Fight Aging!

Some cancerous cells express signatures normally associated with senescent cells, so why not try senolytic compounds against them? This is something of a full circle, given that most of the current senolytic drug candidates were originally characterized and tested as potential chemotherapeutics. The open access paper here is interesting for two points: firstly, that senolytic drugs didn't kill cancerous cells with a senescent signature, and secondly that a suicide gene therapy targeting that signature does work against both normal senescent cells and cancerous cells with a senescent signature. The gene therapy approach reported here is conceptually similar (at a very high level) to the Oisin Biotechnologies gene therapy used to destroy senescent cells, but less flexible. The Oisin Biotechnologies founders have shown that targeting p53, a cancer suppressor, rather than p16 / p16Ink4a, a signature of senescence, is highly effective against cancer, but it appears that p16 is also a viable trigger for cell killing gene therapy mechanisms in many cancers.

p16Ink4a arrests cell cycle progression by inhibiting the S phase. Cellular senescence, a tumor suppressive mechanism defined as irreversible growth arrest and induced by accumulation of DNA damage, is often associated to induction of p16Ink4a. Consequently, p16Ink4a is considered a strong tumor suppressor. Loss-of-function mutations affecting p16Ink4a are a common mark of various human tumors, and considered an essential step towards tumor progression. However, in the presence of mutations affecting RB or CDK4/CDK6, p16Ink4a activity is not sufficient to arrest cell cycle progression. Moreover, p16Ink4a overexpression has been observed at the invasive front of endometrial, colorectal and basal cell carcinoma and correlated with high aggressiveness. Thus, under these conditions targeting p16Ink4a-overexpressing cells could be a potent anti-cancer intervention.

Despite the mutation-enabled bypass of the senescence program, sarcoma cells overexpressing RAS and with inactive p53 induced high level of p16Ink4a. We then hypothesized that treatment with compounds shown to selectively eliminate senescent p16Ink4a-overexpressing cells could be an efficient strategy. Two of the most effective compounds with senolytic properties (i.e. selectively toxic against senescent cells) are ABT-263 and ABT-737, well-known anti-cancer agents inhibiting the BCL2 family of anti-apoptotic proteins. However, neither treatment was toxic for these cancerous cells. This suggests that p16Ink4a overexpressing tumor cells are resistant to currently available compounds with specificity against p16Ink4a+ cells.

We then reasoned that an alternative strategy for elimination of p16Ink4a-overexpressing tumor cells could make use of gene targeting therapy. Suicide gene therapy has been investigated in various types of cancers because of its superior specificity compared to standard genotoxic therapies. A previous effort in testing a suicide gene therapy under the regulation of the p16Ink4a promoter - the so-called INK-ATTAC system - failed to kill p16Ink4a+ cancer cells, despite being effective in eliminating p16Ink4a+ senescent cells. We have recently developed a similar suicide system, called p16-3MR. The major difference is that the p16-3MR gene is under the regulation of the full p16Ink4a promoter, while the INK-ATTAC is regulated by a small portion proximal to the transcription starting site of the INK4a locus.

Our strategy, which we have shown being highly effective in non-proliferating cells, showed high toxicity for cancerous cells both in cell culture and in vivo. Additionally, since it has been shown that in some instances p16Ink4a+ cells are precursor of malignant cells, the 3MR system could allow reduction of tumor incidence via removal of p16Ink4a+ pre-malignant cells. At this stage, extensive research should to be done to test the toxicity of a p16Ink4a-driven suicide gene therapy strategy against additional tumor types.

Link: https://doi.org/10.18632/oncotarget.23752