With ASCO
2014 behind us, I am left with the impression that oligonucleotide therapeutics
have failed to keep pace with important developments in cancer drug
development. Most importantly, cancer
oligonucleotide therapeutics need to take advantage of the latest genomic tools and insights in cancer biology to select the patient populations most likely to
respond treatment to both increase success rates and to save development dollars. After all, this is what you would expect
from a platform most suited to personalized medicine.
In some
cases, drugs are being developed a priori with specific mutations in
mind such as the selective EGFR-mutant inhibitors by Clovis Oncology and
AstraZeneca which have caused quite a stir amongst clinicians and investors at ASCO. In other cases, and this is something
spearheaded by companies like Foundation Medicine and their pharmaceutical
partners, comprehensive next-gen sequencing is employed as trials progress to
identify often complex signatures that render a cancer susceptible to a
treatment.
And
particularly relevant for delivery aspects, other companies such as Endocyte
are using imaging diagnostics to identify those cancers that either express the
right surface receptors for a ligand-targeted agent or those amenable to the
EPR effect relevant for nanoparticle-based delivery.
Although I
believe that Tekmira has also a delivery-related rationale in selecting
adrenocortical carcinoma and neuroendocrine cancers for TKM-PLK1 based on their insights in liposomal
delivery, the oligonucleotide field at large is failing to take advantage of
delivery-related cancer selection strategies.
In terms of
tumor response related to hitting the right targets and pathways, I would like to see the field embrace the personalized genetics approach. Prospectively targeting KRAS mutant
colorectal cancers with a PLK1-RNAi therapeutic would be one example. Going one step further, a development
strategy that looks at the genomic profiles of various cancers and then pull
out the formulation with the right RNAi trigger or antisense oligo against critically activated
pathways would play into the strength of the technology: every signature is
‘actionable’ as the technology leaves no target behind.
Especially
for delivery approaches that can penetrate tumors well, innovative cancer
development could unlock the considerable potential that
oligonucleotide therapeutics have for oncology. Beyond TKM-PLK1, the androgen receptor antisense compound by
ISIS/AstraZeneca could be an important first test case for this concept in
oligonucleotide therapeutics.
