A study published in Proceedings of the National Academy of Sciences (PNAS), reveals that elevated expression of a gene in the deadly skin cancer melanoma can raise the mortality risk from the tumor, making it a potentially new target for treating melanomas that express high levels of this gene.
The study, entitled “Pleckstrin Homology Domain-Interacting Protein (PHIP) as a Marker and Mediator of Melanoma Metastasis”, was conducted by researchers at California Pacific Medical Center Research Institute (CPMCRI), part of the Sutter Health network.
The researchers highlight that this is the first time the role of PHIP (pleckstrin homology domain-interacting protein), has been reported in any cancer.
Mohammed Kashani-Sabet, M.D., director of the Center for Melanoma Research and Treatment at Sutter Pacific Medical Foundation, a senior scientist at CPMCRI, and lead author of the study, explained:
“We’ve shown that this gene is a marker of increased risk of spread and of death due to melanoma. Studying this gene helps us to understand which melanomas are more aggressive. The hope is that further study will lead to targeted treatments for melanoma and other cancers.”
In order to determine the effects high levels of the PHIP protein has on the metastasis of melanoma, the researchers examined mice and human tissue from melanoma patients.
The researchers found that increased expression of PHIP was linked to reduced survival in both humans and mice. The team then suppressed PHIP in melanomas in mice and discovered that they lived longer than mice with active PHIP.
The researchers also examined tissues from 345 individuals with melanoma and found that patients with lower levels of PHIP expression lived longer than those with high levels of PHIP. Approximately one third of study participants had the highest levels of PHIP.
“We learned in both mice and humans, that the more of this (PHIP) a tumor has, the higher the risk is for the cancer spreading and the lower the survival.”
In order to understand which melanomas might carry elevated expression of PHIP, the team examined the genetic makeup of the tumors.
Recent studies were focused on the role of other genes in melanoma, in particular BRAF, a gene which is mutated in about 50% of melanomas. The U.S. Food and Drug Administration approved an inhibitor of mutated BRAF that prolonged the survival of patients with metastatic melanoma in 2011. However, the genes responsible for the metastasis of melanomas without this mutation still remain unknown, which means that patients with melanomas that have no BRAF mutations only have few effective therapies available.
The researchers found that in melanomas without a mutation in BRAF, levels of PHIP were high. In addition, they found that several melanomas with high PHIP levels did not have variations in two other vital genes – NRAS and PTEN. According to the researchers, this finding indicates that PHIP may be responsible for the aggressive behavior of “triple-negative” melanomas that lack these mutations.
The researchers hope that future treatments for individual suffering from melanoma and other cancers can be developed by targeting a gene such as PHIP that promotes metastasis.
According to Kashani-Sabet, human tissue specimens from other institutions and other countries need to be examined in order to confirm that PHIP is a marker for melanomas. In addition, Kashani-Sabet plans to conduct further studies in other cancers where PHIP may play a vital role.
Written By Grace Rattue