Potential breakthrough in understanding tumor dormancy

Cancer cells often migrate from the organ in which they originated and hide in a state of inactivity elsewhere in the body. These cells can reactivate at anytime and pose a serious risk of recurrence and metastatic disease. The likelihood of curing cancer is greatly reduced once the disease has spread.

Tumor dormancy remains one of the greater mysteries in regard to the scientific understanding of cancer progression; identifying and killing inactive tumor cells persists as a prominent challenge in the field of cancer treatment.

However, ongoing research at Massey may provide major new insight for novel cancer therapeutics by targeting cells in a particular state of inactivity called senescence. The research is led by David Gewirtz, Ph.D., member of the Developmental Therapeutics research program at Massey and professor of pharmacology and toxicology at the VCU School of Medicine; Hisashi Harada, Ph.D., member of the Cancer Cell Signaling research program at Massey and associate professor at the Philips Institute for Oral Health Research at the VCU School of Dentistry; and Joseph Landry, Ph.D., member of the Cancer Molecular Genetics research program at Massey and assistant professor of human and molecular genetics at the VCU School of Medicine.

"It is entirely unclear how tumor cells might survive in the body for months or years, only to break out of dormancy and give rise to recurrent disease," Gewirtz said. "Our studies have suggested that one form of tumor dormancy might be that of senescence, a prolonged form of growth arrest that can be shown to be induced in tumor cells by chemotherapeutic drugs and radiation. If dormant tumors are, in fact, in this state of senescence, it is possible that they might be susceptible to elimination by senolytic agents (a class of small molecules under investigation to see if they can selectively induce death of senescent cells)."

Cellular senescence has long been understood as a DNA damage response in which normal cells cease to divide; however, its role in cancer cells is largely unknown. Senolytic agents are drugs that are programmed to seek out and kill cells in a state of senescence.

Research led by Gewirtz and recently published in Biochemical Pharmacology demonstrated that breast and lung cancer cells provoked into a state of senescence by chemotherapy were able to eventually recover and re-multiply at a rapid pace in culture and in mice. This finding challenged a commonly held notion about senescent cancer cells.

"The prevailing viewpoint for many years has been that senescence is an irreversible form of growth arrest," explained Gewirtz. "During the course of the last few years, the scientific community has come to accept that this is not necessarily the case and that cells can re-emerge from senescence and give rise to tumors, where the tumors are sometimes more aggressive than the original disease."

Based on these findings, Gewirtz published an article in Cancer Research suggesting that senescent cells are of significant importance in further research seeking to better understand how tumor cells evade existing cancer therapies and hide in a state of dormancy and to inform the development of novel cancer therapeutics.

"If senescence is a form of tumor dormancy, then tumor cells that escape from senescence and survive will, in some cases, be the source of recurrent disease. Their elimination would provide a survival advantage for patients with cancer," Gewirtz added.

As a means to further explore this concept, Gewirtz, Harada and Landry received a five-year, $1.2 million R01 grant from the National Cancer Institute to study whether senolytic drugs can effectively eliminate senescent-like lung tumor cells in order to prevent, or at least significantly suppress, cancer recurrence. They will test the ability of the drug ABT-263, a BCL-2 inhibitor, to target and destroy cells in a senescent state, and seek to determine the specific role that BCL-2 family proteins (genes that regulate cell death) play in regard to the destruction or preservation of dormant tumor cells.

It is unknown what roles the immune system plays in sustaining therapy-induced tumor dormancy.

"The immune system has been known for some time to control the growth of tumors," Landry said. "It is less clear how cancer therapies, and the senescence they induce, affect this natural response. They are likely to have complicated effects on the control of therapy-induced dormant cells."

One of the major goals of this study will be to establish the involvement of immune responses to tumor cell senescence caused by chemotherapy and radiation in the absence and presence of senolytic drugs.

"We also hope to establish a therapeutic strategy for the elimination of non-small cell lung cancer cells that have the potential to contribute to recurrent disease," Gewirtz said.