Investigators Unlocking the Mysteries of Merkel Cell Carcinoma

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2.17.39_moore.jpgResearchers at the University of Pittsburgh Cancer Institute have documented the molecular activity through which the Merkel cell polyomavirus contributes to 80% of cases of Merkel cell carcinoma—a finding that holds promise for future therapies. The researchers are now working on testing more than 1,350 drugs to identify better methods to treat Merkel cell carcinoma, according to Patrick Moore, MD, MPH, who presented the University of Pittsburgh findings at the Second American Association for Cancer Research (AACR) Frontiers in Basic Cancer Research meeting in San Francisco.

“Our findings hold promise for development, in the near future, of rational chemotherapeutic targeting of Merkel cell carcinoma, an enigmatic and severe cancer,” Dr. Moore said.

Merkel Cell Polyomavirus

In 2008, Dr. Moore, his wife Dr. Yuan Chang, and their colleagues discovered Merkel cell polyomavirus (MCV), the virus that causes Merkel cell cancer. Only seven viruses are known to cause human cancers. This is the second human tumor virus discovered by Moore and Chang, after also discovering the virus causing Kaposi’s sarcoma in 1994. They then found that when MCV undergoes specific mutations, often in immunodeficient patients, it can generate Merkel cell carcinoma. These findings have now been verified in multiple studies.

In the past year, researchers have also found that the Merkel cell virus is ubiquitous—everyone carries it in their skin. “But if this is a ubiquitous infection and everyone is infected, why is Merkel cell carcinoma so rare?” Dr. Moore asked.

2.17.39_chart.jpgThe researchers have recently made discoveries about the inner workings of the virus that help explain how it might transform healthy cells into cancer cells that result in skin cancer. When a patient develops T-cell immune deficiencies such as HIV, the virus increases its replication, making it more likely to fragment and integrate into the host cell. Normally, activities of the virus itself would kill the host cell. But if part of the T antigen of the virus is also mutated, uncontrolled viral oncogene expression can drive tumor cell proliferation, Dr. Moore explained. One of the viral oncogenes, called small T antigen, activates synthesis of cellular oncoproteins through a process called cap-dependent translation.1 Unlike other animal polyomaviruses that have served as classic models of cancer, MCV small T antigen’s targeting of cap-dependent translation can cause abnormal cell growth even after abolishing its ability to target PP2A and heat-shock proteins.

In the 3 years since discovering MCV, Dr. Moore and his colleagues have identified several unique characteristics of the virus.

Unexpected Mechanisms

“MCV induces cell transformation in unexpected ways, and Merkel cell carcinoma has been difficult to treat,” Dr. Moore said. “Discovery of the molecular causes of this cancer provides opportunities to directly target the cellular pathways that are perturbed by the virus.”

MCV is a member of a family of viruses capable of causing multiple tumors in animal models. “In the past 4 years, genomic technologies have led to discovery of six polyomaviruses besides MCV,” Dr. Moore said. “Prior to these discoveries, the only known human polyomaviruses were JC virus, which causes progressive multifocal leukoencephalopathy, and BK virus, which primary causes kidney and bladder disease among transplant patients.

“MCV, a natural component of human skin, is the first polyomavirus consistently associated with human cancer,” he said. “It is part of our flora and only causes cancer when a precise set of mutations occur in this otherwise harmless virus rather than the host cell. This is a new an unexected way for cancers to arise.” Discovery of six more human polyomaviruses opens the possibility that still more cancers may be caused by this previously unknown and unrecognized group of viruses. ■

Disclosure: Drs. Moore and Chang have patents related to MCV that they have assigned to the University of Pittsburgh.

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1. Shuda M, Kwun HJ, Feng H, et al: Human Merkel cell polyomavirus small T antigen is an oncoprotein targeting the 4E-BP1 translation regulator. J Clin Invest 121:3623-3653, 2011.

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