Scientists have used ‘next generation’ antisense technology to specifically target the transcription factor STAT3 within cancer cells, resulting in antitumor activity.
Antisense oligonucleotides are small strands of nucleotides designed to recognise and bind to specific messenger RNA, ultimately silencing a target gene within a cell. This makes antisense technology an attractive approach to cancer therapy, since the antisense oligonucleotides can be designed to target specific genes known to be involved in cancer progression.
Results from a recent study have been published in the journal Science Translational Medicine, describing the design of a ‘next generation’ antisense oligonucleotide to target a specific transcription factor that is involved in tumor growth, STAT3. The researchers used this target as a proof of concept to demonstrate the superiority of oligonucleotides with next-generation chemistry. This new chemistry, containing ethyl modifications, gives the oligonucleotides greater potency than previous forms of antisense therapy.
The researchers were able to demonstrate that the STAT3-targeted antisense oligonucleotide, AZD9150, reduced the expression of STAT3 in a variety of cancer cell types. In addition, they demonstrated that AZD9150 had antitumor activity in tumor models of lymphoma and lung cancer. AZD9150 was then also tested in a phase 1 dose-escalation study in patients with lymphoma or non-small lung cell cancers that had become resistant to standard treatment. In this clinical trial AZD9150 demonstrated anti-tumor activity in these patients. Either stable disease or partial response was achieved in 44% of patients. There was even some evidence of tumor shrinkage in a subset of patients treated with AZD9150.
The researchers suggest that AZD9150 should be further tested in phase 2 and 3 clinical trials, with emphasis on determining the reasons why specific subsets of patients respond to treatment.
Overall the study demonstrated that the new generation antisense oligonucleotides are viable for specific targeting of cancer-related genes and signaling pathways, providing an avenue to rationally design and target molecules that have been unable to be targeted by conventional therapies.
Participants are currently being recruited to take part in a clinical trial assessing AZD9150 in the treatment of gastrointestinal cancer and ovarian cancer. The study is being conducted by the National Cancer Institute, in collaboration with the National Institutes of Health Clinical Centre, Bethesda, Maryland, United States.
Hong, D, Kurzrock, R, Kim, Y, Woessner, R, Younes, A, Nemunaitis, J, Fowler, N, Zhou, T, Schidt, J, Jo, M, Lee, SJ, Yamashita, M, Hughes, SG, Fayad, L, Piha-Paul, S, Nadella, MVP, Mohseni, M, Lawson, D, Reimer, C, Blakey, DC, Xiao, X, Hsu, J, Revenko, A, Monia, BP, MacLeod, AR. “AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in lymphoma and lung cancer” Science Translational Medicine Vol. 7, Issue 314, pp. 314ra185 DOI: 10.1126/scitranslmed.aac5272
clinicaltrials.gov “AZD9150, a STAT3 Antisense Oligonucleotide, in People With Malignant Ascites” Available from: https://www.clinicaltrials.gov/ct2/show/study/NCT02417753?term=AZD9150.&rank=2#contacts Last Accessed November 24, 2015.
Written by Deborah Tallarigo, PhD