DNMT1

A pair of medications that make malignant cells act as if they have a virus could hold new promise for treating colorectal cancers and other solid tumors, reports a new study. The preclinical research determined how low doses of a DNMT inhibitor sensitize cancer cells to an EZH2 inhibitor, resulting in a one-two punch that combats cancer cells better than either drug alone. The findings are the foundation for an upcoming Phase I clinical trial to evaluate this combination in people with colorectal cancer or other solid tumors. A pair of medications that make malignant cells act as if they have a virus could hold new promise for treating colorectal cancers and other solid tumors, reports a study published today in Science Advances. The preclinical research, led by Van Andel Institute scientists, determined how low doses of a DNMT inhibitor sensitize cancer cells to an EZH2 inhibitor, resulting in a one-two punch that combats cancer cells better than either drug alone. The findings are the foundation for an upcoming Phase I clinical trial to evaluate this combination in people with colorectal cancer or other solid tumors. "DNMT inhibitors are approved to treat blood cancer while EZH2 inhibitors are approved to treat blood cancer and a rare type of sarcoma. To date, they've had limited individual success in solid tumors like colorectal cancer," said Van Andel Institute Professor Scott Rothbart, Ph.D., the study's corresponding author. "Our findings highlight the promise of combination cancer therapies by revealing how these two medications interact, with the DNMT inhibitor priming cancer cells in a way that makes the EZH2 inhibitor more effective." DNMT and EZH2 inhibitors work by controlling the epigenetic processes that regulate gene expression. In cancer, epigenetic errors enable malignant cells to survive and proliferate -- and offer critical targets for treatment. Previous studies show that DNMT inhibitors cause cancer cells to behave as if infected by a virus, which makes the cells more susceptible to attack by one's own immune system. In their new study, Rothbart and colleagues demonstrated that combining DNMT and EZH2 inhibitors activate this viral mimicry process more effectively than either drug on its own. The upcoming trial will be the first time these two medication types will be combined to enhance the activities of these inhibitors in solid tumors. Colorectal cancers are the second leading cause of cancer death globally, according to the World Health Organization. More than 1.9 million cases were diagnosed in 2020, with incidence expected to rise to 3.2 million cases by 2040. Although screening and early detection have driven down colorectal cancer rates among older people in the U.S., rates are rising in younger people. "Although it is not clear why colorectal cancer cases are rising among young people, it is clear that we need more effective treatment strategies," Rothbart said. "Combining medications may be a powerful way to simultaneously target multiple drivers of cancer. In addition to revealing how DNMT and EZH2 inhibitors work together, our findings suggest that epigenetic drugs also may sensitize tumors to immunotherapy, which offers another important opportunity to enhance cancer treatment." The upcoming trial will be supported by the Van Andel Institute-Stand Up To Cancer© (SU2C) Epigenetics Dream Team, a multi-institutional collaboration that evaluates promising potential combination therapies for cancer, and a National Cancer Institute Specialized Programs of Research Excellence (SPORE) award, a prestigious five-year grant that supports a team of scientists seeking to improve epigenetic cancer therapies. Today's findings were made possible in part by a SPORE-supported subproject on DNMT and EZH2 inhibitors led by Rothbart and Stephen Baylin, M.D., of Johns Hopkins University and Van Andel Institute. Baylin also serves as co-leader of the VAI-SU2C Epigenetics Dream Team and is an author on today's study. The study's first authors are Alison A. Chomiak, Ph.D., and Rochelle L. Tiedemann, Ph.D., of VAI. Other authors include Yanqing Liu, M.D., Ashley K. Wiseman, M.S., and Kate E. Thurlow, M.Sc., of VAI; Xiangqian Kong, Ph.D., Ying Cui, Ph.D., and Michael E. Topper, Ph.D., of Johns Hopkins University; and Evan M. Cornett, Ph.D., of Indiana University.

本文为转化医学网原创，转载请注明出处 作者：Rainbow 导读： 目前用于乳腺癌的传统治疗方法，包括免疫检查点阻断，在某些癌症中表现出有限的效果，特别是三阴性乳腺癌。表观遗传改变，特别是DNMT和HDAC的改变，与乳腺癌的发病机制有关。 3月15日，深圳大学研究团队在期刊《Cell Death Discovery》上在线发表题为“Dual inhibitors of DNMT and HDAC induce viral mimicry to induce antitumour immunity in breast cancer”的研究论文，研究结果表明， 15a作为一种新型有效的DNMTs和HDACs双重抑制剂具有巨大的潜力，并提高了乳腺癌体内模型的生存率。这种效应至少部分归因于病毒模拟反应的诱导。因此，15a代表了一种有前景的候选药物，用于安全有效地靶向癌症，从而为治疗各种预后不良的人类肿瘤开辟了途径。 https://www.nature.com/articles/s41420-024-01895-7 研究背景 01 尽管乳腺癌的早期检测和治疗取得了显著进展，但该疾病的异质性和侵袭性使得检测和治疗具有挑战性。因此，乳腺癌仍然是女性癌症相关死亡的主要原因，仅次于肺癌。免疫检查点阻断（ICB）疗法的采用虽然在治疗黑色素瘤和肺癌方面已经取得了早期成功，但进展相对缓慢。 因此，开发创新策略和治疗方法以提高患者的存活率至关重要。 在2022年最近发现的肿瘤特征中，非突变表观遗传重编程已经成为一种新颖特征。癌症是一种复杂的疾病，涉及遗传和表观遗传改变。表观遗传机制对癌症生物学的多个方面产生重要影响，包括促进原发肿瘤生长和侵袭，以及调节肿瘤微环境内的免疫应答。这些机制涉及DNA甲基化和组蛋白修饰之间的复杂相互作用。 在参与表观遗传调控的各类酶中，DNA甲基转移酶（DNMT）和组蛋白去乙酰化酶（HDAC）尤为重要。 事实上，已经开发出靶向药物，如DNMT抑制剂地西他滨和HDAC抑制剂伏立诺他（SAHA），以特异性靶向这些酶。 研究发现 02 研究人员证明了DNMT 和 HDAC 在乳腺癌中过表达和正相关。DNMT和HDAC抑制剂的联合应用显示出协同的抗肿瘤效果，而研究人员先前设计的双重DNMT和HDAC抑制剂（称为DNMT/HDACi）15a在体内外能够有效抑制乳腺癌细胞的增殖、迁移和侵袭，并诱导凋亡。机制上，15a通过促进乳腺癌细胞内源逆转录病毒元件的表达诱导病毒模拟反应，从而增加细胞内双链RNA水平以激活RIG-I-MAVS通路。这进而促进干扰素和趋化因子的产生，并增强干扰素刺激基因和PD-L1的表达。15a与抗PD-L1抗体的联合在体内具有累加效应。 这些发现表明，这种DNMT/HDACi具有免疫调节功能，并增强了免疫检查点阻断治疗的有效性。 研究结论 03 综上所述，研究结果表明， 15a作为一种新型有效的DNMTs和HDACs双重抑制剂具有巨大的潜力，并提高了乳腺癌体内模型的生存率。这种效应至少部分归因于病毒模拟反应的诱导。因此，15a代表了一种有前景的候选药物，用于安全有效地靶向癌症，从而为治疗各种预后不良的人类肿瘤开辟了途径。 参考资料： https://www.nature.com/articles/s41420-024-01895-7 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。 热门·直播/活动 🕓 上海｜06月14日-16日 ▶ 第六届上海国际癌症大会将于6月14-16日在上海举办，学科交叉，共同推进肿瘤研究与诊治多模态！ 🕓 北京｜09月20日-21日 ▶ 第五届单细胞技术应用研讨会暨空间组学前沿研讨会欢迎您的参与！ 点击对应文字 查看详情

DUBLIN--( BUSINESS WIRE )--The "Epigenetic Therapeutics: Global Markets" report has been added to ResearchAndMarkets.com's offering. The global epigenetic therapeutics market was valued at $6.4 billion in 2022. The market is expected to reach $9.8 billion by 2028, growing at a compound annual growth rate (CAGR) of 7.7% over the forecast period. Growth factors include aging populations, increased frequency of cancer risk associated with aging and increased prevalence of cancers cases such as acute-T-cell leukemia, breast cancer, ovarian cancer, Non-Small-Cell lung cancers. Epigenetic drug therapy serves as an ultimate treatment option when a cancer patient is not responding to the conventional therapies such as chemotherapy. Technological innovations in epigenetic drug discovery and development are driving increased use of epigenetic therapeutics, which also is pushing market growth. However, loss of exclusivity in the case of a few branded drugs and the entry of generic drugs into the market is the restraining the growth of this market. In 2022, the PRAP inhibitors segment held the largest share of the global market for epigenetic therapeutics, with 51.7% of the market, followed by Kinase inhibitors (37.5%), HDAC inhibitors (5.8%), IDH inhibitors (2.8%), DNMT inhibitors (1.9%) and KMT inhibitors (0.2%). Report Scope This report is a comprehensive study of the global market for epigenetic therapeutics. It describes the epigenetic therapeutics market, which is segmented by product type and region. Based on product type, the market is segmented into PRAP inhibitors, Kinase inhibitors, IDH inhibitors, HDAC inhibitors, DNMT inhibitors and KMT inhibitors. The market is segmented by region into North America, Latin America, Europe, Asia-Pacific, and the Rest of the World (RoW). This report examines the factors driving growth in the epigenetic drugs market, and it reviews major players, established companies and new entrants. The report, however, does not cover epigenetic diagnostic assays and instruments. The report includes: 77 tables A comprehensive overview of the global markets for epigenetic therapeutics Analyses of the global market trends with historical market revenue data (sales figures) for 2020-2022, estimates for 2023, and projections of compound annual growth rates (CAGRs) through 2028 Understanding of the upcoming market potential for epigenetic therapeutics with an emphasis on new products and technologies, and areas of focus to forecast this market into various segments and sub-segments Estimation of the actual market size and revenue forecast for the global epigenetic therapeutics market, and corresponding market share analysis product type and region In-depth information (facts and figures) concerning major market dynamics (DROs), technology advancements, new products and applications in epigenomics, and COVID-19 impact on the industry Coverage of the technological, economic, and business considerations of the market for epigenetic therapeutics, with analyses and growth forecasts through 2028 A look at the recent breakthrough innovations, key technological issues, market regulations, and current status on the intellectual property rights on epigenetic therapeutics Review of patent trends and research publications for innovations in the genome-editing technologies Insight into the recent industry structure, government regulations and policies, development issues, and the vendor landscape Analysis of the competitive environment and market opportunities based on the company's business strategies, product mapping, and operational integration Descriptive company profiles of the leading pharma corporations, including AstraZeneca, Bristol-Myers Squibb, GSK, Ipsen, Seagen, and Incyte Key Attributes Key Topics Covered Chapter 1 Introduction Study Goals and Objectives Reasons for Doing this Study Scope of Report Methodology Information Sources Geographic Breakdown Chapter 2 Summary and Highlights Highlights of the Market for Epigenetic Therapeutics Chapter 3 Market Overview and Definitions Overview Epigenetics Chapter 4 Market Trends Market Drivers Aging Population Risk of Cancer in Major Countries Penetration of Targeted Medicine in Emerging Markets Market Opportunity Market Restraints Chapter 5 Market Breakdown by Product Type Introduction PRAP Inhibitors Kinase Inhibitors IDH Inhibitors HDAC Inhibitors DNMT Inhibitors KMT Inhibitors Chapter 6 Impact of COVID-19 Introduction Impact of COVID-19 on the Medical Devices and Pharmaceutical Industries Decline/Delay in Elective Procedures Impact of COVID-19 on Medical Device and Pharmaceutical Product Segments Impact of COVID-19 on Epigenetic Therapeutics Markets Chapter 7 Market Breakdown by Region Market Overview and Discussion North America Latin America Europe Asia-Pacific Rest of the World Chapter 8 Emerging/Upcoming Technologies CRISPR Antibody Drug Conjugates Multitargeting Agents Chapter 9 Competitive Landscape Industry Scenario Company Shares Chapter 10 Patent Analysis Patent Analysis, by Manufacturer Chapter 11 Pipeline Analysis Clinical Trials Scenario Chapter 12 Company Profiles AstraZeneca Bristol-Myers Squibb Clovis Oncology GSK PLC Incyte Ipsen Seagen Servier Laboratories, Ltd. For more information about this report visit https://www.researchandmarkets.com/r/kdiz64 About ResearchAndMarkets.com ResearchAndMarkets.com is the world's leading source for international market research reports and market data. We provide you with the latest data on international and regional markets, key industries, the top companies, new products and the latest trends.