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3. Targeting epigenetic modifications in cancer therapy: erasing the roadmap to cancer

Author

Mohammad, Helai P., Barbash, Olena, and Creasy, Caretha L.

Subjects
Research, Health aspects, Cancer treatment -- Health aspects, Atezolizumab -- Research, Ruxolitinib -- Research, Daratumumab -- Research, Antineoplastic agents -- Health aspects, Proteins -- Research, Drug discovery, Cancer, Decitabine, Abiraterone, Clinical trials, Fulvestrant, Ipilimumab, Carboplatin, Therapeutics, Epigenetic inheritance, Enzalutamide
Abstract

Author(s): Helai P. Mohammad [sup.1] , Olena Barbash [sup.1] , Caretha L. Creasy [sup.1] Author Affiliations: (1) Epigenetics Department, Oncology, GlaxoSmithKline, Collegeville, USA Main Epigenetic alterations are covalent modifications to [...], Epigenetic dysregulation is a common feature of most cancers, often occurring directly through alteration of epigenetic machinery. Over the last several years, a new generation of drugs directed at epigenetic modulators have entered clinical development, and results from these trials are now being disclosed. Unlike first-generation epigenetic therapies, these new agents are selective, and many are targeted to proteins which are mutated or translocated in cancer. This review will provide a summary of the epigenetic modulatory agents currently in clinical development and discuss the opportunities and challenges in their development. As these drugs advance in the clinic, drug discovery has continued with a focus on both novel and existing epigenetic targets. We will provide an overview of these efforts and the strategies being employed. Targeting epigenetic modifications is an effective cancer therapeutic approach and can be combined with other therapeutics for maximal effect.

Published
2019
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4. Supplementary Table 1 from A687V EZH2 Is a Driver of Histone H3 Lysine 27 (H3K27) Hypertrimethylation

Author

Ott, Heidi M., primary, Graves, Alan P., primary, Pappalardi, Melissa B., primary, Huddleston, Michael, primary, Halsey, Wendy S., primary, Hughes, Ashley M., primary, Groy, Arthur, primary, Dul, Edward, primary, Jiang, Yong, primary, Bai, Yuchen, primary, Annan, Roland, primary, Verma, Sharad K., primary, Knight, Steven D., primary, Kruger, Ryan G., primary, Dhanak, Dashyant, primary, Schwartz, Benjamin, primary, Tummino, Peter J., primary, Creasy, Caretha L., primary, and McCabe, Michael T., primary

Published
2023
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7. Supplementary Table S4 from Rational Targeting of Cooperating Layers of the Epigenome Yields Enhanced Therapeutic Efficacy against AML

Author

Duy, Cihangir, primary, Teater, Matt, primary, Garrett-Bakelman, Francine E., primary, Lee, Tak C., primary, Meydan, Cem, primary, Glass, Jacob L., primary, Li, Meng, primary, Hellmuth, Johannes C., primary, Mohammad, Helai P., primary, Smitheman, Kimberly N., primary, Shih, Alan H., primary, Abdel-Wahab, Omar, primary, Tallman, Martin S., primary, Guzman, Monica L., primary, Muench, David, primary, Grimes, H. Leighton, primary, Roboz, Gail J., primary, Kruger, Ryan G., primary, Creasy, Caretha L., primary, Paietta, Elisabeth M., primary, Levine, Ross L., primary, Carroll, Martin, primary, and Melnick, Ari M., primary

Published
2023
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8. Supplementary Table 3 from A687V EZH2 Is a Driver of Histone H3 Lysine 27 (H3K27) Hypertrimethylation

Author

Ott, Heidi M., primary, Graves, Alan P., primary, Pappalardi, Melissa B., primary, Huddleston, Michael, primary, Halsey, Wendy S., primary, Hughes, Ashley M., primary, Groy, Arthur, primary, Dul, Edward, primary, Jiang, Yong, primary, Bai, Yuchen, primary, Annan, Roland, primary, Verma, Sharad K., primary, Knight, Steven D., primary, Kruger, Ryan G., primary, Dhanak, Dashyant, primary, Schwartz, Benjamin, primary, Tummino, Peter J., primary, Creasy, Caretha L., primary, and McCabe, Michael T., primary

Published
2023
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9. Supplementary Figures S1-S6 from Rational Targeting of Cooperating Layers of the Epigenome Yields Enhanced Therapeutic Efficacy against AML

Author

Duy, Cihangir, primary, Teater, Matt, primary, Garrett-Bakelman, Francine E., primary, Lee, Tak C., primary, Meydan, Cem, primary, Glass, Jacob L., primary, Li, Meng, primary, Hellmuth, Johannes C., primary, Mohammad, Helai P., primary, Smitheman, Kimberly N., primary, Shih, Alan H., primary, Abdel-Wahab, Omar, primary, Tallman, Martin S., primary, Guzman, Monica L., primary, Muench, David, primary, Grimes, H. Leighton, primary, Roboz, Gail J., primary, Kruger, Ryan G., primary, Creasy, Caretha L., primary, Paietta, Elisabeth M., primary, Levine, Ross L., primary, Carroll, Martin, primary, and Melnick, Ari M., primary

Published
2023
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11. Supplementary Figure 3 from A687V EZH2 Is a Driver of Histone H3 Lysine 27 (H3K27) Hypertrimethylation

Author

Ott, Heidi M., primary, Graves, Alan P., primary, Pappalardi, Melissa B., primary, Huddleston, Michael, primary, Halsey, Wendy S., primary, Hughes, Ashley M., primary, Groy, Arthur, primary, Dul, Edward, primary, Jiang, Yong, primary, Bai, Yuchen, primary, Annan, Roland, primary, Verma, Sharad K., primary, Knight, Steven D., primary, Kruger, Ryan G., primary, Dhanak, Dashyant, primary, Schwartz, Benjamin, primary, Tummino, Peter J., primary, Creasy, Caretha L., primary, and McCabe, Michael T., primary

Published
2023
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12. Supplementary Figure 4 from A687V EZH2 Is a Driver of Histone H3 Lysine 27 (H3K27) Hypertrimethylation

Author

Ott, Heidi M., primary, Graves, Alan P., primary, Pappalardi, Melissa B., primary, Huddleston, Michael, primary, Halsey, Wendy S., primary, Hughes, Ashley M., primary, Groy, Arthur, primary, Dul, Edward, primary, Jiang, Yong, primary, Bai, Yuchen, primary, Annan, Roland, primary, Verma, Sharad K., primary, Knight, Steven D., primary, Kruger, Ryan G., primary, Dhanak, Dashyant, primary, Schwartz, Benjamin, primary, Tummino, Peter J., primary, Creasy, Caretha L., primary, and McCabe, Michael T., primary

Published
2023
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13. Data from A687V EZH2 Is a Driver of Histone H3 Lysine 27 (H3K27) Hypertrimethylation

Author

Ott, Heidi M., primary, Graves, Alan P., primary, Pappalardi, Melissa B., primary, Huddleston, Michael, primary, Halsey, Wendy S., primary, Hughes, Ashley M., primary, Groy, Arthur, primary, Dul, Edward, primary, Jiang, Yong, primary, Bai, Yuchen, primary, Annan, Roland, primary, Verma, Sharad K., primary, Knight, Steven D., primary, Kruger, Ryan G., primary, Dhanak, Dashyant, primary, Schwartz, Benjamin, primary, Tummino, Peter J., primary, Creasy, Caretha L., primary, and McCabe, Michael T., primary

Published
2023
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14. Data from Rational Targeting of Cooperating Layers of the Epigenome Yields Enhanced Therapeutic Efficacy against AML

Author

Duy, Cihangir, primary, Teater, Matt, primary, Garrett-Bakelman, Francine E., primary, Lee, Tak C., primary, Meydan, Cem, primary, Glass, Jacob L., primary, Li, Meng, primary, Hellmuth, Johannes C., primary, Mohammad, Helai P., primary, Smitheman, Kimberly N., primary, Shih, Alan H., primary, Abdel-Wahab, Omar, primary, Tallman, Martin S., primary, Guzman, Monica L., primary, Muench, David, primary, Grimes, H. Leighton, primary, Roboz, Gail J., primary, Kruger, Ryan G., primary, Creasy, Caretha L., primary, Paietta, Elisabeth M., primary, Levine, Ross L., primary, Carroll, Martin, primary, and Melnick, Ari M., primary

Published
2023
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15. Supplementary Figure 6 from A687V EZH2 Is a Driver of Histone H3 Lysine 27 (H3K27) Hypertrimethylation

Author

Ott, Heidi M., primary, Graves, Alan P., primary, Pappalardi, Melissa B., primary, Huddleston, Michael, primary, Halsey, Wendy S., primary, Hughes, Ashley M., primary, Groy, Arthur, primary, Dul, Edward, primary, Jiang, Yong, primary, Bai, Yuchen, primary, Annan, Roland, primary, Verma, Sharad K., primary, Knight, Steven D., primary, Kruger, Ryan G., primary, Dhanak, Dashyant, primary, Schwartz, Benjamin, primary, Tummino, Peter J., primary, Creasy, Caretha L., primary, and McCabe, Michael T., primary

Published
2023
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16. Supplementary Table 2 from A687V EZH2 Is a Driver of Histone H3 Lysine 27 (H3K27) Hypertrimethylation

Author

Ott, Heidi M., primary, Graves, Alan P., primary, Pappalardi, Melissa B., primary, Huddleston, Michael, primary, Halsey, Wendy S., primary, Hughes, Ashley M., primary, Groy, Arthur, primary, Dul, Edward, primary, Jiang, Yong, primary, Bai, Yuchen, primary, Annan, Roland, primary, Verma, Sharad K., primary, Knight, Steven D., primary, Kruger, Ryan G., primary, Dhanak, Dashyant, primary, Schwartz, Benjamin, primary, Tummino, Peter J., primary, Creasy, Caretha L., primary, and McCabe, Michael T., primary

Published
2023
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17. Supplementary Figure 2 from A687V EZH2 Is a Driver of Histone H3 Lysine 27 (H3K27) Hypertrimethylation

Author

Ott, Heidi M., primary, Graves, Alan P., primary, Pappalardi, Melissa B., primary, Huddleston, Michael, primary, Halsey, Wendy S., primary, Hughes, Ashley M., primary, Groy, Arthur, primary, Dul, Edward, primary, Jiang, Yong, primary, Bai, Yuchen, primary, Annan, Roland, primary, Verma, Sharad K., primary, Knight, Steven D., primary, Kruger, Ryan G., primary, Dhanak, Dashyant, primary, Schwartz, Benjamin, primary, Tummino, Peter J., primary, Creasy, Caretha L., primary, and McCabe, Michael T., primary

Published
2023
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20. Supplementary Figure 7 from A687V EZH2 Is a Driver of Histone H3 Lysine 27 (H3K27) Hypertrimethylation

Author

Ott, Heidi M., primary, Graves, Alan P., primary, Pappalardi, Melissa B., primary, Huddleston, Michael, primary, Halsey, Wendy S., primary, Hughes, Ashley M., primary, Groy, Arthur, primary, Dul, Edward, primary, Jiang, Yong, primary, Bai, Yuchen, primary, Annan, Roland, primary, Verma, Sharad K., primary, Knight, Steven D., primary, Kruger, Ryan G., primary, Dhanak, Dashyant, primary, Schwartz, Benjamin, primary, Tummino, Peter J., primary, Creasy, Caretha L., primary, and McCabe, Michael T., primary

Published
2023
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21. Supplementary Figure 5 from A687V EZH2 Is a Driver of Histone H3 Lysine 27 (H3K27) Hypertrimethylation

Author

Ott, Heidi M., primary, Graves, Alan P., primary, Pappalardi, Melissa B., primary, Huddleston, Michael, primary, Halsey, Wendy S., primary, Hughes, Ashley M., primary, Groy, Arthur, primary, Dul, Edward, primary, Jiang, Yong, primary, Bai, Yuchen, primary, Annan, Roland, primary, Verma, Sharad K., primary, Knight, Steven D., primary, Kruger, Ryan G., primary, Dhanak, Dashyant, primary, Schwartz, Benjamin, primary, Tummino, Peter J., primary, Creasy, Caretha L., primary, and McCabe, Michael T., primary

Published
2023
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22. Supplementary Figure 1 from A687V EZH2 Is a Driver of Histone H3 Lysine 27 (H3K27) Hypertrimethylation

Author

Ott, Heidi M., primary, Graves, Alan P., primary, Pappalardi, Melissa B., primary, Huddleston, Michael, primary, Halsey, Wendy S., primary, Hughes, Ashley M., primary, Groy, Arthur, primary, Dul, Edward, primary, Jiang, Yong, primary, Bai, Yuchen, primary, Annan, Roland, primary, Verma, Sharad K., primary, Knight, Steven D., primary, Kruger, Ryan G., primary, Dhanak, Dashyant, primary, Schwartz, Benjamin, primary, Tummino, Peter J., primary, Creasy, Caretha L., primary, and McCabe, Michael T., primary

Published
2023
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23. Supplementary Data from Phase I Study of the Novel Enhancer of Zeste Homolog 2 (EZH2) Inhibitor GSK2816126 in Patients with Advanced Hematologic and Solid Tumors

Author

Yap, Timothy A., primary, Winter, Jane N., primary, Giulino-Roth, Lisa, primary, Longley, Jemma, primary, Lopez, Juanita, primary, Michot, Jean-Marie, primary, Leonard, John P., primary, Ribrag, Vincent, primary, McCabe, Michael T., primary, Creasy, Caretha L., primary, Stern, Melissa, primary, Pene Dumitrescu, Teodora, primary, Wang, Xiaowei, primary, Frey, Steve, primary, Carver, Jennifer, primary, Horner, Thierry, primary, Oh, Choon, primary, Khaled, Ahmed, primary, Dhar, Arindam, primary, and Johnson, Peter W.M., primary

Published
2023
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24. EZH2 Is Required for Germinal Center Formation and Somatic EZH2 Mutations Promote Lymphoid Transformation

Author

Béguelin, Wendy, Popovic, Relja, Teater, Matt, Jiang, Yanwen, Bunting, Karen L., Rosen, Monica, Shen, Hao, Yang, Shao Ning, Wang, Ling, Ezponda, Teresa, Martinez-Garcia, Eva, Zhang, Haikuo, Zheng, Yupeng, Verma, Sharad K., McCabe, Michael T., Ott, Heidi M., Van Aller, Glenn S., Kruger, Ryan G., Liu, Yan, McHugh, Charles F., Scott, David W., Chung, Young Rock, Kelleher, Neil, Shaknovich, Rita, Creasy, Caretha L., Gascoyne, Randy D., Wong, Kwok-Kin, Cerchietti, Leandro, Levine, Ross L., Abdel-Wahab, Omar, Licht, Jonathan D., Elemento, Olivier, and Melnick, Ari M.

Published
2013
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26. Loss of tumor suppressor KDM6A amplifies PRC2-regulated transcriptional repression in bladder cancer and can be targeted through inhibition of EZH2

Author

Ler, Lian Dee, Ghosh, Sujoy, Chai, Xiaoran, Thike, Aye Aye, Heng, Hong Lee, Siew, Ee Yan, Dey, Sucharita, Koh, Liang Kai, Lim, Jing Quan, Lim, Weng Khong, Myint, Swe Swe, Loh, Jia Liang, Ong, Pauline, Sam, Xin Xiu, Huang, Dachuan, Lim, Tony, Tan, Puay Hoon, Nagarajan, Sanjanaa, Cheng, Christopher Wai Sam, Ho, Henry, Ng, Lay Guat, Yuen, John, Lin, Po-Hung, Chuang, Cheng-Keng, Chang, Ying-Hsu, Weng, Wen-Hui, Rozen, Steven G., Tan, Patrick, Creasy, Caretha L., Pang, See-Tong, McCabe, Michael T., Poon, Song Ling, and Teh, Bin Tean

Published
2017
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27. Development and Validation of Reagents and Assays for EZH2 Peptide and Nucleosome High-Throughput Screens

Author

Diaz, Elsie, Machutta, Carl A., Chen, Stephanie, Jiang, Yong, Nixon, Christopher, Hofmann, Glenn, Key, Danielle, Sweitzer, Sharon, Patel, Mehul, Wu, Zining, Creasy, Caretha L., Kruger, Ryan G., LaFrance, Louis, Verma, Sharad K., Pappalardi, Melissa B., Le, Baochau, Van Aller, Glenn S., McCabe, Michael T., Tummino, Peter J., Pope, Andrew J., Thrall, Sara H., Schwartz, Benjamin, and Brandt, Martin

Published
2012
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28. Mutation of A677 in histone methyltransferase EZH2 in human B-cell lymphoma promotes hypertrimethylation of histone H3 on lysine 27 (H3K27)

Author

McCabe, Michael T., Graves, Alan P., Ganji, Gopinath, Diaz, Elsie, Halsey, Wendy S., Jiang, Yong, Smitheman, Kimberly N., Ott, Heidi M., Pappalardi, Melissa B., Allen, Kimberly E., Chen, Stephanie B., Pietra, Anthony Della, Dul, Edward, Hughes, Ashley M., Gilbert, Seth A., Thrall, Sara H., Tummino, Peter J., Kruger, Ryan G., Brandt, Martin, Schwartz, Benjamin, and Creasy, Caretha L.

Published
2012

29. A PHASE 1 DOSE-ESCALATION STUDY OF UGN-301 (ZALIFRELIMAB) AS MONOTHERAPY AND IN COMBINATION WITH OTHER AGENTS IN PATIENTS WITH RECURRENT NON-MUSCLE INVASIVE BLADDER CANCER (NMIBC).

Author

Creasy, Caretha L., Lansford, Heather, and Schoenberg, Mark

Subjects
*NON-muscle invasive bladder cancer, *TOLL-like receptor agonists, *INTRAVESICAL administration, *CARCINOMA in situ, *CYTOTOXIC T lymphocyte-associated molecule-4
Abstract

Zalifrelimab is an anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody that neutralizes the inhibitory effects of CTLA-4 on the immune responses of tumor-specific T cells. While systemic anti-CTLA-4 therapy has demonstrated clinical efficacy in solid tumors, CTLA-4 inhibition has also been associated with toxicity due to immune activation. UGN-301 is an intravesical formulation of zalifrelimab prepared with reverse thermal hydrogel. Local administration into the bladder is expected to increase drug concentrations in the target organ without significant systemic exposure, potentially diminishing the systemic toxicity associated with CTLA-4 blockade. This master protocol comprises multiple treatment arms to evaluate the safety and determine the recommended phase 2 dose (RP2D) of UGN-301 as monotherapy and in combination with other agents in patients with recurrent NMIBC. Arm A will investigate UGN-301 monotherapy dose-escalation, Arm B will investigate UGN-301 dose-escalation + UGN-201 (imiquimod), a toll-like receptor 7 agonist with immune-stimulating anti-tumor effects and Arm C will investigate UGN-301 dose escalation + gemcitabine. Additional combinations are planned Each arm will enroll up to 30 patients (minimum 3 at each dose level and 6 at the RP2D) with recurrent NMIBC with high-grade Ta/T1 disease and/or carcinoma in situ (CIS) who failed at least 1 prior course of therapy. Arm A may also enroll patients with intermediate risk low-grade Ta/T1 disease. Patients will receive 6 once-weekly intravesical instillations as induction with optional maintenance at 6, 9, and 12 months for Ta/T1 patients without disease recurrence and CIS patients with complete response. After 2 monotherapy dose levels are cleared, combination arms may commence. Decision rules for dose-escalation, de-escalation, and expansion are based on a Bayesian Logistic Regression Model for pre-defined criteria related to toxicity, pharmacokinetics, and preliminary efficacy. The totality of accrued study data across all dose groups will be used to select the RP2D of UGN-301 as monotherapy and in combination with other agents. Both combinations arms have been initiated and the study is recruiting in the United States, Italy and Spain (NCT05375903). [ABSTRACT FROM AUTHOR]

Published
2025
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30. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations

Author

McCabe, Michael T., Ott, Heidi M., Ganji, Gopinath, Korenchuk, Susan, Thompson, Christine, Van Aller, Glenn S., Liu, Yan, Graves, Alan P., Pietra, III, Anthony Della, Diaz, Elsie, LaFrance, Louis V., Mellinger, Mark, Duquenne, Celine, Tian, Xinrong, Kruger, Ryan G., McHugh, Charles F., Brandt, Martin, Miller, William H., Dhanak, Dashyant, Verma, Sharad K., Tummino, Peter J., and Creasy, Caretha L.

Subjects
Physiological aspects, Genetic aspects, Research, Risk factors, Health aspects, Gene mutation -- Health aspects, Methyltransferases -- Physiological aspects -- Genetic aspects -- Research, Lymphomas -- Risk factors -- Genetic aspects -- Research, Gene mutations -- Health aspects
Abstract

To identify inhibitors of EZH2 methyltransferase activity, a high-throughput biochemical screen with a five-member PRC2 protein complex was performed (14). This work identified a small-molecule EZH2 inhibitor with a [K.sub.i.sup.app] [...], In eukaryotes, post-translational modification of histones is critical for regulation of chromatin structure and gene expression. EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2) and is involved in repressing gene expression through methylation of histone H3 on lysine 27 (H3K27). EZH2 overexpression is implicated in tumorigenesis and correlates with poor prognosis in several tumour types (1-5). Additionally, somatic heterozygous mutations of Y641 and A677 residues within the catalytic SET domain of EZH2 occur in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (6-10). The Y641 residue is the most frequently mutated residue, with up to 22% of germinal centre B-cell DLBCL and follicular lymphoma harbouring mutations at this site. These lymphomas have increased H3K27 tri-methylation (H3K27me3) owing to altered substrate preferences of the mutant enzymes (9,11-13). However, it is unknown whether specific, direct inhibition of EZH2 methyltransferase activity will be effective in treating EZH2 mutant lymphomas. Here we demonstrate that GSK126, a potent, highly selective, S-adenosyl-methionine-competitive, smallmolecule inhibitor of EZH2 methyltransferase activity, decreases global H3K27me3 levels and reactivates silenced PRC2 target genes. GSK126 effectively inhibits the proliferation of EZH2 mutant DLBCL cell lines and markedly inhibits the growth of EZH2 mutant DLBCL xenografts in mice. Together, these data demonstrate that pharmacological inhibition of EZH2 activity may provide a promising treatment for EZH2 mutant lymphoma.

Published
2012

35. Genomic landscape of lung adenocarcinoma in East Asians

Author

Chen, Jianbin, Yang, Hechuan, Teo, Audrey Su Min, Amer, Lidyana Bte, Sherbaf, Faranak Ghazi, Tan, Chu Quan, Alvarez, Jacob Josiah Santiago, Lu, Bingxin, Lim, Jia Qi, Takano, Angela, Nahar, Rahul, Lee, Yin Yeng, Phual, Cheryl Zi Jin, Chua, Khi Pin, Suteja, Lisda, Chen, Pauline Jieqi, Chang, Mei Mei, Koh, Tina Puay Theng, Ong, Boon-Hean, Anantham, Devanand, Hsu, Anne Ann Ling, Gogna, Apoorva, Too, Chow Wei, Aung, Zaw Win, Lee, Yi Fei, Wang, Lanying, Lim, Tony Kiat Hon, Wilm, Andreas, Choi, Poh Sum, Ng, Poh Yong, Toh, Chee Keong, Lim, Wan-Teck, Ma, Siming, Lim, Bing, Liu, Jin, Tam, Wai Leong, Skanderup, Anders Jacobsen, Yeong, Joe Poh Sheng, Tan, Eng-Huat, Creasy, Caretha L., Tan, Daniel Shao Weng, Hillmer, Axel M., Zhai, Weiwei, Chen, Jianbin, Yang, Hechuan, Teo, Audrey Su Min, Amer, Lidyana Bte, Sherbaf, Faranak Ghazi, Tan, Chu Quan, Alvarez, Jacob Josiah Santiago, Lu, Bingxin, Lim, Jia Qi, Takano, Angela, Nahar, Rahul, Lee, Yin Yeng, Phual, Cheryl Zi Jin, Chua, Khi Pin, Suteja, Lisda, Chen, Pauline Jieqi, Chang, Mei Mei, Koh, Tina Puay Theng, Ong, Boon-Hean, Anantham, Devanand, Hsu, Anne Ann Ling, Gogna, Apoorva, Too, Chow Wei, Aung, Zaw Win, Lee, Yi Fei, Wang, Lanying, Lim, Tony Kiat Hon, Wilm, Andreas, Choi, Poh Sum, Ng, Poh Yong, Toh, Chee Keong, Lim, Wan-Teck, Ma, Siming, Lim, Bing, Liu, Jin, Tam, Wai Leong, Skanderup, Anders Jacobsen, Yeong, Joe Poh Sheng, Tan, Eng-Huat, Creasy, Caretha L., Tan, Daniel Shao Weng, Hillmer, Axel M., and Zhai, Weiwei

Abstract

Lung cancer is the world's leading cause of cancer death and shows strong ancestry disparities. By sequencing and assembling a large genomic and transcriptomic dataset of lung adenocarcinoma (LUAD) in individuals of East Asian ancestry (EAS; n = 305), we found that East Asian LUADs had more stable genomes characterized by fewer mutations and fewer copy number alterations than LUADs from individuals of European ancestry. This difference is much stronger in smokers as compared to nonsmokers. Transcriptomic clustering identified a new EAS-specific LUAD subgroup with a less complex genomic profile and upregulated immune-related genes, allowing the possibility of immunotherapy-based approaches. Integrative analysis across clinical and molecular features showed the importance of molecular phenotypes in patient prognostic stratification. EAS LUADs had better prediction accuracy than those of European ancestry, potentially due to their less complex genomic architecture. This study elucidated a comprehensive genomic landscape of EAS LUADs and highlighted important ancestry differences between the two cohorts. Genomic and transcriptomic analysis of lung adenocarcinoma (LUAD) in Asia indicates that Asian LUADs have fewer mutations, lower driver prevalence and fewer copy number alterations than European LUADs.

Published
2020

36. Genomic landscape of lung adenocarcinoma in East Asians

Author

Chen, Jianbin, primary, Yang, Hechuan, additional, Teo, Audrey Su Min, additional, Amer, Lidyana Bte, additional, Sherbaf, Faranak Ghazi, additional, Tan, Chu Quan, additional, Alvarez, Jacob Josiah Santiago, additional, Lu, Bingxin, additional, Lim, Jia Qi, additional, Takano, Angela, additional, Nahar, Rahul, additional, Lee, Yin Yeng, additional, Phua, Cheryl Zi Jin, additional, Chua, Khi Pin, additional, Suteja, Lisda, additional, Chen, Pauline Jieqi, additional, Chang, Mei Mei, additional, Koh, Tina Puay Theng, additional, Ong, Boon-Hean, additional, Anantham, Devanand, additional, Hsu, Anne Ann Ling, additional, Gogna, Apoorva, additional, Too, Chow Wei, additional, Aung, Zaw Win, additional, Lee, Yi Fei, additional, Wang, Lanying, additional, Lim, Tony Kiat Hon, additional, Wilm, Andreas, additional, Choi, Poh Sum, additional, Ng, Poh Yong, additional, Toh, Chee Keong, additional, Lim, Wan-Teck, additional, Ma, Siming, additional, Lim, Bing, additional, Liu, Jin, additional, Tam, Wai Leong, additional, Skanderup, Anders Jacobsen, additional, Yeong, Joe Poh Sheng, additional, Tan, Eng-Huat, additional, Creasy, Caretha L., additional, Tan, Daniel Shao Weng, additional, Hillmer, Axel M., additional, and Zhai, Weiwei, additional

Published
2020
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37. Discovery of Isoxazole Amides as Potent and Selective SMYD3 Inhibitors

Author

Su, Dai-Shi, primary, Qu, Junya, additional, Schulz, Mark, additional, Blackledge, Chuck W., additional, Yu, Hongyi, additional, Zeng, Jenny, additional, Burgess, Joelle, additional, Reif, Alexander, additional, Stern, Melissa, additional, Nagarajan, Raman, additional, Pappalardi, Melissa Baker, additional, Wong, Kristen, additional, Graves, Alan P., additional, Bonnette, William, additional, Wang, Liping, additional, Elkins, Patricia, additional, Knapp-Reed, Beth, additional, Carson, Jeffrey D., additional, McHugh, Charles, additional, Mohammad, Helai, additional, Kruger, Ryan, additional, Luengo, Juan, additional, Heerding, Dirk A., additional, and Creasy, Caretha L., additional

Published
2019
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38. Phase I Study of the Novel Enhancer of Zeste Homolog 2 (EZH2) Inhibitor GSK2816126 in Patients with Advanced Hematologic and Solid Tumors

Author

Yap, Timothy A., primary, Winter, Jane N., additional, Giulino-Roth, Lisa, additional, Longley, Jemma, additional, Lopez, Juanita, additional, Michot, Jean-Marie, additional, Leonard, John P., additional, Ribrag, Vincent, additional, McCabe, Michael T., additional, Creasy, Caretha L., additional, Stern, Melissa, additional, Pene Dumitrescu, Teodora, additional, Wang, Xiaowei, additional, Frey, Steve, additional, Carver, Jennifer, additional, Horner, Thierry, additional, Oh, Choon, additional, Khaled, Ahmed, additional, Dhar, Arindam, additional, and Johnson, Peter W.M., additional

Published
2019
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39. Rational Targeting of Cooperating Layers of the Epigenome Yields Enhanced Therapeutic Efficacy against AML

Author

Duy, Cihangir, primary, Teater, Matt, additional, Garrett-Bakelman, Francine E., additional, Lee, Tak C., additional, Meydan, Cem, additional, Glass, Jacob L., additional, Li, Meng, additional, Hellmuth, Johannes C., additional, Mohammad, Helai P., additional, Smitheman, Kimberly N., additional, Shih, Alan H., additional, Abdel-Wahab, Omar, additional, Tallman, Martin S., additional, Guzman, Monica L., additional, Muench, David, additional, Grimes, H. Leighton, additional, Roboz, Gail J., additional, Kruger, Ryan G., additional, Creasy, Caretha L., additional, Paietta, Elisabeth M., additional, Levine, Ross L., additional, Carroll, Martin, additional, and Melnick, Ari M., additional

Published
2019
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42. A Phase I Study of GSK2816126, an Enhancer of Zeste Homolog 2(EZH2) Inhibitor, in Patients (pts) with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL), Other Non-Hodgkin Lymphomas (NHL), Transformed Follicular Lymphoma (tFL), Solid Tumors and Multiple Myeloma (MM)

Author

Yap, Timothy Anthony, Winter, Jane N., Leonard, John P., Ribrag, Vincent, Constantinidou, Anastasia, Giulino-Roth, Lisa, Michot, Jean-Marie, Khan, Tariq A., Horner, Thierry, Carver, Jennifer, Dumetrescu, Teodora Pene, He, Zangdong, McCabe, Michael T., Creasy, Caretha L., Dhar, Arindam, Carpenter, Christopher, Johnson, Peter M., Constantinidou, Anastasia [0000-0001-5316-7574], Ribrag, Vincent [0000-0002-5221-353X], Michot, Jean-Marie [0000-0003-3482-3331], McCabe, Michael T. [0000-0001-5715-9563], Creasy, Caretha L. [0000-0002-3735-6401], and Johnson, Peter M. [0000-0001-7231-1180]

Abstract

128 22

Published
2016

45. Efficacy and safety of trametinib in Japanese patients with advanced biliary tract cancers refractory to gemcitabine

Author

Ikeda, Masafumi, primary, Ioka, Tatsuya, additional, Fukutomi, Akira, additional, Morizane, Chigusa, additional, Kasuga, Akiyoshi, additional, Takahashi, Hideaki, additional, Todaka, Akiko, additional, Okusaka, Takuji, additional, Creasy, Caretha L., additional, Gorman, Shelby, additional, Felitsky, Daniel J., additional, Kobayashi, Mikiro, additional, Zhang, Fanghong, additional, and Furuse, Junji, additional

Published
2017
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47. Cooperative Gene Repression By DNA Methylation and LSD1-Mediated Enhancer Inactivation in Acute Myeloid Leukemia

Author

Duy, Cihangir, primary, Teater, Matt, additional, Garrett-Bakelman, Francine E., additional, Lee, Tak C, additional, Meydan, Cem, additional, Glass, Jacob Lowell, additional, Li, Meng, additional, Mohammad, Helai, additional, Smitheman, Kimberly, additional, Shih, Alan H., additional, Abdel-Wahab, Omar, additional, Paietta, Elisabeth, additional, Tallman, Martin S., additional, Guzman, Monica L., additional, Kruger, Ryan G., additional, Creasy, Caretha L., additional, Levine, Ross L., additional, Carroll, Martin, additional, and Melnick, Ari, additional

Published
2016
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48. A Phase I Study of GSK2816126, an Enhancer of Zeste Homolog 2(EZH2) Inhibitor, in Patients (pts) with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL), Other Non-Hodgkin Lymphomas (NHL), Transformed Follicular Lymphoma (tFL), Solid Tumors and Multiple Myeloma (MM)

Author

Yap, Timothy A., primary, Winter, Jane N., additional, Leonard, John P., additional, Ribrag, Vincent, additional, Constantinidou, Anastasia, additional, Giulino-Roth, Lisa, additional, Michot, Jean-Marie, additional, Khan, Tariq A, additional, Horner, Thierry, additional, Carver, Jennifer, additional, Pene Dumetrescu, Teodora, additional, He, Zangdong, additional, McCabe, Michael T., additional, Creasy, Caretha L., additional, Dhar, Arindam, additional, Carpenter, Christopher, additional, and Johnson, Peter M, additional

Published
2016
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49. The epigenetic modifier EZH2 controls melanoma growth and metastasis through silencing of distinct tumour suppressors

Author

Zingg, Daniel, Debbache, Julien, Schaefer, Simon M, Tuncer, Eylul, Frommel, Sandra C, Cheng, Phil; https://orcid.org/0000-0003-2940-006X, Arenas-Ramirez, Natalia, Haeusel, Jessica, Zhang, Yudong, Bonalli, Mario, McCabe, Michael T, Creasy, Caretha L, Levesque, Mitchell P, Boyman, Onur, Santoro, Raffaella, Shakhova, Olga, Dummer, Reinhard, Sommer, Lukas, Zingg, Daniel, Debbache, Julien, Schaefer, Simon M, Tuncer, Eylul, Frommel, Sandra C, Cheng, Phil; https://orcid.org/0000-0003-2940-006X, Arenas-Ramirez, Natalia, Haeusel, Jessica, Zhang, Yudong, Bonalli, Mario, McCabe, Michael T, Creasy, Caretha L, Levesque, Mitchell P, Boyman, Onur, Santoro, Raffaella, Shakhova, Olga, Dummer, Reinhard, and Sommer, Lukas

Abstract

Increased activity of the epigenetic modifier EZH2 has been associated with different cancers. However, evidence for a functional role of EZH2 in tumorigenesis in vivo remains poor, in particular in metastasizing solid cancers. Here we reveal central roles of EZH2 in promoting growth and metastasis of cutaneous melanoma. In a melanoma mouse model, conditional Ezh2 ablation as much as treatment with the preclinical EZH2 inhibitor GSK503 stabilizes the disease through inhibition of growth and virtually abolishes metastases formation without affecting normal melanocyte biology. Comparably, in human melanoma cells, EZH2 inactivation impairs proliferation and invasiveness, accompanied by re-expression of tumour suppressors connected to increased patient survival. These EZH2 target genes suppress either melanoma growth or metastasis in vivo, revealing the dual function of EZH2 in promoting tumour progression. Thus, EZH2-mediated epigenetic repression is highly relevant especially during advanced melanoma progression, which makes EZH2 a promising target for novel melanoma therapies.

Published
2015

50. Efficacy and safety of trametinib in Japanese patients with advanced biliary tract cancers refractory to gemcitabine.

Author

Ikeda, Masafumi, Ioka, Tatsuya, Fukutomi, Akira, Morizane, Chigusa, Kasuga, Akiyoshi, Takahashi, Hideaki, Todaka, Akiko, Okusaka, Takuji, Creasy, Caretha L., Gorman, Shelby, Felitsky, Daniel J., Kobayashi, Mikiro, Zhang, Fanghong, and Furuse, Junji

Abstract

Gemcitabine‐based therapy remains the mainstay of treatment for patients with biliary tract cancers (BTCs) with no second‐line treatment(s) established yet. Aberrant activation of the MAPK pathway in patients with BTC indicates its importance in BTC. Trametinib is a potent, highly selective, allosteric non‐competitive inhibitor of MEK1/MEK2. In this phase IIa open‐label, single‐arm study, we investigated the efficacy and safety of trametinib in Japanese patients with advanced BTC refractory to gemcitabine‐based therapy. All patients received oral trametinib 2 mg once daily until progressive disease (PD), death, or unacceptable toxicity. The primary objective was to determine the 12‐week non‐PD rate. Secondary assessments included safety, progression‐free survival (PFS), overall survival, and overall response rate. Targeted exome sequencing was used to identify biomarkers for sensitivity or resistance to trametinib monotherapy. Twenty patients (median age, 61.5 years) with carcinoma of gall bladder (40%), intrahepatic (25%) or extrahepatic (30%) bile duct, and ampulla of Vater (5%) were enrolled. The non‐PD rate at week 12 was 10% (95% confidence interval, 1.2‐31.7); it did not reach the threshold rate of 25%. Median PFS was 10.6 weeks (95% confidence interval, 4.6‐12.1) and 1‐year overall survival was 20.0%. Stable disease and PD were observed in 13 (65%) and seven (35%) patients, respectively. No new safety signals were reported. Although the primary end‐point was not met, prolonged PFS was observed in one patient having six somatic variants including synonymous NF1 exon 12 splice variant and a loss‐of‐function variant in ARID1A. Efforts to understand responsive mutations and sensitivity to targeted therapies are warranted. This trial was registered with ClinicalTrials.gov: NCT01943864. [ABSTRACT FROM AUTHOR]

Published
2018
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