Washington University Licenses Gene Linked to Cancer Spread
Bill Harbour, MD, leads team to unique melanoma discovery and more
Washington University in St. Louis has licensed a gene linked to the spread of cancer in melanoma patients to Castle Biosciences Inc.
Washington University scientists – ophthalmologic oncologist Bill Harbour, MD, and geneticist Anne Bowcock, PhD – discovered the link between the BAP1 gene and cancer metastasis. Their research, published in 2010 in the medical journal Science, revealed that BAP1 mutations occurred in 84 percent of melanomas that developed in the eye and later spread, but were rare in eye tumors that didn’t metastasize. The duo also identified an individual with a germline BAP1 mutation, indicating that this mutation may be genetic and gives validity to a familial cancer syndrome. Mutations in the BAP1 gene have been found in skin melanomas, mesotheliomas, meningiomas and cancers of the breast, ovary, kidney and lung.
Harbour, the Paul A. Cibis Distinguished Professor of Ophthalmology and Visual Sciences, and Bowcock, professor of genetics, of pediatrics and of medicine, collaborated with the university’s Office of Technology Management (OTM), which filed patents related to the BAP1 discovery that gave the university the option to license the technology.
Bradley Castanho, PhD, director of the university’s OTM, called the situation “a win-win for the university.”
“Licensing the technology maximizes the opportunities for WUSTL scientists and the university to take this discovery to the market,” said Castanho, “where it could be developed into a diagnostic test for cancer metastasis.”
Texas-based Castle Biosciences is validating the BAP1 technology for use in both ocular melanoma and melanoma that develops on the skin. The company plans to incorporate BAP1 as a target in a clinical test for melanoma metastasis. The licensing agreement also provides Castle Biosciences an option to license the gene for use in detecting the spread of other cancers.
The new license is the second one between the university and Castle Biosciences for Harbour-related technology findings. The first exclusive license, in 2009, was related to technology to predict the risk of metastasis in patients with ocular melanoma. The company has finished technical and clinical validation studies, and the analysis led to a new standard of care for patients with the disease.
An Earlier Link
In a recently released Washington University paper available online in the journal Clinical Cancer Research, Harbour discusses a drug commonly used to treat seizures that appears to make eye tumors less likely to grow if they spread to other parts of the body. Uveal melanoma, the second most common form of melanoma, may be very aggressive and metastasize from the eye to other organs, especially the liver.
“Melanoma in general, and uveal melanoma in particular, is notoriously difficult to treat once it has metastasized and grown in a distant organ,” said Harbour, principal investigator of the study, professor of cell biology and molecular oncology, and director of the Center for Ocular Oncology at the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. “We previously identified an aggressive class 2 molecular type of uveal melanoma that, in most cases, already has metastasized by the time the eye cancer is diagnosed, even though imaging the body can’t detect it yet. This microscopic amount of cancer can remain dormant in the liver and elsewhere for several years before it begins to grow and becomes lethal.”
Once this happens, said Harbour, the prospects for survival are poor.
Harbour’s new study shows that drugs known as histone deacetylase (HDAC) inhibitors alter the conformation of the DNA of the aggressive form of uveal melanoma, which changes the way key genes are expressed, rendering the tumor cells less aggressive.
“We looked at uveal melanoma cells in the laboratory and in an animal model, and we found that HDAC inhibitors can block the growth and proliferation of tumor cells,” he said. “HDAC inhibitors appear to reverse the aggressive molecular signature that we had identified several years ago as a marker for metastatic death. When we look at aggressive melanoma cells under the microscope after treatment with HDAC inhibitors, they look more like normal cells and less like tumor cells.”
Because HDAC inhibitors already are on the market, Harbour said he believes it may be possible to quickly begin testing the drugs in patients with aggressive forms of uveal melanoma. The drugs have relatively mild side effects that aren’t as severe as those seen in patients undergoing chemotherapy. One HDAC inhibitor, for example, is the anti-seizure drug valproic acid, with drowsiness as its most common side effect, which is typical of all HDAC inhibitors.
In the Works
Clinical trials of HDAC inhibitors could begin in 2012, Harbour said. Already, other researchers have applied for funding to begin testing an HDAC inhibitor called SAHA (suberoylanilide hydroxic acid) in patients with metastatic uveal melanoma.
“This is a reasonable place to start in the challenging effort to improve survival in patients with metastatic uveal melanoma,” Harbour said. “I suspect that the best role for HDAC inhibitors will be to slow or prevent the growth of tumor cells that have spread out of the eye but cannot yet be detected. This might lengthen the time between the original eye treatment and the appearance of detectable cancer in the liver and elsewhere.”
Like the chicken pox virus that lives for years in nerve cells without affecting health, Harbour pointed out that treatment with HDAC inhibitors may allow patients with aggressive melanomas to live for many years without any detectable spread of their disease.
Harbour’s team previously developed a screening test to predict whether the cancer would be likely to spread to the liver and other parts of the body. The test is helpful because even though less than 4 percent of patients with uveal melanoma have detectable metastatic disease, up to half will eventually die of metastasis even after successful treatment of the tumor with radiation, surgery, or, in the worst cases, removal of the eye.
Tumors that tend to remain contained within the eye are called class 1 uveal melanomas. With a needle biopsy, doctors can quickly determine whether a tumor is likely to be a class 1 cancer or whether it carries a molecular signature that identifies it as a high-risk, class 2 melanoma. Harbour and his colleagues developed a test to identify the class 2 molecular signature, and that test is now being used around the world to detect the aggressive form of uveal melanoma.
This development coincides with the published paper identifying a mutation in the gene, BAP1, that helped further explain why some eye tumors develop the class 2 signature and acquire the ability to spread. Harbour explained that HDAC inhibitors appear to reverse some of the effects of BAP1 mutations on the melanoma cell.