A study published in EBioMedicine has shown how a peptide targets and kills senescent cancer cells, potentially paving the way for a new class of interventions.
Why kill senescent cancer cells?
Senescence and cancer are usually considered to be completely opposed, and in many ways, they are. The key feature of senescent cells is that they no longer replicate, and the key aspect of cancer is uncontrolled replication. Senescence is widely known as an evolved anti-cancer mechanism. Therefore, the idea of wanting to remove senescent cancer cells, or even the existence of senescent cancer cells at all, seems counterintuitive.
The researchers note that oncogenes (which cause cancer) often lead to induced senescence , but these oncogene-induced senescent (OIS) cells are still dangerous for multiple reasons. Other mutations can lead to these cells replicating despite their induced senescence , and the SASP can cause tumors to progress . Additionally, certain cancer therapies, given at suboptimal levels, can induce senescence of both cancer and normal cells , and other cancer therapies work by inducing temporary senescence .
With these multifarious problems in mind, the researchers set out to find ways to remove these harmful and potentially very dangerous cells.
Developing and using a peptide
The researchers of this study highlight previous research showing that the FOXO4-DRI peptide disrupts the FOXO4-TP53 interaction, thus causing TP53-mediated apoptosis (cellular death) . In this study, the researchers used molecular modeling to rationally design a peptide that would preferentially bind with FOXO4 and kill senescent cells more easily. Through computational analysis, the researchers chose a certain site on the FOXO-4 protein and discovered compounds that more strongly bound to this protein than FOXO4-DRI and had greater senolytic activity.
The researchers then tested one of these compounds, ES2, in both in vitro cell cultures and in vivo mouse models. In cell cultures of melanoma, colorectal cancer, and breast cancer, while dividing cells were largely unaffected, ES2 killed a substantial majority of senescent cancer cells, even cells with mutated forms of TP53. In mice, senescent human melanoma cells were found to be substantially removed to a very high degree of statistical significance over a saline placebo.
They took a look at why ES2 was so deadly to these cells. The mechanism of action was what they expected, with TP53 mediation being the key driver of apoptosis. They confirmed their results by examining TP53-knockout cells, which, as expected, were resistant to the ES2 peptide.
The researchers then examined a combination therapy. They injected a mouse model of melanoma with ES2 and dabrafenib, a compound that targets a specific oncogene and induces senescence in the targeted cells. The results were exactly what they wanted: the dabrafenib induced senescence, and the ES2 killed the newly senescent cells.
Finally, the researchers investigated ES2 in ordinary, healthy aged mice. While the senolytic did not accomplish much of significance according to blood and weight metrics, it was shown to be non-toxic to these animals, and it halved the number of senescent cells in the liver.
The researchers acknowledge that they have quite a lot of work to do before they have a demonstratably superior senolytic that is suitable for therapeutic human use. However, their research shows the viability of using computational analysis to create better senolytics, and it paves the way for further studies that use senesence inducers plus senolytics to effectively treat cancer.
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