One-Two Punch May Improve Cancer Treatment Results

Arresting tumor cells in a non-dividing state, known as cellular senescence, is one of the results of treatment with certain types of chemotherapies. Converting rapidly dividing tumor cells into senescent ones has shown to improve patient outcomes, but elimination of these still potentially harmful cells is needed.

In a new study published in Nature, Clemens A. Schmitt, MD, of the Charit–Universittsmedizin Berlin in Germany, and colleagues at the Max Delbrck Center for Molecular Medicine and the Berlin School of Integrative Oncology, demonstrated a way to exploit a metabolic vulnerability of senescent cells. “We provide here a novel strategy to utilize the senescence-associated hypermetabolism to selectively kill these cells, while leaving non-senescent normal cells spared,” said Schmitt.

The new strategy provides evidence for an anticancer approach that targets a cellular process or condition of the cell rather than a distinct molecular pathway.

The researchers found senescent cells were hungrier for sugar compared with their non-senescent counterparts. This was unexpected, Schmitt told Cancer Network, because dividing cells require energy to duplicate their DNA and organelles, while senescent cells do not.

“The hypermetabolic nature of senescent cells as compared to the very same but proliferating tumor cells was a surprise,” said Schmitt.

The studies are so far in mouse models using human cell lines, of lymphoma and other solid tumors, but the results point to ways that combination therapies could bring about better efficacy for patients.

The researchers transplanted B-cell lymphoma cells into a mouse model and treated the mice with cyclophosphamide to induce senescence when the lymphoma was fully developed. These therapy-induced senescent lymphomas could be detected noninvasively, using two different positron emission tomography (PET) signals. A negative signal using ¹⁸F-fluorothymidine (FLT)-PET, used to visualize cell growth, marked the animals treated with chemotherapy, while the untreated animals showed high proliferation.

The second positive signal, using ¹⁸F-fluorodeoxyglucose (FDG)-PET, showed that lymphomas treated with cyclophosphamide had higher levels of glucose compared with those not treated with the senescence-inducing chemotherapy.

The senescent tumor cells produced and relied on more energy compared with the dividing cells. The researchers found that “senescence-associated proteotoxic stress” could explain this discrepancy. An acute induction of secretory proteins results in a quality issue for the cells, which activates pathways to cope with the buildup of misfolded and toxic proteins, requiring autophagy to clean up. This process requires energy, said Schmitt. “Senescent cells in which we block energy supply or autophagy die out because of this proteotoxic stress,” he added.

To specifically target the senescent tumor cells after chemotherapy, the study authors treated the mice with lysosomal protease inhibitors to block autophagy or the cells’ ability to use energy. Both approaches resulted in cell death for the senescent tumor cells. This one-two punch method is a variation on the “synthetic lethality” approach, which exploits the vulnerability of tumor cells while leaving normal cells intact.

Chemotherapy that results in DNA damage can either cause tumor cells to die (via programmed cell death) or to arrest their growth (senescence), depending on the genetics of the cells. Tumor cell senescence may be better than a dividing tumor cell, but it is not desirable in the long run, because of the inflamed tumor microenvironment that occurs, said Schmitt. Dead cells can’t spring back to life, but senescent cells can begin the cell cycle again, causing cancer relapse-the reason why methods to ultimately kill therapy-induced senescent cells are needed.

The study authors are following up this study with further research in mice, using tumor cell lines. According to Schmitt, there is a forthcoming clinical trial to test the hypothesis that chemotherapy followed by reprogramming the metabolism of senescent cells can lead to more efficient tumor eradication.