A Future of Combination Therapies that Transform Cancer Cells into Senescent Cells, and then Suppress and Destroy Them

The research community is presently expanding the understanding of the biochemistry and role of senescent cells in aging and age-related disease. This is happening in the wake of a series of landmark animal studies demonstrating extension of life and reversal of markers of tissue aging through selective destruction of senescent cells, events that have attracted the attention of many research groups and funding organizations. There is considerably increased investment in the field when compared to even as recently as five years ago, a time at which it was a real struggle for even prestigious research groups to raise the funds needed for animal studies of senescent cell removal. This is an object lesson for anyone who thinks science moves on the shortest path towards important gains. Significant evidence for the role of senescent cells in aging and disease has existed for decades, and the SENS proposals have included their removal as a potential rejuvenation therapy since the turn of the century. In any case, I predict that this ongoing gain in knowledge will accelerate as senolytic therapies, treatments based on the targeted removal of senescent cells, continue to prove effective on their way to the clinic. The size of the field and its funding will increase greatly.

This is going to produce interesting outcomes as researchers involved in other areas of medicine assimilate the new findings and come to appreciate the importance of senescent cells. In the cancer research community, for example, there are already established programs aiming to use the induction of senescence as a form of therapy. Cellular senescence acts as a form of defense against cancer, a way to make cells irreversibly halt replication and then largely self-destruct, or attract immune cells to destroy them. Since preventing replication and destroying cells is exactly the goal of cancer therapies, this seems a potentially viable approach. The challenge here, as researchers are now realizing, is that those newly formed senescent cells that are not destroyed go on to cause a lot of harm. Arguably this is visible in the long-term damage caused by even successful chemotherapy. Senescent cells generate a potent mix of signals, the senescence-associated secretory phenotype (SASP) that disrupts tissue structure, changes the behavior of other cells for the worse, and generates high levels of chronic inflammation.

The present state of knowledge is, however, enough to clearly envisage a class of near future cancer therapies made up of the combination of treatments to (a) induce senescence in cancer cells, (b) attempt to reduce the SASP by altering the internal processes of senescent cells, and (c) to destroy as many of these newly senescent cells as possible. I'm not convinced that trying to modulate SASP signaling is a cost-effective path forward in comparison to destruction of senescent cells, given the current state of the field, but a fair number of research groups are undertaking work in that direction. I think it to be the most complex option, requiring much more new knowledge, and with a lower chance of success for any given research group and project. Further, sufficiently good senolytic therapies should render it unnecessary: just deliver them alongside the therapy that induces senescence in cancer cells. In any case, this open access paper outlines the vision for combination therapies along these lines:

Aging tumour cells to cure cancer: "pro-senescence" therapy for cancer

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.

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.

SASP has profound effects on the surrounding tumour microenvironment and it represents a promising target for cancer therapy. Several groups have recently proposed therapies that reprogram the SASP to enhance the tumour-suppressive role of senescence in cancer and restrain the negative effects of the SASP. For instance, we have recently shown that Stat3 regulates the SASP of Pten-loss induced cellular senescence (PICS). In Pten null senescent tumours, Stat3 activation promotes an immunosuppressive tumour microenvironment that impairs senescence surveillance. However, pharmacological inhibition of Janus kinase 2 (JAK2) in these tumours induces the reprogramming of the SASP, thus leading to an antitumour immune response that promotes the clearance of senescence tumour cells. The SASP is also controlled by mTOR (mechanistic target of rapamycin). Indeed, mTOR inhibitors reduced SASP.

The use of senolytic therapies may also enhance the efficacy of pro-senescence therapies by removing senescence cells from the tumour. Senolytic therapies may be administered concomitantly with or after pro-senescence compounds to decrease potential negative side effects of the SASP in tumours where the tumour immune clearance does not take place. As recently reported, senescent tumour cells rely on pro-survival networks and are therefore more susceptible to the inhibition of these pathways. For instance, Bcl-2/Bcl-x inhibitors may be used in combination with pro-senescence compounds to enhance the efficacy of pro-senescence therapy. Since senescent tumour cells also undergo to metabolic reprogramming, pharmacological inhibition of specific metabolic demands may be used to promote the clearance of senescent cells in tumours treated with pro-senescence therapies. Such an approach has been successfully tested in a model of lymphoma but it still remains to be validated in additional tumour models. In conclusion, we believe that pro-senescence therapy for cancer is a promising new therapeutic strategy and that in the future novel, therapies based on senescence induction in cancer will be the standard of care for the treatment of cancer patients.

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