Potential New Therapeutic Option May Combat Drug Resistance in HER2+ Breast Cancer and Ovarian Cancer

A therapeutic strategy that targets cancer-associated gene amplifications via triplex-forming oligonucleotides (TFOs) demonstrated in vivo efficacy, which compared favorably to current precision medicines in patients with HER2-positive breast and ovarian cancer, potentially introducing an alternative option to combat drug resistance in these patient populations, according to research published in Nature Biotechnology.¹

In addition to its in-vivo efficacy, investigators reported that TFOs targeting HER2 yielded copy number–dependent DNA double strand breaks (DSBs) and were successful in activating p53-independent apoptosis in HER2 cancer cell and human xenograft models. Overall, treatment of HER2-positive breast cancer xenografts with a TFO, HER2-205, resulted in a 52% reduction in tumor volume when compared with untreated control groups. The finding is comparable with a 58% reduction garnered from treatment with trastuzumab (Herceptin).

“Our findings are exciting as they offer a new option to fight breast and ovarian cancers as effectively as clinically utilized drugs now targeting the HER2 protein,” senior author Faye Rogers, PhD, associate professor of Therapeutic Radiology at Yale Cancer, said in a press release.² “A number of anticancer therapies have been developed to inhibit the protein products of amplified cancer driver genes, but have met drug resistance.”

The research team’s goal was to develop a potential drug platform that could directly convert amplified oncogenic driver genes into DNA damage to ultimately induce cell death. The strategy utilizes TFOs that are capable of recognizing “unique polypurine sites” within the amplified chromosomal region to provoke apoptosis.

After assessing the correlation between level of triplex-induced DNA damage and increased gene copy numbers via a neutral comet assay, the team observed that HER2-205 better induced DNA damage than HER2-1. Moreover, HER2-205 induced significantly more DSBs than HER2-1 in cell lines that contained multiple copies of the HER2 gene.

When looking at HER2-targeting TFOs, the results suggest triplex-induced apoptosis may provide the foundation for potential therapeutic options capable of targeting cancers that develop from gene amplification and sparing tissues that are not gene amplified.

“We plan to extend this platform, particularly focusing on cancers with limited precision medicine options,” Rogers explained. “We will also focus our efforts on drug delivery, since inadequate bioavailability to the tumor can significantly impact therapeutic effect.”

Additional findings from the study indicated that tumor growth reduction was observed with intraperitoneal administration of HER2-205. Additionally, investigators reported a tumor tripling time of 29 ± 5.7 days following initial dosing with HER2-205 compared with a of 24 ± 2.1 days in tumors treated with trastuzumab. Moreover, control oligonucleotide MIX24 (ANOVA) did not appear to impact BT474's tumor growth vs the control buffer alone, investigators reported a tumor tripling time of 15.7 ± 4.9 days for control tumors vs 16.3 ± 6.6 days in tumors treated with MIX24 (P = .99).

“We envision the use of this drug design platform as a treatment option for several cancers with gene amplification and resistance to current therapies,” the investigators concluded.

References

1. Kaushik Tiwari M, Colon-Rios DA, Tumu HCR, et al. Direct targeting of amplified gene loci for proapoptotic anticancer therapy. Nat Biotechnol. Published online October 28, 2021. doi:10.1038/s41587-021-01057-5
2. Yale Cancer Center study shows new strategy to fight drug resistance in HER2-positive breast and ovarian cancers. News release. Yale School of Medicine. October 28, 2021. Accessed December 2, 2021. https://tinyurl.com/2p8wrkhj