Senotherapeutics Will Reduce the Side-Effects of Cancer Radiotherapy

Treatment with radiation to kill cancerous cells results in an increased burden of senescent cells, both in and around the tumor. This is a fair trade-off; a senescent cancerous cell may be harmful in and of itself, but it is a good deal less harmful in the long run than an active cancer cell. Unfortunately senescent cells produce pro-growth, pro-inflammatory signaling that is disruptive of tissue function, raises the risk of suffering a range of age-related conditions, and increases the risk of both reoccurrence of the treated cancer and the development of later unrelated cancers.

Thus given the work taking place outside the cancer research community on the development of therapies to selectively destroy senescent cells, suppress senescent cell signaling, or prevent cells from becoming senescent, researchers are starting to consider how to integrate these approaches into the treatment of cancer. At the very least, it seems sensible to start by applying senolytics to destroy lingering senescent cells after cancer therapy is complete, in order to reduce the lasting side-effects of such therapies. Beyond that it is an open question as to when and whether it is a good idea to combine targeting of senescent cells with cancer therapy. It isn't at all clear as to when it will be beneficial to remove senescent cells during treatment.

Radiation-induced senescence: therapeutic opportunities

Cellular senescence, which is a normal consequence of aging, is characterized by irreversible cell cycle arrest in response to various stress stimuli, resistance to apoptosis and senescent-associated secretory phenotype (SASP). Cellular senescence is a cell fate decision and normal physiological event, which plays essential roles in development, prevention of cancer, and the wound healing process. However, when cells are subjected to sustained sub-lethal injury including radiation therapy or chemotherapy, continued oxidative stress and chronic inflammation prompt entry into cellular senescence. The chronic state of radiation-induced senescence together with secretion of pro-inflammatory factors, a phenomenon known as the SASP, contribute to the major pathology of radiation-induced normal tissue and organ injury.

Factors influencing the role of cellular senescence in the tumor tissue widely vary in part due to the tumor tissue heterogeneity, the oncogenic status, immune cell recognition by acute vs chronic senescence and radiation dose regimen, to name a few. For example, acute induction of cellular senescence is considered important for cancer prevention by stimulating the immune system to rapidly eliminate the genetically unstable cells, whereas chronic cellular senescence creates a tumor promoting environment through a secretion of SASP. Chronic cellular senescence also contribute to the radiation-induced late effects in the normal tissues and organs such as lung and skin fibrosis, cognitive dysfunction/necrosis to name a few. Overall, the SASP of senescent cancer cells is considered to be primarily detrimental in therapy resistance, immunosuppression and metastasis.

Senolytics are a class of drugs that selectively eliminate senescent cells. Multiple pharmacological strategies are under investigation to remove senescent cells. They include small molecules, peptides, and antibodies. Our new preliminary data show the potential of senolytic as well as anti-cancer agents to illustrate the foregoing point. Alvespimycin (17-DMAG), an HSP-90 inhibitor, reduced normal tissue damage after a radiation exposure without compromising radiotherapy effectiveness. Using another class of senolytics, other researchers have shown some functional and structural improvement in cardiovascular function, and radiation-induced muscle weakness using the combined senolytics, dasanitib and quercetin. Using another class of senolytics, navitoclax, a Bcl-2 family inhibitor, improved radiation-induced pulmonary fibrosis, radiation-induced hematotoxicity, age related hematopoietic stem cell (HSC) dysfunction, and delayed malignant glioma/">malignant glioma recurrence by eliminating the radiation-induced senescent astrocytes. The potential of navitoclax to mitigate normal tissue radiation damage while sensitizing radiation cytotoxicity in tumors is further supported by navitoclax's ability to overcome hypoxia-driven radiosensitivity.

Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.