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Antisense Oligonucleotides for the Treatment of RAS Q61 Mutant Cancers

First in class selective inhibitors of RAS(Q61) mutant, with potential therapeutic benefit demonstrated in vitro and in vivo

Therapeutics

Project Overview

The RAS protein is involved in signaling pathways for cell growth, differentiation, and survival. The three genes that encode for RAS in humans (KRAS, HRAS, NRAS) are the most frequently mutated oncogenes, found in up to 20% of all cancers.
RAS-mutant cancers have been shown to respond poorly to existing chemotherapy, particularly the RAS(Q61) mutation, highlighting the therapeutic need for new RAS mutant-specific therapies.
Dana-Farber scientists have developed RAS (Q61) antisense oligonucleotide that inhibited growth in RAS(Q61)-mutated cancers.
This technology is available for licensing or for further development at Dana-Farber under a sponsored research arrangement.

Technology

Although covalent inhibition of one common driver mutation, KRAS(G12C) succeeded, the same strategy cannot be applicable for other common mutations ,including RAS(Q61). Therefore, there is still a significant therapeutic need for new RAS-mutant specific therapies,

To address this need, researchers at Dana-Farber Cancer Institute have developed antisense oligonucleotides (ASOs) to selectively bind ESE motifs in RAS(Q61) mutant oncogenes. Specifically, the team designed mutant-specific oligonucleotides to interfere with ESE-mediated splicing, rendering the RAS(Q61) protein non-functional in a mutant-selective manner.

Judicial chemical modifications impart the ASOs with a high binding affinity and stability against naturally occurring nucleases. Treatment of RAS-dependent cell lines with the ASOs demonstrated robust growth inhibition. Most importantly, ASO treatment resulted in significant tumor volume reduction as demonstrated by in vivo studies with xenograft mouse models derived from RAS(Q61) mutant cell lines.

Further Information:

Kobayashi, Yoshihisa, et al. “Silent mutations reveal therapeutic vulnerability in RAS Q61 cancers.” Nature 603.7900 (2022): 335-342. https://doi.org/10.1038/s41586-022-04451-4

Selected technology advantages:

Selectivity for mutated genes

Chemical modifications impart ASOs cellular stability and binding affinity to target

Potential therapeutic benefit demonstrated in vitro and in vivo

First in class selective inhibitor of RAS(Q61) mutant

Team Members: Pasi Jänne, MD, PhD, Yoshihisa Kobayashi, MD, PhD

Applications

Potential treatment of a variety of RAS(Q61) mutant driven cancers including lung, pancreatic, colon, gastric, and skin cancers.

Opportunities

Dana-Farber is looking for partners to further develop this asset either via out-licensing or for further development at Dana-Farber under a sponsored research arrangement.

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