what made miR-26a a particularly attractive candidate for microRNA replacement is that a) it is a broadly expressed microRNA and over-expression in non-target cells therefore should be well tolerated; and b) its over-expression in a liver cancer cell line decreased cell proliferation which was attributed to miR-26a directly targeting the cell cycle regulators Cyclin D2 and E2.

They then chose AAV technology to deliver a microRNA mimic to the livers of the same mouse model. AAV delivery to normal liver can be extraordinarily efficient, with essentially 100% transduction using so-called self-complementary vectors in mice. The track record for HCC has been more mixed, but using a self-complementary vector of the AAV8 serotype the authors achieved more than 90% transduction. To their great satisfaction, tumor growth was greatly retarded following systemic administration of the mimic compared to an expression vector in which the microRNA cassette had been deleted (60% tumor burden to 20% tumor burden). Importantly, whereas there was wide-spread apoptosis in the liver cancer, the surrounding normal tissues and more distant tissues with a high proliferative index (e.g. testis) appeared to be untouched. This was the first demonstration of efficacy for a systemically administered microRNA mimic that was not targeted against the cancer-initiating oncogene itself.

Further support that miR-26a is a good candidate for mimicry in liver cancer comes from a bioinformatic study just published in the New England Journal of Medicine which confirmed in a population of HBV-related HCC in China the down-regulation of miR-26 in liver cancer. Moreover, as predicted by the Kota et al. study, liver cancer patients with the least amounts of miR-26 had a worse prognosis. On the other hand, it is the same miR-26 lo patients that benefited most from interferon-alpha therapy. Such a finding may have its clinical use since for a drug with borderline efficacy like interferon in liver cancer. Being able to exclude those patients that will not benefit from a given drug may give them an opportunity to try other drugs or at least be spared of the side-effects. When used during drug development as a companion diagnostic, of course, such a test would moreover have major benefits for increasing the success rate of developing a drug candidate. Companies in the microRNA Rx/Dx space like Rosetta Genomics, Asuragen, and Regulus may want to take a look at being part of a companion Dx-Rx development program where patients are selected for a miR-26 mimicry liver cancer trial based on their miR-26a status. More generally, I shall look forward to seeing a wider adoption of microRNAs as companion Dx and, looking out from my soapbox, even a tighter integration of microRNA Dx/Rx capabilities.

In summary, miR-26a mimicry is yet another promising small RNA approach to treating a disease with a high unmet medical need, not just sometime in a distant future, but very tangible. Again, the lesson here is that once a given organ can be addressed by small RNA delivery, a flood of therapeutic targets immediately become available to keep Small RNA Therapeutics busy for some time on this one organ alone.


Anonymous said...

Great Blog! Nice to see new posts!

bio7mm said...

What do you think about Stealth Biotech's blockmir technology?

Do you think it will prove to be more effective than current microRNA and siRNA therapeutic approaches?

If it someday delivers on its' promise, it could advance the microRNA therapeutics field to the next level.

Dirk Haussecker said...

Blockmirs…it is certainly an interesting approach and fundamentally different from generally antagonizing a microRNA. The notion behind microRNA therapeutics is that a given microRNA has evolved to specifically modulate entire pathways. By blocking only one or at most a few microRNA target sites on mRNAs, blockmirs, although potentially more specific, are somewhat counter to this principle and it remains to be seen how many suitable candidates there will be. Similarly, a given microRNA-mRNA interaction usually does not regulate expression of one mRNA that much as it is typically regulated by the activity of multiple microRNAs.

I consider these approaches as complementary rather than opposing each other.

By Dirk Haussecker. All rights reserved.

Disclaimer: This blog is not intended for distribution to or use by any person or entity who is a citizen or resident of, or located in any locality, state, country or other jurisdiction where such distribution, publication, availability or use would be contrary to law or regulation or which would subject the author or any of his collaborators and contributors to any registration or licensing requirement within such jurisdiction. This blog expresses only my opinions, they may be flawed and are for entertainment purposes only. Opinions expressed are a direct result of information which may or may not be accurate, and I do not assume any responsibility for material errors or to provide updates should circumstances change. Opinions expressed in this blog may have been disseminated before to others. This blog should not be taken as investment, legal or tax advice. The investments referred to herein may not be suitable for you. Investments particularly in the field of RNAi Therapeutics and biotechnology carry a high risk of total loss. You, the reader must make your own investment decisions in consultation with your professional advisors in light of your specific circumstances. I reserve the right to buy, sell, or short any security including those that may or may not be discussed on my blog.