The clearance of senescent cells has been receiving a great deal of attention in the last year or so and quite rightly so, given the impressive results thus far. As the body ages, cells become damaged and cease dividing, entering a state known as senescence.
Normally, these senescent cells destroy themselves through a programmed cell destruction mechanism known as apoptosis, and the immune system then clears them away. Unfortunately, as we age, an increasing number of these cells escape this process, as cellular signaling and the immune system become dysfunctional.
These “zombie” cells remain in the body and produce a range of toxic signals that cause inflammation, can even affect healthy neighboring cells [1], and increase the risk of cancer [2] and other diseases [3, 4]. Fortunately, a new class of drugs – known collectively as senolytics [5] – are able to remove these toxic, dysfunctional cells from the body.
Today, we have another example of researchers using senolytic therapies to treat diseases; in this case, cancer is the focus. Perhaps more interestingly, researchers in this paper not only propose to use senolytic therapies but to combine them with another new type of cancer treatment, “pro-senescence” therapy. As we recently reported, a strong connection between senescent cells and cancer relapse after chemotherapy has been established.
Chemotherapy not only kills cancer cells, it also does a great deal of damage to surrounding healthy cells and turns them senescent, increasing the risk of relapse [6]
In contrast to normal cells, one of the hallmarks of cancer cells is the capability to escape senescence, thus acquiring a limitless replicative potential that is the prelude to invasion, metastasis and additional features of malignancy. However, cancer cells can undergo senescence if subjected to certain insults such as oncogenic stress, DNA damage and metabolic changes. This type of senescence response occurs immediately and also independently of telomere shortening, a phenomenon known as “premature” senescence. For instance, several anticancer chemotherapies and radiotherapies are known to induce senescence in both normal and cancer cells. Senescence can also occur in tumour cells in vivo as a consequence of overexpression of oncogenes or loss of tumour suppressor genes, demonstrating for the first time that senescence acts as a barrier against tumorigenesis. Analysis of tumour samples from patients demonstrated that, whereas benign tumours accumulate markers of senescence, invasive cancers lack senescence. Subsequent publications validated these findings in different types of tumour. Given the surprising discovery that senescence limits the development of cancer, we and others envisioned targeted therapies that selectively enhanced senescence in cancer cells used for the therapy of various tumours. This approach, named “pro-senescence” therapy for cancer, differs from the chemotherapy-induced senescence that affects both normal and cancer cells.Several small molecule inhibitors that are currently in clinical development have been reported to induce senescence in cancer. Among these compounds, inhibitors of the cyclin-dependent kinases CDK4/6 have been associated with a high percentage of responses in patients affected by breast cancer and are the most promising pro-senescence compounds currently being tested in the clinic. Compounds that enhance the level of the tumour suppressor gene p53, such as MDM2 inhibitors and PRIMA-1 analogues, have been reported to enhance senescence in tumour cells with normal and mutant p53 and are currently being tested in the clinic. Many compounds that are currently being tested at the preclinical level are also promising pro-senescence therapies. Inhibitors of SirT1, a protein deacetylase that negatively regulates p53 function in cancer, induced senescence in preclinical tumour models. MYC inhibitors can also drive a cellular senescence response. Source: Swiss Medical Weekly
However, as exciting as a dual therapy approach is, and as much as it represents exactly the kind of revolution in medicine we need, there are technical problems to overcome. The accurate detection of senescent cells is a real problem for researchers, and traditional methods to measure them using SA-β-galactosidase is not good enough [7].
Another challenge in the field of senescence therapy for cancer is the lack of clinically validated biomarkers for the identification of senescence in human tumours. The prognostic use of senescence-associated-β-galactosidase (SA-β-galactosidase), a well characterised in vitro marker for senescence, has been tested in small trials evaluating the efficacy of neo-adjuvant chemotherapies. Results from these trials demonstrate that this marker increases upon treatment and predicts patient outcome. However, the use of SA-β-galactosidase alone as a unique marker of senescence has been criticised since it can lead to many false positives. Recent findings have identified of new markers of senescence with prognostic relevance. However, neither SA-β-galactosidase staining nor additional markers have been used so far in large clinical trials to evaluate the efficacy of pro-senescence compounds. Thus, development of novel biomarkers that can accurately assess the occurrence of senescence in cancer patients is the need of the hour. This would help improve the stratification of patients who may respond to therapies that enhance senescence in cancer. Source: Swiss Medical Weekly
Conclusion
Combination therapies that include both senolytic and pro-senescence therapies are a compelling direction in which to advance cancer treatment. It is quite reasonable to believe that in a few years, these will become the standard of care, replacing harsh chemotherapy and improving patient outcomes.
Literature
[1] van Deursen, J. M. (2014). The role of senescent cells in ageing. Nature, 509(7501), 439-446.
[2] Coppé, J. P., Desprez, P. Y., Krtolica, A., & Campisi, J. (2010). The senescence-associated secretory phenotype: the dark side of tumor suppression. Annual Review of Pathological Mechanical Disease, 5, 99-118.
[3] Childs, B. G., Baker, D. J., Wijshake, T., Conover, C. A., Campisi, J., & van Deursen, J. M. (2016). Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science, 354(6311), 472-477.
[4] Xu, M., Bradley, E. W., Weivoda, M. M., Hwang, S. M., Pirtskhalava, T., Decklever, T., … & Lowe, V. (2016). Transplanted senescent cells induce an osteoarthritis-like condition in mice. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, glw154.
[5] Zhu, Y., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., … & O’Hara, S. P. (2015). The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging cell, 14(4), 644-658.
[6] Demaria, M., O’Leary, M. N., Chang, J., Shao, L., Liu, S., Alimirah, F., … & Alston, S. (2016). Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse. Cancer Discovery, CD-16.
[7] Matjusaitis, M., Chin, G., Sarnoski, E. A., & Stolzing, A. (2016). Biomarkers to identify and isolate senescent cells. Ageing research reviews, 29, 1-12.
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