Induction of telomere dysfunction prolongs disease control of therapy-resistant melanoma

Gao Zhang; Lawrence W. Wu; Ilgen Mender; Michal Barzily-Rokni; Marc R. Hammond; Omotayo Ope; Chaoran Cheng; Themistoklis Vasilopoulos; Sergio Randell; Norah Sadek; Aurelie Beroard; Min Xiao; Tian Tian; Jiufeng Tan; Umar Saeed; Eric Sugarman; Clemens Krepler; Patricia Brafford; Katrin Sproesser; Sengottuvelan Murugan; Rajasekharan Somasundaram; Bradley Garman; Bradley Wubbenhorst; Jonathan Woo; Xiangfan Yin; Qin Liu; Dennie T. Frederick; Benchun Miao; Wei Xu; Giorgos C. Karakousis; Xiaowei Xu; Lynn M. Schuchter; Tara C. Mitchell; Lawrence N. Kwong; Ravi K. Amaravadi; Yiling Lu; Genevieve M. Boland; Zhi Wei; Katherine Nathanson; Utz Herbig; Gordon B. Mills; Keith T. Flaherty; Meenhard Herlyn; Jerry W. Shay

doi:10.1158/1078-0432.CCR-17-2773

Induction of telomere dysfunction prolongs disease control of therapy-resistant melanoma

Gao Zhang, Lawrence W. Wu, Ilgen Mender, Michal Barzily-Rokni, Marc R. Hammond, Omotayo Ope, Chaoran Cheng, Themistoklis Vasilopoulos, Sergio Randell, Norah Sadek, Aurelie Beroard, Min Xiao, Tian Tian, Jiufeng Tan, Umar Saeed, Eric Sugarman, Clemens Krepler, Patricia Brafford, Katrin Sproesser, Sengottuvelan MuruganRajasekharan Somasundaram, Bradley Garman, Bradley Wubbenhorst, Jonathan Woo, Xiangfan Yin, Qin Liu, Dennie T. Frederick, Benchun Miao, Wei Xu, Giorgos C. Karakousis, Xiaowei Xu, Lynn M. Schuchter, Tara C. Mitchell, Lawrence N. Kwong, Ravi K. Amaravadi, Yiling Lu, Genevieve M. Boland, Zhi Wei, Katherine Nathanson, Utz Herbig, Gordon B. Mills, Keith T. Flaherty, Meenhard Herlyn, Jerry W. Shay

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

Abstract

Purpose: Telomerase promoter mutations are highly prevalent in human tumors including melanoma. A subset of patients with metastatic melanoma often fail multiple therapies, and there is an unmet and urgent need to prolong disease control for those patients. Experimental Design: Numerous preclinical therapy-resistant models of human and mouse melanoma were used to test the efficacy of a telomerase-directed nucleoside, 6-thio-2'-deoxyguanosine (6-thio-dG). Integrated transcrip-tomics and proteomics approaches were used to identify genes and proteins that were significantly downregulated by 6-thio-dG. Results: We demonstrated the superior efficacy of 6-thio-dG both in vitro and in vivo that results in telomere dysfunction, leading to apoptosis and cell death in various preclinical models of therapy-resistant melanoma cells. 6-thio-dG concomitantly induces telomere dysfunction and inhibits the expression level of AXL. Conclusions: In summary, this study shows that indirectly targeting aberrant telomerase in melanoma cells with 6-thio-dG is a viable therapeutic approach in prolonging disease control and overcoming therapy resistance.

Original language	English (US)
Pages (from-to)	4771-4784
Number of pages	14
Journal	Clinical Cancer Research
Volume	24
Issue number	19
DOIs	https://doi.org/10.1158/1078-0432.CCR-17-2773
State	Published - Oct 1 2018
Externally published	Yes

ASJC Scopus subject areas

Oncology
Cancer Research

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Zhang, G., Wu, L. W., Mender, I., Barzily-Rokni, M., Hammond, M. R., Ope, O., Cheng, C., Vasilopoulos, T., Randell, S., Sadek, N., Beroard, A., Xiao, M., Tian, T., Tan, J., Saeed, U., Sugarman, E., Krepler, C., Brafford, P., Sproesser, K., ... Shay, J. W. (2018). Induction of telomere dysfunction prolongs disease control of therapy-resistant melanoma. Clinical Cancer Research, 24(19), 4771-4784. https://doi.org/10.1158/1078-0432.CCR-17-2773

Induction of telomere dysfunction prolongs disease control of therapy-resistant melanoma. / Zhang, Gao; Wu, Lawrence W.; Mender, Ilgen; Barzily-Rokni, Michal; Hammond, Marc R.; Ope, Omotayo; Cheng, Chaoran; Vasilopoulos, Themistoklis; Randell, Sergio; Sadek, Norah; Beroard, Aurelie; Xiao, Min; Tian, Tian; Tan, Jiufeng; Saeed, Umar; Sugarman, Eric; Krepler, Clemens; Brafford, Patricia; Sproesser, Katrin; Murugan, Sengottuvelan; Somasundaram, Rajasekharan; Garman, Bradley; Wubbenhorst, Bradley; Woo, Jonathan; Yin, Xiangfan; Liu, Qin; Frederick, Dennie T.; Miao, Benchun; Xu, Wei; Karakousis, Giorgos C.; Xu, Xiaowei; Schuchter, Lynn M.; Mitchell, Tara C.; Kwong, Lawrence N.; Amaravadi, Ravi K.; Lu, Yiling; Boland, Genevieve M.; Wei, Zhi; Nathanson, Katherine; Herbig, Utz; Mills, Gordon B.; Flaherty, Keith T.; Herlyn, Meenhard; Shay, Jerry W.

In: Clinical Cancer Research, Vol. 24, No. 19, 01.10.2018, p. 4771-4784.

Research output: Contribution to journal › Article › peer-review

Zhang, G, Wu, LW, Mender, I, Barzily-Rokni, M, Hammond, MR, Ope, O, Cheng, C, Vasilopoulos, T, Randell, S, Sadek, N, Beroard, A, Xiao, M, Tian, T, Tan, J, Saeed, U, Sugarman, E, Krepler, C, Brafford, P, Sproesser, K, Murugan, S, Somasundaram, R, Garman, B, Wubbenhorst, B, Woo, J, Yin, X, Liu, Q, Frederick, DT, Miao, B, Xu, W, Karakousis, GC, Xu, X, Schuchter, LM, Mitchell, TC, Kwong, LN, Amaravadi, RK, Lu, Y, Boland, GM, Wei, Z, Nathanson, K, Herbig, U, Mills, GB, Flaherty, KT, Herlyn, M & Shay, JW 2018, 'Induction of telomere dysfunction prolongs disease control of therapy-resistant melanoma', Clinical Cancer Research, vol. 24, no. 19, pp. 4771-4784. https://doi.org/10.1158/1078-0432.CCR-17-2773

Zhang, Gao ; Wu, Lawrence W. ; Mender, Ilgen ; Barzily-Rokni, Michal ; Hammond, Marc R. ; Ope, Omotayo ; Cheng, Chaoran ; Vasilopoulos, Themistoklis ; Randell, Sergio ; Sadek, Norah ; Beroard, Aurelie ; Xiao, Min ; Tian, Tian ; Tan, Jiufeng ; Saeed, Umar ; Sugarman, Eric ; Krepler, Clemens ; Brafford, Patricia ; Sproesser, Katrin ; Murugan, Sengottuvelan ; Somasundaram, Rajasekharan ; Garman, Bradley ; Wubbenhorst, Bradley ; Woo, Jonathan ; Yin, Xiangfan ; Liu, Qin ; Frederick, Dennie T. ; Miao, Benchun ; Xu, Wei ; Karakousis, Giorgos C. ; Xu, Xiaowei ; Schuchter, Lynn M. ; Mitchell, Tara C. ; Kwong, Lawrence N. ; Amaravadi, Ravi K. ; Lu, Yiling ; Boland, Genevieve M. ; Wei, Zhi ; Nathanson, Katherine ; Herbig, Utz ; Mills, Gordon B. ; Flaherty, Keith T. ; Herlyn, Meenhard ; Shay, Jerry W. / Induction of telomere dysfunction prolongs disease control of therapy-resistant melanoma. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 19. pp. 4771-4784.

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title = "Induction of telomere dysfunction prolongs disease control of therapy-resistant melanoma",

abstract = "Purpose: Telomerase promoter mutations are highly prevalent in human tumors including melanoma. A subset of patients with metastatic melanoma often fail multiple therapies, and there is an unmet and urgent need to prolong disease control for those patients. Experimental Design: Numerous preclinical therapy-resistant models of human and mouse melanoma were used to test the efficacy of a telomerase-directed nucleoside, 6-thio-2'-deoxyguanosine (6-thio-dG). Integrated transcrip-tomics and proteomics approaches were used to identify genes and proteins that were significantly downregulated by 6-thio-dG. Results: We demonstrated the superior efficacy of 6-thio-dG both in vitro and in vivo that results in telomere dysfunction, leading to apoptosis and cell death in various preclinical models of therapy-resistant melanoma cells. 6-thio-dG concomitantly induces telomere dysfunction and inhibits the expression level of AXL. Conclusions: In summary, this study shows that indirectly targeting aberrant telomerase in melanoma cells with 6-thio-dG is a viable therapeutic approach in prolonging disease control and overcoming therapy resistance.",

author = "Gao Zhang and Wu, {Lawrence W.} and Ilgen Mender and Michal Barzily-Rokni and Hammond, {Marc R.} and Omotayo Ope and Chaoran Cheng and Themistoklis Vasilopoulos and Sergio Randell and Norah Sadek and Aurelie Beroard and Min Xiao and Tian Tian and Jiufeng Tan and Umar Saeed and Eric Sugarman and Clemens Krepler and Patricia Brafford and Katrin Sproesser and Sengottuvelan Murugan and Rajasekharan Somasundaram and Bradley Garman and Bradley Wubbenhorst and Jonathan Woo and Xiangfan Yin and Qin Liu and Frederick, {Dennie T.} and Benchun Miao and Wei Xu and Karakousis, {Giorgos C.} and Xiaowei Xu and Schuchter, {Lynn M.} and Mitchell, {Tara C.} and Kwong, {Lawrence N.} and Amaravadi, {Ravi K.} and Yiling Lu and Boland, {Genevieve M.} and Zhi Wei and Katherine Nathanson and Utz Herbig and Mills, {Gordon B.} and Flaherty, {Keith T.} and Meenhard Herlyn and Shay, {Jerry W.}",

note = "Funding Information: The research was funded by NIH grants P01CA114046, P50CA174523, P50CA70907, 1U54CA224070, DoD PRCRP grant CA150619, AG01228, the Southland Financial Corporation Distinguished Chair in Geriatric Research, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, and the Melanoma Research Foundation; NIH grant 5R01CA136533 to U. Herbig; and by the Tara Miller Foundation to L.M. Schuchter. The support for Shared Resources utilized in this study was provided by Cancer Center Support Grant (CCSG) CA010815 to The Wistar Institute, CA016672 to the MDACC, and CA142543 to UTSW. Part of this work was performed in laboratories constructed with support from NIH grant C06 RR30414. The authors thank all former and current lab members for comments and helpful discussions; J. Hayden and F. Keeney (Wistar Microscopy Facility), C. Chang, S. Billouin, and T. Nguyen (Wistar Genomics Facility), J.S. Faust (Wistar Flow Cytometry Facility), D. DiFrancesco (Wistar Animal Facility), and F. Chen (Wistar Histotechnology Facility) for technical support; and M.B. Powell for providing human melanoma cells (Stanford University). The authors apologize to those whose work was not cited or mentioned here due to space constraints. Funding Information: L.N. Kwong reports receiving a commercial research grant from Array Biopharma. G.B. Mills reports receiving a commercial research grant from Adelson Medical Research Foundation, AstraZeneca, Critical Outcome Technologies, Komen Research Foundation, NanoString, Breast Cancer Research Foundation, Karus, Illumina, Takeda/Millenium Pharamceuticals, Pfizer, has received speakers bureau honoraria from Symphogen, MedImmune, Astra-Zeneca, ISIS Pharmaceuticals, Lily, Novartis, ImmunoMet, Allostery, Tarveda, Pfizer, has ownership interest (including patents) Catena Pharmaceuticals, PTV Ventures, Spindletop Ventures, Myriad Genetics, ImmunoMet, and is a consultant/advisory board member for Adventist Health, AstraZeneca, Provista Diagnostics, Signalchem Lifesciences, Symphogen, Lilly, Novartis, Tarveda, Tau Therapeutics, Allostery, Catena Pharmaceuticals, Critical Outcome Technologies, ISIS Pharmaceuticals, ImmunoMet, Takeda/Millenium Pharmaceuticals, MedImmune,and Precision Medicine.J.W.Shay hasownership interest(including patents) in Barricade Therapeutics. No potential conflicts of interest were disclosed by the other authors.",

year = "2018",

month = oct,

day = "1",

doi = "10.1158/1078-0432.CCR-17-2773",

language = "English (US)",

volume = "24",

pages = "4771--4784",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

number = "19",

}

TY - JOUR

T1 - Induction of telomere dysfunction prolongs disease control of therapy-resistant melanoma

AU - Zhang, Gao

AU - Wu, Lawrence W.

AU - Mender, Ilgen

AU - Barzily-Rokni, Michal

AU - Hammond, Marc R.

AU - Ope, Omotayo

AU - Cheng, Chaoran

AU - Vasilopoulos, Themistoklis

AU - Randell, Sergio

AU - Sadek, Norah

AU - Beroard, Aurelie

AU - Xiao, Min

AU - Tian, Tian

AU - Tan, Jiufeng

AU - Saeed, Umar

AU - Sugarman, Eric

AU - Krepler, Clemens

AU - Brafford, Patricia

AU - Sproesser, Katrin

AU - Murugan, Sengottuvelan

AU - Somasundaram, Rajasekharan

AU - Garman, Bradley

AU - Wubbenhorst, Bradley

AU - Woo, Jonathan

AU - Yin, Xiangfan

AU - Liu, Qin

AU - Frederick, Dennie T.

AU - Miao, Benchun

AU - Xu, Wei

AU - Karakousis, Giorgos C.

AU - Xu, Xiaowei

AU - Schuchter, Lynn M.

AU - Mitchell, Tara C.

AU - Kwong, Lawrence N.

AU - Amaravadi, Ravi K.

AU - Lu, Yiling

AU - Boland, Genevieve M.

AU - Wei, Zhi

AU - Nathanson, Katherine

AU - Herbig, Utz

AU - Mills, Gordon B.

AU - Flaherty, Keith T.

AU - Herlyn, Meenhard

AU - Shay, Jerry W.

N1 - Funding Information: The research was funded by NIH grants P01CA114046, P50CA174523, P50CA70907, 1U54CA224070, DoD PRCRP grant CA150619, AG01228, the Southland Financial Corporation Distinguished Chair in Geriatric Research, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, and the Melanoma Research Foundation; NIH grant 5R01CA136533 to U. Herbig; and by the Tara Miller Foundation to L.M. Schuchter. The support for Shared Resources utilized in this study was provided by Cancer Center Support Grant (CCSG) CA010815 to The Wistar Institute, CA016672 to the MDACC, and CA142543 to UTSW. Part of this work was performed in laboratories constructed with support from NIH grant C06 RR30414. The authors thank all former and current lab members for comments and helpful discussions; J. Hayden and F. Keeney (Wistar Microscopy Facility), C. Chang, S. Billouin, and T. Nguyen (Wistar Genomics Facility), J.S. Faust (Wistar Flow Cytometry Facility), D. DiFrancesco (Wistar Animal Facility), and F. Chen (Wistar Histotechnology Facility) for technical support; and M.B. Powell for providing human melanoma cells (Stanford University). The authors apologize to those whose work was not cited or mentioned here due to space constraints. Funding Information: L.N. Kwong reports receiving a commercial research grant from Array Biopharma. G.B. Mills reports receiving a commercial research grant from Adelson Medical Research Foundation, AstraZeneca, Critical Outcome Technologies, Komen Research Foundation, NanoString, Breast Cancer Research Foundation, Karus, Illumina, Takeda/Millenium Pharamceuticals, Pfizer, has received speakers bureau honoraria from Symphogen, MedImmune, Astra-Zeneca, ISIS Pharmaceuticals, Lily, Novartis, ImmunoMet, Allostery, Tarveda, Pfizer, has ownership interest (including patents) Catena Pharmaceuticals, PTV Ventures, Spindletop Ventures, Myriad Genetics, ImmunoMet, and is a consultant/advisory board member for Adventist Health, AstraZeneca, Provista Diagnostics, Signalchem Lifesciences, Symphogen, Lilly, Novartis, Tarveda, Tau Therapeutics, Allostery, Catena Pharmaceuticals, Critical Outcome Technologies, ISIS Pharmaceuticals, ImmunoMet, Takeda/Millenium Pharmaceuticals, MedImmune,and Precision Medicine.J.W.Shay hasownership interest(including patents) in Barricade Therapeutics. No potential conflicts of interest were disclosed by the other authors.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - Purpose: Telomerase promoter mutations are highly prevalent in human tumors including melanoma. A subset of patients with metastatic melanoma often fail multiple therapies, and there is an unmet and urgent need to prolong disease control for those patients. Experimental Design: Numerous preclinical therapy-resistant models of human and mouse melanoma were used to test the efficacy of a telomerase-directed nucleoside, 6-thio-2'-deoxyguanosine (6-thio-dG). Integrated transcrip-tomics and proteomics approaches were used to identify genes and proteins that were significantly downregulated by 6-thio-dG. Results: We demonstrated the superior efficacy of 6-thio-dG both in vitro and in vivo that results in telomere dysfunction, leading to apoptosis and cell death in various preclinical models of therapy-resistant melanoma cells. 6-thio-dG concomitantly induces telomere dysfunction and inhibits the expression level of AXL. Conclusions: In summary, this study shows that indirectly targeting aberrant telomerase in melanoma cells with 6-thio-dG is a viable therapeutic approach in prolonging disease control and overcoming therapy resistance.

AB - Purpose: Telomerase promoter mutations are highly prevalent in human tumors including melanoma. A subset of patients with metastatic melanoma often fail multiple therapies, and there is an unmet and urgent need to prolong disease control for those patients. Experimental Design: Numerous preclinical therapy-resistant models of human and mouse melanoma were used to test the efficacy of a telomerase-directed nucleoside, 6-thio-2'-deoxyguanosine (6-thio-dG). Integrated transcrip-tomics and proteomics approaches were used to identify genes and proteins that were significantly downregulated by 6-thio-dG. Results: We demonstrated the superior efficacy of 6-thio-dG both in vitro and in vivo that results in telomere dysfunction, leading to apoptosis and cell death in various preclinical models of therapy-resistant melanoma cells. 6-thio-dG concomitantly induces telomere dysfunction and inhibits the expression level of AXL. Conclusions: In summary, this study shows that indirectly targeting aberrant telomerase in melanoma cells with 6-thio-dG is a viable therapeutic approach in prolonging disease control and overcoming therapy resistance.

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