Autophagy: The Strange Dining Habits of Cancer Cells
Many cancer cells lead a difficult existence. Those mired deep in the core of a tumor, for example, have limited access to oxygen, growth factors, and nutrients from the blood vessels that feed the tumor. But when things get tough, the tough start eating. In these most dire of situations, many cancer cells will engage in an act of self-cannibalism called autophagy, gobbling up regular meals of cytoplasmic parts and degrading them into macromolecules that they recycle into other components that they need to survive. (View a video of cancer cells consuming themselves through autophagy online.)
NCI Support Enables Growth of Autophagy-related Research
Funding for autophagy-related research from NCI’s Division of Cancer Biology (DCB) has increased dramatically over the past several years. As a result of the emerging science in this area of research, DCB is planning an invitation-only workshop to bring together leaders in the field. The workshop will focus on how autophagy affects cancer cells, particularly its role in allowing the cells to maintain homeostasis at all stages of cancer development and growth.
“Autophagy research is an emerging area of interest within DCB,” said Dr. Barbara Spalholz, chief of DCB’s Cancer Cell Biology Branch. “We expect that the interaction between cancer and cell biologists at the workshop will highlight the importance of autophagy in cancer, identify potential preventive strategies, and reveal novel therapeutic targets.”
Normal cells rely on autophagy to maintain a balance between the synthesis and degradation of proteins and organelles during development or in times of stress. Cancer cells rely on this process as well, not just to survive in the inhospitable environment of a tumor, but also to ward off the effects of chemotherapy and radiation. “Pretty much every therapeutic regimen out there is inducing this pathway” in cancer cells, explained Dr. John Cleveland of The Scripps Research Institute in Jupiter, FL. Activation of autophagy, he continued, “is an intrinsic cell-survival mechanism that cancer cells turn on to recoup essential building blocks when they’re being poisoned or irradiated.”
A greater understanding of autophagy’s role in cancer has led some researchers to investigate whether blocking autophagy can make cancer treatments more effective, cutting off what amounts to an important escape route. The work is in its earliest stages, with the first human trials of autophagy inhibitors launched only in the last several years. But if successful, researchers believe the process could work for many cancer types as a way to help eradicate primary tumors and help prevent or eliminate metastases. (With a similar goal in mind, researchers are actively studying a process known as glycolysis, which is another source of nutrients for cancer cells.)
Survive and Resist
Autophagy is a process of capture and transfer. Beginning with some form of stress that causes the cell to ramp up its self-eating machinery, a double-membraned pouch, called an autophagosome, begins engulfing old or unneeded components, such as proteins and organelles, from the cell’s cytoplasm. The autophagosome then fuses with lysosomes, another type of membrane-bound structure replete with digestive enzymes, to form autolysosomes, which degrade the captured items into components (such as amino acids, fatty acids, and nucleotides) that the cell can reuse.
At the Cancer Institute of New Jersey, Dr. Eileen White and colleagues are among the leading research groups trying to better define the role of autophagy in cancer and determine whether interfering with this process could be used to treat cancer. In 2006, they were among the first to demonstrate that cancer cells from deep within a tumor had significantly elevated levels of autophagy, and that “it was supporting survival in that hypoxic environment,” she said.
In their continued research, the team has found a consistent pattern. “When you stress tumor cells,” Dr. White explained, “they start eating themselves, getting smaller and smaller and smaller, and at some point they stop dividing and just sit there; they are essentially dormant.” But once the stress is removed, in as little as 24 hours the cells can reinstate normal metabolic behavior and begin proliferating again. “As long as they can do that, and avoid being killed by stress or therapy, then that is the inherent problem,” Dr. White said.
A number of studies support the role of autophagy in treatment resistance, including resistance to targeted therapies. Spanish researchers reported last year, for example, that HER2-positive breast cancer cells that were resistant to trastuzumab (Herceptin) had significantly elevated autophagy activity (based on the levels of certain proteins involved in the autophagy process). Treating the same cells with an autophagy inhibitor led to reduced cell proliferation, and adding trastuzumab on top of autophagy inhibition restored the cells’ sensitivity to trastuzumab.
Although autophagy may be able to kill cells, in tumor cells its survival-promoting abilities appear to trump any propensity it may have to induce death, explained Dr. Ravi Amaravadi from the University of Pennsylvania Abramson Cancer Center, who is involved in several early-phase clinical trials testing autophagy inhibition. But based on what’s been seen in lab-based studies, he cautioned, there may be substantial differences in the autophagy activity in different cancer types, or even from tumor to tumor. Nevertheless, the available evidence suggests that autophagy “seems to be a process that could be important in many cancers,” he said.
When Dr. Herbert Zeh and his colleagues at the University of Pittsburgh Medical Center Cancer Centers started investigating autophagy in pancreatic cancer, one of the deadliest and most treatment-resistant cancer types, they began to consider the disease from a different perspective. “We thought, maybe it’s not a disease of unchecked cell proliferation,” he said. “What if the real problem is that the cells just forgot how to die the right way?” Dr. Zeh is the principal investigator of a phase I/II trial testing autophagy inhibition in patients with stage II or III pancreatic cancer.
By combining treatments that inhibit autophagy with traditional therapies that go after rapidly dividing cells, they hypothesize, cancer cells can be forced to undergo apoptosis, the most common form of cell suicide. “It’s a novel concept because we’re not just trying to make tumor cells die,” Dr. Zeh said. “We’re trying to ensure that they do it in the appropriate way.”
Looking Ahead for the Best Recipe
A number of clinical trials testing autophagy inhibition are actively recruiting patients with a variety of cancers, including breast, colorectal, myeloma, and chronic lymphocytic leukemia. All of the trials are using an off-patent drug called hydroxychloroquine, or HCQ, which can interfere with the autophagy process and is already used to treat several conditions, including malaria and rheumatoid arthritis. In most trials, HCQ is being combined with other therapies.
HCQ is thought to work by altering a lysosome’s internal pH, explained Dr. White, derailing the vesicle’s ability to degrade its contents and complete the recycling process. “We’re not sure if it’s the best [autophagy inhibitor], but it’s being used in patients already,” she continued, which can speed its clinical development and more quickly show whether autophagy inhibition improves patient outcomes.
Data from the largest trial to date involving HCQ—in patients with newly diagnosed glioblastoma multiforme—were presented at the American Society of Clinical Oncology annual meeting earlier this year. In the multi-institutional phase I/II trial, HCQ was combined with temozolomide and radiation therapy. Although some serious toxic effects were seen at the highest dose tested, Dr. Amaravadi said, at a lower dose, these effects waned and there was strong evidence of autophagy inhibition.
While much more work needs to be done on many fronts—such as better understanding the genetics of autophagy and identifying and validating robust biomarkers that measure the extent of autophagic behavior in a cell—the available evidence, Dr. Amaravadi believes, “suggests that there is potential for this drug.” But, he stressed, there is no evidence yet to support adding HCQ to any cancer regimens in hopes of improving outcomes.
A number of pharmaceutical companies are investigating autophagy inhibitors, Dr. Cleveland said, but the work is preliminary. As a potential therapeutic target, he continued, the autophagy pathway has significant promise, but it has potential pitfalls. Autophagy, for example, appears to have the ability to prevent healthy cells from becoming cancerous, by allowing them to degrade junk that might otherwise induce DNA damage and drive a cell toward malignancy. The same pathway also helps the immune system recognize potential threats, so disrupting it could, in theory, inhibit the body’s ability to mount an immune response against cancer.
“There are a lot of unknowns about autophagy,” Dr. Cleveland said. “It has different functions in different kinds of contexts…so our studies have to be carefully done. Being smart about how to deliver these drugs will be very important.”