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Spring 2024
About
©2024 BJHA
Researchers: Hadley Carr, Grace Martin
Designer: Kira Karafotas
While mRNA was discovered in 1961, it wasn’t until 30 years later that we began to see breakthroughs in RNA-based therapy research.³ These therapies can target specific genetic components within the cell that other drugs cannot, thus evolving as a powerful platform for the treatment of various diseases.4 Among these diseases is glioblastoma, an aggressive type of brain cancer.5 Tinos Therapeutics, a company founded by Brown professor Dr. Nikos Tapinos and biotech executive Wendy Parrow, hopes to target glioblastoma with their development of a RNA-based therapeutic that has shown promise as a treatment.
Since arriving at Brown in 2016, Tapinos has investigated RNA modifications in cancer stem cells at his lab, the Tapinos Laboratory of Cancer Epigenetics and Plasticity.6 Through his research on stem cells using patient-derived tumors, Tapinos found that RNA modifications played a crucial role in regulating protein production as the intermediate between DNA and protein production. By altering the modification pattern of protein transcription, he discovered that cancer cells could be tricked into degrading proteins that contribute to tumor growth instead of producing them.
Tapinos’ research focuses on targeting RNA demethylase, an enzyme that can remove methyl groups from RNA.7 When demethylation is inhibited, it can trigger the degradation of tumor-causing mRNA.8 RNA demethylase is highly expressed in tumor cells, rendering it an attractive therapeutic target.9 Using the ZINC database, a library containing billions of compounds, and an artificial intelligence algorithm, the 3D structure of RNA demethylase was analyzed and 60,000 candidate inhibitor compounds were discovered.10 However, this list needed to be narrowed down. Tapinos investigated the potential of the compounds to become drugs by testing their permeability through the blood-brain barrier in silico, a critical consideration for treating brain tumors. After settling on 30 possible compounds, each one was synthesized and the end result was the development of a drug that blocked demethylase activity with nanomolar potency. Initial testing on patient-derived glioma cells from brain tumors showed that their drug effectively reduced tumor growth in vitro and in vivo. Further testing revealed promising results for their drug’s efficacy in mitigating colon, pancreatic, ovarian, lung, and pediatric brain cancers. These findings suggest this novel therapeutic approach could have broad applications across various solid tumors.
Recognizing the potential of their findings, Tapinos transitioned the research from his academic lab to a company, Tinos Therapeutics, in July 2023. Currently, Tinos Therapeutics is securing funding to advance their research and begin the manufacturing process to create and refine their drug. They aim to start phase 1 clinical trials by 2026, which will establish their drug’s safety and dose range. In five years, they hope to launch their drug and eventually deliver it to the market. Due to the promising preclinical evidence, there is potential for the FDA to grant them a breakthrough therapy designation, expediting the drug’s development and review period by two to three years, allowing for earlier availability.11
Another exciting project at Tinos Therapeutics is the creation of a siRNA-based cancer therapeutic that targets chromatin within cancer cells in order to stop their replication. A type of RNA interference technology known as siRNA activates RISC (RNA-induced silencing complex), which degrades the sense strand of the siRNA and keeps the antisense strand bound to RISC.12 The antisense strand leads RISC to a complementary mRNA target to be degraded.12 With this mechanism, siRNA can inhibit specific gene expression through in vivo insertion. Tinos leverages this property of siRNA to target the expression of chromatin, effectively “closing down” chromatin in cancer cells in order to stop their division and proliferation.13
During an extensive literature review, Tapinos identified approximately 280 epigenetic modifiers involved in brain tumors. In order to pinpoint the most promising target, Tapinos collaborated with a lab in Singapore to clone all 280 epigenetic genes. They then performed in vivo and in vitro screenings, overexpressing the proteins and assessing their impact on cancer growth. The screenings revealed that histone deacetylase was the number one target and a sub-pattern for histone H3.3, playing a role in inducing heterochromatin production — a dense form of chromatin that blocks transcription of cancer cells.14 Through the use of siRNA therapeutics, these histone acetylase targets can be silenced. Preliminary data shows that after heterochromatin formation, the silenced state is inherited by daughter cells following DNA replication, stopping the ability to divide and spread for generations. These developments provide a promising outlook on RNA-based therapies being used as cancer treatments.
Through both siRNA and mRNA research, Tino Therapeutics is pushing the boundaries of oncological science by consistently innovating in this emerging field. The company’s proven track record of original thinking continues to bring to healthcare new and needed solutions that are poised to change the landscape of cancer medicine and save lives.
2 National Human Genome Research Institute. Understanding COVID-19 mRNA Vaccines. Genome.gov. Published August 30, 2021. https://www.genome.gov/about-genomics/fact-sheets/Understanding-COVID-19-mRNA-Vaccines
3 National Institute of Allergy and Infectious Diseases. Decades in the Making: mRNA COVID-19 Vaccines. www.niaid.nih.gov. Published April 4, 2024. https://www.niaid.nih.gov/diseases-conditions/decades-making-mrna-covid-19-vaccines
4 Kim YK. RNA therapy: rich history, various applications and unlimited future prospects. Experimental & Molecular Medicine. 2022;54:455-465. doi:https://doi.org/10.1038/s12276-022-00757-5
5 Hanif F, Muzaffar K, Perveen K, Malhi S, Simjee S. Glioblastoma Multiforme: A Review of its Epidemiology and Pathogenesis through Clinical Presentation and Treatment. Asian Pacific Journal of Cancer Prevention : APJCP. 2017;18(1):3-9. doi:https://doi.org/10.22034/APJCP.2017.18.1.3
6 The Tapinos Laboratory of Cancer Epigenetics and Plasticity. Published 2024. https://www.tapinoslab.com/
7 Shen D, Wang B, Gao Y, et al. Detailed resume of RNA m6A demethylases. Acta Pharmaceutica Sinica B. 2022;12(5):2193-2205. doi:https://doi.org/10.1016/j.apsb.2022.01.003
8 Tapinos N, Zepecki JP, Karambizi D, et al. miRNA-mediated loss of m6A increases nascent translation in glioblastoma. Ruzov A, ed. PLOS Genetics. 2021;17(3):e1009086. doi:https://doi.org/10.1371/journal.pgen.1009086
9 Shen W, Pu J, Zuo Z, et al. The RNA Demethylase ALKBH5 Promotes the Progression and Angiogenesis of Lung Cancer by Regulating the Stability of the LncRNA PVT1. Cancer Cell International. 2022;22:353. doi:https://doi.org/10.1186/s12935-022-02770-0
10 Gentile F, Yaacoub JC, Gleave J, et al. Artificial intelligence–enabled virtual screening of ultra-large chemical libraries with deep docking. Nature Protocols. 2022;17:672-697. doi:https://doi.org/10.1038/s41596-021-00659-2
11 Tapinos, Nikos. Interview by Hadley Carr, Sophia Huang, and Grace Martin. 8 April 2024.
12 Wills T. Breakthrough therapy designation: The real-world impact of structural novelty. CAS Insights. Published September 23, 2022. https://www.cas.org/resources/cas-insights/breakthrough-therapy-designation-real-world-impact