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Some cancer cells express some of the same genes that senescent cells do, so it makes sense that drugs that destroy senescent cells may also destroy cancer cells. This was what the researchers in this new study set out to test.

Abstract

p16Ink4a is a potent cell cycle inhibitor engaged to support cell cycle arrest during cellular senescence. However, in tumors carrying mutations in key downstream effectors, p16Ink4a is highly expressed but fails to block cell proliferation. p16Ink4a-overexpressing tumor cells are highly aggressive and no targeted interventions are available. To study the effect of specific therapies, we generated murine sarcomas by overexpressing RAS oncogene and disrupting p53 activity. We observed that p16Ink4a-overexpressing murine sarcoma cells were resistant to ABT-263 and ABT-737, anti-cancer small molecules previously shown to eliminate p16Ink4a+ senescent cells. We then generated sarcoma cells carrying a suicide and reporter gene, called 3MR, under the regulation of the full p16Ink4a promoter. Activation of the suicide efficiently killed p16Ink4a-overexpressing sarcoma cells in vitro and in vivo.

These data suggest that suicide gene therapy could represent an important therapeutic approach for the treatment of highly aggressive p16Ink4a+ cancers.

However, in this experiment, the researchers discovered that the chosen senolytic drugs were not effective at destroying cancer cells with senescence-associated gene expression. While cancer cells and senescent cells do share some common properties, they are also quite different at an epigenetic level.

The researchers did, however, demonstrate that a so-called “suicide gene therapy” that causes both senescent cells and cancer cells to kill themselves worked by targeting senescence-associated p16Ink4a. This approach is similar to that of SENS spin-off company Oisin Biotechnologies, which is using a suicide gene therapy to eliminate senescent cells.

Conclusion

Small molecules carry the risk of off-target and unwanted effects; for example, they could destroy cancer but also impair wound healing by harming beneficial p16Ink4a+ cells, including macrophages. Gene therapies offer far higher selectivity and, ultimately, are likely to be the most efficient method of causing cancerous and senescent cells to self-destruct.

Literature

[1] Kohli, J., Campisi, J., & Demaria, M. (2017). A novel suicide gene therapy for the treatment of p16 Ink4a-overexpressing tumors. Oncotarget, 9(7), 7274-7281.

About the author

Steve Hill

Steve serves on the LEAF Board of Directors and is the Editor in Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 500 articles on the topic as well as attending various medical industry conferences. In 2019 he was listed in the top 100 journalists covering biomedicine and longevity research in the industry report – Top-100 Journalists covering advanced biomedicine and longevity created by the Aging Analytics Agency. His work has been featured in H+ magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, and, Keep me Prime, and New Economy Magazine. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project. In 2015 he led the Major Mouse Testing Program (MMTP) for the International Longevity Alliance and in 2016 helped the team of the SENS Research Foundation to reach their goal for the OncoSENS campaign for cancer research.
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