Wednesday, June 4, 2014

Oligonucleotide Therapeutics Need to Embrace New Genomic Era in Cancer Medicine

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.

2 comments:

Anonymous said...

I wouldn't be surprised if an Isis gen.2.5 drug targeting mutant KRAS found its way into the pipeline eventually, given that a number of abstracts have been presented at meetings over the last year (such as the one below).

Presentation Title: Characterization of next generation (Gen2.5) KRAS antisense inhibitors in NSCLC, PDAC, and CRC models

Author Block: Alexey S. Revenko, Gourab Bhattachrjee, Chris May, Brett P. Monia, A. Robert MacLeod. Isis Pharmaceuticals, Carlsbad, CA

Abstract Body: KRAS is among the first described oncogenes and one of the most frequently mutated genes in human solid tumors. Despite substantial efforts to identify specific KRAS inhibitors, no effective therapeutic strategies to target KRAS directly have been identified. Here we describe the selective inhibition of KRAS with next generation (Gen2.5) antisense oligonucleotides.

We recently demonstrated preclinical and clinical activity of a next-generation constrained-ethyl (cEt) modified (Gen 2.5) antisense oligonucleotides (ASOs) targeting STAT3 mRNA (STAT3Rx/AZD9150).

Systemic delivery of unformulated STAT3Rx/AZD9150 produced robust target RNA and protein reductions in a broad range of xenograft models (AACR 2013). More importantly, STAT3Rx/AZD9150 showed striking clinical activity in the phase I dose escalation study, producing anti-tumor activity in 4 out of 6 patients with advanced treatment-refractory lymphoma (ASCO 2013).

In this study, we generated a panel of high affinity Gen2.5 ASO targeting KRAS.

Anti-proliferative effects of the KRAS ASOs were evaluated on a panel of colorectal carcinoma (CRC), non-small cell lung carcinoma (NSCLC) and pancreatic ductal adenocarcinoma (PDAC) cell lines.

KRAS ASOs potently and selectively inhibited growth of KRAS mutant CRC lines but did not affect the growth of KRAS WT CRC cells in 2D growth assays. Evaluation of KRAS depletion in NSCLC and PDAC lines revealed that sensitivity of these lines to growth inhibition in 2D assays required mutant KRAS status and the presence of a previously described “KRAS addiction” gene expression signature (Singh et al 2009).

Surprisingly, further evaluation of KRAS ASO mediated depletion of NSCLC and PDAC lines in 3D growth assays (e.g. soft agar colony formation and polystyrene sponge (Alvetex)) resulted in strong inhibition of colony formation in all mutant KRAS lines, but not WT KRAS lines, and the sensitivity to KRAS depletion was independent of the expression of the “KRAS addiction” signature.

Collectively, we have shown that KRAS mutational status confers specific sensitivity to the ASO-mediated KRAS knockdown (KRAS oncogene addiction).

Our data also highlights that antisense-mediated inhibition of KRAS may represent a promising and translatable approach to target KRAS therapeutically.


@Bioterp said...

Been thinking about Chromogranin A (CgA) recent wrt TKMR GI-NET tumors. Sounds like CgA is a decent biomarker for these GI-NET tumors.

"In the present study, we have also observed that patients with endocrine tumors showed progressively higher CgA levels as the disease progressed"
http://jco.ascopubs.org/content/25/15/1967.long

Would be interested in any other thoughts you would have on how TKMR is using CgA as a biomarker

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.