A Cautious View of Senolytics from the Cancer Research Community
Today’s open access publication is an examination of therapy induced senescence in the treatment of cancers, and the role that senolytic therapies might play in cancer therapy. Senolytic therapies selectively destroy senescent cells, which accumulate with age, but are also created in sizable numbers by chemotherapy and radiotherapy. Senescent cells cease replication and begin to generate a potent mix of signals – the senescence-associated secretory phenotype (SASP) – that provoke chronic inflammation, disrupt tissue structure and function, and encourage other nearby cells to also become senescent. Cancer treatment shortens life expectancy, and it is thought that an increased burden of senescent cells is an important component of this outcome.
Many different senolytic approaches are presently under development for the treatment of age-related conditions, particularly those with a strong inflammatory component, given the effects of the SASP on the immune system. The results to date in aged animal models are very compelling, a reversal of age-related diseases that is far more reliable and impressive than that produced by any other method of treating aging. It is a short step to consider that these therapies should also be applied to cancer survivors, in order to remove the negative long-term consequences of therapy induced senescence. In effect, someone who has undergone chemotherapy or radiotherapy is more aged than his or her peers, and senolytics should reverse that additional aging in the same way as they should reverse the senescence burden of normal aging.
Beyond that, however, it is very unclear as to whether or not it is a good idea to apply senolytics during cancer treatment. The answer may vary from cancer to cancer and chemotherapeutic to chemotherapeutic. Senescent cells can have pro- and anti-cancer effects, and tip from one to the other as any given scenario of treatment and tumor growth progresses. A great deal more research must likely be undertaken in order to answer these questions.
Within the last few years, senescence has been increasingly recognized as a central component of tumor biology and the response to anti-cancer therapies. In its simplest form, senescence is a stress response that occurs subsequent to replicative-, oxidative-, oncogene-, and therapy-induced insults. Senescent cells undergo a prolonged growth arrest, yet remain metabolically viable, and can be identified by an array of phenotypes. Senescence is also almost universally accompanied by the secretion of various soluble and insoluble factors, termed the senescence associated secretory phenotype (SASP). However, despite these hallmark features, it is important to understand that the senescent phenotype can be highly variable, based on cell type and senescence-inducing stimulus.
Premalignant and malignant (tumor) cells, although typically undergoing rapid replication, can also enter a senescent cell state, characterized by a stable growth arrest and the presence of multiple senescence hallmarks. During malignant transformation, for example, senescence can serve to delay or subvert the progression to tumorigenesis of premalignant cells, thereby acting as a tumor suppressive mechanism. In established malignancies undergoing treatment, a plethora of anti-cancer drugs with variable mechanisms of action have been shown to promote a form of therapy-induced senescence (TIS) both in vitro and in vivo. For example, conventional therapies such as etoposide, doxorubicin, and cisplatin are established inducers of TIS.
While TIS has long been established in the cancer field, a full understanding of how senescence may impact patient outcome has been evolving and is far from complete. The long-held traditional paradigm argued that senescence was an irreversible cell fate, and as such, TIS was purported to be a beneficial outcome of therapy in that it could lead to permanent abrogation of established tumor growth. However, in recent years, multiple reports have been generated in support of the premise that cells that have entered into TIS can, in fact, escape the senescent growth arrest. Furthermore, tumor cells that escape senescence have been reported to develop more aggressive phenotypes associated with increased stemness and drug resistance.
In addition, TIS in non-tumor cells has been linked with several untoward effects of cancer therapy, including cancer relapse, and more importantly, senescent tumor cells themselves have been demonstrated to directly account for the emergence of recurrent cancer phenotypes. Therefore, while the senescent growth arrest may confer short-term advantages with regards to tumor progression, these beneficial effects may only be short-lived, and may be permissive for the development of more pernicious cancer phenotypes over an extended period of time.
There is little question that senolytic agents constitute a promising addition to conventional and possibly also targeted cancer therapies that promote tumor cell senescence. It is now largely accepted that senescence is likely to be an undesirable outcome of cancer therapy in terms of the detrimental effects of the secretions from senescent cells as well as the potential of senescent tumor cells to escape from arrest and regenerate the disease. However, there is limited information available as to whether senescence is actually a central response to therapy in the clinic, either in the primary tumor or in residual surviving tumor cells, despite extensive evidence for this outcome in preclinical experimental model systems.
Other issues that remain to be resolved include the lack of uniformity in the action of senolytics against aging related pathologies and tumor cell senescence, durability of the response, the development of resistance and toxicity to normal tissue. Nevertheless, there do appear to be a variety of strategies available for circumventing issues of toxicity, including structural modifications and drug delivery systems. Consequently, it is likely that a more in-depth understanding of the factors that determine which “types” of senescence are susceptible to the senolytics will ultimately result in these agents being incorporated into standard of care, at least for certain types of cancers and in combination with select antitumor drugs.