Targeting telomeres to overcome therapy resistance in advanced melanoma

PHILADELPHIA — (March 21, 2018) — A study conducted at The Wistar Institute in collaboration with The University of Texas Southwestern Medical Center has demonstrated the efficacy of targeting aberrantly active telomerase to treat therapy-resistant melanoma. The research was published in the journal Clinical Cancer Research.

The introduction of targeted therapies and immune checkpoint blockade therapies has revolutionized the therapeutic options for patients with advanced melanoma. However, the long-term therapeutic benefit of these new approaches is still hindered by the onset of therapy resistance, which can develop through different mechanisms.

A hallmark of several cancer types, including melanoma, is the aberrant regulation of telomerase activity due to mutations in the regulatory element of the telomerase gene, which results in increased production of the protein. Telomerase is an enzyme responsible for protecting the integrity of chromosome ends during replication. While it is absent in most normal adult cells that don't actively proliferate, telomerase is reactivated in cancer cells, allowing continuous cell divisions and making them immortal.

"Our work presents pre-clinical evidence that targeting the aberrant telomerase activity may provide a universal strategy to overcome therapy resistance and achieve long-term melanoma control," said lead researcher Meenhard Herlyn, D.V.M., D.Sc., Caspar Wistar Professor in Melanoma Research and director of The Wistar Institute Melanoma Research Center.

Herlyn and his collaborators used a modified telomerase substrate they had previously described, called 6-thio-dG, to impair telomerase activity by inducing telomere dysfunction. They showed that 6-thio-dG induced cell death in melanoma cells carrying mutations in the BRAF gene without affecting the viability of normal skin cells, and it impaired the growth of several BRAF-mutant melanoma cell lines transplanted in mice. The BRAF gene is mutated in approximately half of all cases of melanoma.

The team also studied the ability of 6-thio-dG treatment to stop proliferation and tumor growth of therapy-resistant melanoma cells. They created a large panel of human melanoma cell lines with acquired resistance to targeted therapy and immunotherapy and showed a general sensitivity of these cells to 6-thio-dG both in vitro and in vivo in mouse models.

"Our results add to the mounting evidence supporting the existence of an important relationship between telomeres and telomerase and cancer," said Gao Zhang, Ph.D., a staff scientist in the Herlyn Lab and first author of the study. "Our data suggest that 6-thio-dG may be used either as monotherapy following first- and second-line therapies to prolong disease control after onset of resistance, or in combination with first-line therapies to overcome intrinsic resistance."

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This work was supported by National Institutes of Health grants P01 CA114046, P50 CA174523, U54 CA224070, Peer Reviewed Cancer Research Program (PRCRP) grant CA150619 from the Department of Defense and grants from the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and the Melanoma Research Foundation. Core support for the study was provided by the Cancer Center Support Grants P30 CA010815 to The Wistar Institute and CA016672 to the MD Anderson Cancer Center, and by grant CA70907 to UT South Western. Part of this work was performed in laboratories constructed with support from NIH grant C06 RR30414.

Co-authors of this study from The Wistar Institute include Lawrence W. Wu, Omotayo Ope, Sergio Randell, Norah Sadek, Aurelie Beroard, Min Xiao, Jiufeng Tan, Umar Saeed, Eric Sugarman, Clemens Krepler, Patricia Brafford, Katrin Sproesser, Rajasekharan Somasundaram, Jonathan Woo, Xiangfan Yin, and Qin Liu. Other co-authors include Ilgen Mender and Jerry W. Shay from UT Southwestern Medical Center; Michal Barzily-Rokni, Marc R. Hammond, Genevieve M. Boland, Dennie T. Frederick, Benchun Miao, and Keith T. Flaherty from Massachusetts General Hospital Cancer Center; Chaoran Cheng, Tian Tian, Zhi Wei from New Jersey Institute of Technology; Themistoklis Vasilopoulos and Utz Herbig from Rutgers University; Sengottuvelan Murugan, Wei Xu, Giorgos C. Karakousis, Lynn M. Schuchter, Tara C. Gangadhar, Ravi K. Amaravadi, Bradley Garman, Bradley Wubbenhorst, Katherine Nathanson, and Xiaowei Xu from the University of Pennsylvania; and Lawrence N. Kwong, Yiling Lu and Gordon B. Mills from The University of Texas MD Anderson Cancer Center.

The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.

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