The upcoming phase I top-line data for ISIS-STAT3Rx in liver
cancer (HCC) to be presented at the upcoming EORTC-NCI-AACR triple meeting in Barcelona (Nov 18-21) will be an important test of the
potential utility of RNAseH antisense oligonucleotides (ASOs) incorporating
high-affinity chemistry in oncology.
Based on the body language by ISIS Pharmaceuticals* and last week's $7.5M milestone payment from partner AstraZeneca for progress on ISIS-STAT3Rx (aka AZD9150) , I am tempted to speculate on more than
just ‘encouraging’ results. On the other
hand, Regulus Therapeutics partner Sanofi at the Canton Nucleic Acid Forum (CNAF) also last week, noted the need
for formulating antisense oligonucleotides to get their anti-miR21 oncology candidate into liver cancer tissue. It is likely that they will be using liposomes for that (--> Tekmira?).
* I was surprised that
at the CNAF in Guangzhou,
China, Brett Monia from ISIS mentioned STAT3Rx and cancer right after gene
silencing in the liver as the next interesting application for ASOs- that is ahead of even the exciting CNS opportunity.
The discrepancy in body language may be explained by just
cultural differences (conservative, blasé Big Pharma versus risk-taking, enthusiastic biotech); it may also be a reflection of
different requirements for effective tissue concentrations with RNaseH versus
anti-microRNA modalities or different target requirements.
Whatever the reason, the Sanofi comments clearly support the notion
that getting naked, even phosphorothioated oligonucleotides into cancer tissues
is not as robust as with other tissues such as the liver and kidney.
I am therefore pleased that it is a Big Pharma, the last
place where I had expected that from, that is connecting the dots and is
considering delivery formulations, even the supposedly ‘toxic’ LNPs. The concept is that the nanoparticle would
facilitate a higher tumor concentration of the oligonucleotide, and once in the tumor interstitial space,
cellular delivery may be facilitated via two routes. Firstly, it may be traditional liposome-dependent cell uptake and cytosolic release. Alternatively, those LNPs that get stuck in
the interstitial space would spill the phosphorothioate oligo which may then diffuse further and get into the target cell by self-delivery.
The same concept, of course, applies not only to phosphorothioate ASOs, but also to self-delivering RNAi
triggers (+/- conjugation).
But why stop there? I propose that for cancer delivery, one should strongly consider and co-formulate
RNAi triggers and ASOs into a shared nanoparticle. They could target either the same gene, or
they could target different genes thus taking into account the desire for a
multi-pronged attack on cancer (-> resistance). In that
scenario you would benefit from the superior gene silencing efficacy of RNAi
triggers in those cells that they were able to reach, but then extent your reach with the help of the more agile, penetrative single-stranded antisense molecules.
As such, PS-ASOs have an advantage in addressing intra-tumor heterogeneity of the EPR effect which is a
well-recognized problem of nanoparticle delivery for cancer.
Another benefit of combining RNAi triggers with RNaseH ASOs
is that you could achieve additive gene silencing activity when going
after a shared target. For example, if
the RNaseH ASO and the RNAi trigger had both say a 70% knockdown activity on
their own in the nucleus and cytoplasm, respectively, the combined activity
would likely be ~90% which genetically could make a huge difference.
There is also a potency benefit, although more minor, when
going after different targets because at least in RNAi, the best you can hope
for when combining RNAi triggers against different targets is that they do not
interfere/compete with each other.
With solid cancer
data from both Tekmira (RNAi) and ISIS/AZ out over the coming weeks, we will
soon get a sense of whether the field has moved forward in oncology and what
the next steps ought to be.
