Fight Aging!

There is considerable enthusiasm in the cancer research community regarding the prospects for improved patient outcomes via the use of senolytics to clear senescent cells from tissues. It seems fairly clear that an increased burden of senescent cells results from the use of traditional cancer therapies, chemotherapy and radiotherapy, and that this is most likely the cause of a large fraction of the greater risk of age-related disease and shorter remaining life expectancy in cancer survivors. Undergoing those forms of cancer therapy is literally a matter of signing up for accelerated aging - and still the preferable alternative, of course, when the other option is death by runaway cell growth and metastasis.

It seems plausible that senolytic therapies can be applied after cancer treatment has ended to mitigate the long-term consequences of that treatment. There are more senescent cells, induced by treatment, and effective senolytics will remove a large fraction of those cells. This is straightforward. What is less straightforward is whether (and in what circumstances) it will be helpful or harmful to use senolytics alongside cancer treatments, at the same time. For some cancers and stages of cancer, this may dramatically improve outcomes. We might think of the forms of leukemia that appear to create senescent cells in order to produce a more favorable growth environment, for example. In other cases, it might not be so helpful, but time will tell.

Targeting senescence as an anti-cancer therapy

Senescence exerts multiple and sometimes opposing effects in tumorigenesis. The oncogenic activation events involved in cancer initiation trigger oncogene-induced senescence (OIS) in preneoplastic lesions and limit their progression. Consequently, mutations that disable senescence are needed for tumours to progress to more malignant stages. Most cancer therapies work, at least in part, by triggering senescence (therapy-induced senescence, TIS). But TIS in non-cancerous cells has been linked to some of the side effects associated with chemotherapy. And lingering senescent cells present in the tumour and TME contribute to sustain cancer development and progression.

Different types of senescent cells are present in the tumour microenvironment (TME) during cancer initiation, progression and in response to therapy. Many preneoplastic lesions are enriched in senescent cells. This is because activation of oncogenes (e.g., RAS in lung or BRAF in nevi) or loss of tumour suppressor (e.g., PTEN in the prostate) induces senescence, what restrains tumour progression. Another contributor to senescence-induction in the context of tumorigenesis are anti-cancer treatments, as radiotherapy, conventional chemotherapy and some targeted therapies: that cause so-called therapy-induced senescence (TIS) in the tumour cells. Cancer therapies can also induce senescence in cells other than the tumour cells. Indeed, induction of senescence in normal tissues has been suggested to cause some of the side effects associated with chemotherapy.

Finally, other cells in the TME might also undergo senescence. Stromal senescent cells are an emerging factor contributing to tumorigenesis and promote cancer drug resistance. Senescent cells in the TME can also arise in a paracrine fashion, as factors secreted by tumour (senescent) cells can induce senescence in the stroma or render infiltrating immune cells senescent. For example, a study using a p16INK4A luciferase reporter mice show how after implanting different tumour cells grafts that do not express the luciferase reporter, luciferase activity arises in the tumour-associated stroma, demonstrating the ability of tumours to induce senescence in their surroundings.

In this review, we enumerate how current anti-cancer therapies induce senescence in tumour cells and how senolytic agents could be deployed to complement anticancer therapies. While senescent cells influence many aspects of tumour progression, a way to deploy senotherapeutics for cancer treatment is the so-called "one-two punch" approach. The rationale of "one-two punch" therapies is that many cancer therapies induce senescence and using senolytics (as a second punch) would therefore target a newly exposed vulnerability in the cancer cells. "One-two punch" represents an emerging and promising new strategy in cancer treatment.

One-two punch protocols have been tried with a wide range of senolytics, including cardiac glycosides, BRD4 inhibitors, and galacto-coated nanoparticles loaded with doxorubicin or navitoclax or the Gal-Nav prodrug. There are several clinical trials evaluating the effect of the senolytic navitoclax in combination with chemotherapy in cancer patients. However, the contribution of senescence and senolysis to the therapeutic effect will not be evaluated on most of those trials. In addition, other senolytics, such as the dasatinib and quercetin combination or fisetin, are being evaluated in different trails, including one aiming to improve frailty in adult survivors of childhood cancer.

In addition to clinical trials, retrospective analysis is another way to test the potential of drugs repurposed as senolytics. For example, cancer patients treated with the cardiac glycoside digoxin during chemotherapy have a better overall survival. Cardiac glycosides have pleiotropic effects, and the aforementioned study attributed the effect to immunogenic cell death. But given that cardiac glycosides have senolytic properties, it would be worthy investigating whether senolysis might explain those results.