Autophagy-induced tumor dormancy in ovarian cancer

Cells that encounter a variety of stresses undergo an evolutionarily conserved process of self-digestion termed autophagy. The importance of this intracellular damage response for pathophysiology has been established across multiple fields, including infectious disease, neurodegeneration, heart failure, and cancer (1). In cancer in particular, the debate continues to rage as to whether or not autophagy is primarily a mechanism of cell death or cell survival. This is important to understand in order to preferentially promote the clinical development of therapeutic interventions that can either inhibit or enhance autophagy in tumor cells. A number of clinically available cancer therapeutics, including DNA-damaging chemotherapy, radiation therapy, and molecularly targeted therapies have been found to induce autophagy in cell culture and animal models (2). Recent investigations have found that inhibition of therapy-induced autophagy with chloroquine derivatives can enhance cell death in established tumors, leading to enhanced tumor regression and delayed tumor regrowth (3). In this study, a combination of experiments involving RNA interference and drugs were used to demonstrate that therapy-induced autophagy in established tumors allows tumor cells to survive therapeutic stress (3). The cytoprotective role of autophagy following chemotherapy has been confirmed by other investigators (4–6). These findings have led to a growing number of early-phase clinical trials that aim to establish the safety and preliminary efficacy of combining agents that induce autophagy with hydroxychloroquine in patients with advanced malignancies refractory to standard treatments. Collectively, these actively accruing clinical trials represent the first attempt to manipulate autophagy for therapeutic benefit in cancer. Autophagy inhibition with chloroquine has also been found to significantly delay the onset of spontaneous tumors in a transgenic mouse model of Myc-induced lymphoma (7). This study suggested that autophagy inhibition may have a role not only in combination therapies for patients with active metastatic disease, but also in the prevention of early disease. However, conducting a clinical trial of a novel autophagy inhibitor, or in the case of hydroxychloroquine, an old drug being used for new indication, in tumor-free patients is difficult, requiring large numbers of patients, and long periods of follow-up. While the known safety and tolerability of chloroquine derivatives suggest they may be ideal drugs to test as chemopreventative agents, committing the resources necessary to conduct prevention trials may not be warranted until a potential benefit of this strategy has been established in a clinical setting with short-term outcomes, such as in metastatic disease. Another clinical setting that could be more feasible to investigate autophagy inhibitors is in the setting of minimal residual disease with high risk of relapse. A common problem across multiple malignancies is that cancer therapy can initially result in a complete remission, but there is an extremely high chance of relapse. This indicates there are clinically undetectable tumor cells that are dormant and have the ability to regrow at a later date. This is an ideal setting to investigate the role of autophagy and the effects of pharmacological autophagy inhibitors. In this issue of the JCI, Lu, Bast, and colleagues report an ovarian cancer model of minimal residual disease and identify a role for autophagy in supporting tumor dormancy (8). Additionally, their analysis of the effects of controlled expression of the autophagy-inducing tumor suppressor gene aplasia Ras homolog member I (ARHI) in human ovarian cancer cells in vitro versus in vivo sheds light on the relationship between autophagic cell death and autophagic cell survival and implicates an underappreciated role for the tumor microenvironment in deciding this fate.