Targeting TERT in Melanoma

靶向黑色素瘤中的 TERT

基本信息

批准号：
10247101
负责人：
Jessie Villanueva
金额：
$ 4.9万
依托单位：
WISTAR INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-07 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10247101
关键词：
Address Affect Apoptosis Automobile Driving BRAF gene Biological Assay Cell Death Cells Clinical Combined Modality Therapy Complement Data Dependence Disease Disease Progression Down-Regulation Drug resistance Ectopic Expression Effectiveness Exhibits Frequencies Genes Genetic Goals Heat-Shock Proteins 90 Immune checkpoint inhibitor Immunotherapy Impairment Incidence Knowledge Length MEK inhibition MEKs Malignant Neoplasms Melanoma Cell Metabolism Metastatic Melanoma Metastatic to Mitochondria Mitogen-Activated Protein Kinase Inhibitor Modeling Molecular Molecular Target Mutate Mutation Neoplasm Metastasis Oncogenes Outcome Pathway interactions Patients Pharmaceutical Preparations Pharmacology Play Promoter Regions Proteins Public Health RNA-Directed DNA Polymerase Recurrent disease Research Resistance Resistance development Resources Role Survival Rate T-Lymphocyte TERT gene Telomerase Telomerase Inhibitor Therapeutic United States Work Xenograft Model Xenograft procedure addiction anti-PD1 antibodies base cancer therapy cytotoxic design effective therapy experience improved improved outcome inhibitor/antagonist kinase inhibitor melanoma migration mitochondrial metabolism mouse model mutant novel novel therapeutic intervention novel therapeutics nucleoside analog outcome forecast patient subsets pre-clinical prevent promoter response small molecule inhibitor targeted treatment telomere therapy resistant treatment response tumor

项目摘要

Project Summary Melanoma is a devastating disease, with five-year survival rates for metastatic disease under 15%. Exciting new therapies have emerged for BRAF-mutant melanoma, but NRAS mutant melanoma continues to have poor prognosis and limited therapeutic options. Even with the newest targeted- and immuno-therapies, a large percent of patients does not benefit and/or experience disease progression. In particular, the ~30% of melanoma patients whose tumors have mutations in the NRAS oncogene, and those who become re- sistant to current therapies, have limited treatment options and poor prognosis. Developing effective thera- pies for NRAS mutant melanoma and overcoming resistance to BRAF/MEK inhibition is of utmost im- portance in melanoma. Identifying vulnerabilities in NRAS-driven melanomas is critical to design effective treatments for this class of tumors, as there are currently no drugs to directly inhibit mutant NRAS. Mutations in the TERT promoter, (the catalytic subunit of Telomerase) are found in approximately 70% of melanomas, constituting the most frequent genetic alteration in this cancer. Preliminary studies by our team indicate that melanomas are highly addicted to TERT, as depletion or inhibition of TERT causes striking and rapid apoptosis. These data support the hypothesis that TERT plays a critical role in melanoma and constitutes a compelling tar- get for therapy. The goal of this proposal is to establish the efficacy of targeting TERT in melanoma, alone and in combination with other promising therapies. A corollary of this goal is to dissect the contribution of TERT to melanoma survival and progression. In Aim 1, we propose to systematically dissect the contribu- tion of TERT’s telomere-dependent and -independent roles for melanoma progression and survival, with particular focus on NRAS-mutant melanoma, which is in urgent need of new therapies. To date no group has systematically explored TERT inhibition in melanoma pre-clinical and patient-derived xenograft models, particularly in combination with other therapies. In Aim 2 we will address this gap in knowledge by as- sessing the efficacy of combining novel TERT-based approaches with promising anti-melanoma therapies, including inhibitors of mitochondrial metabolism and immunotherapies. We expect that the proposed work will enable us to: i) Mechanistically determine the contribution of telomere-dependent and telomere- independent functions of TERT in melanoma;; ii) Develop novel combination strategies for NRAS mutant melanoma and melanomas resistant to therapy;; iii) Provide actionable information that will guide the design of novel, TERT-based combination therapies aimed at preventing and overcoming drug resistance, and en- hancing the durability of responses and survival benefits for melanoma patients. Additionally, we expect that our studies will pave the way for novel treatments for other cancers with TERT and/or RAS mutations, heightening the potential impact of our proposal.

项目概要黑色素瘤是一种毁灭性的疾病，转移性疾病的五年生存率低于 15%，令人兴奋。针对 BRAF 突变黑色素瘤的新疗法已经出现，但 NRAS 突变黑色素瘤仍然存在即使采用最新的靶向和免疫疗法，预后也很差，治疗选择也有限。很大一部分患者没有受益和/或经历疾病进展，特别是约 30%。肿瘤中 NRAS 癌基因发生突变的黑色素瘤患者，以及那些患有复发性黑色素瘤的患者目前的治疗方法有效，治疗选择有限且预后较差。对于 NRAS 突变黑色素瘤来说，克服对 BRAF/MEK 抑制的耐药性具有最大的意义。在黑色素瘤中的重要性。识别 NRAS 驱动的黑色素瘤的脆弱性对于设计此类黑色素瘤的有效治疗方法至关重要肿瘤，因为目前没有药物可以直接抑制突变的 NRAS TERT 启动子，（端粒酶的催化亚基）存在于大约 70% 的黑色素瘤中，占大多数。我们团队的初步研究表明，这种癌症中存在频繁的基因改变。对 TERT 高度依赖，因为 TERT 的消耗或抑制会导致显着且快速的细胞凋亡。支持这样的假设：TERT 在黑色素瘤中发挥着关键作用，并构成了令人信服的目标。该提案的目标是确定单独针对黑色素瘤的 TERT 治疗的效率。并与其他有前景的疗法相结合。这一目标的必然结果是剖析以下方面的贡献： TERT 对黑色素瘤存活和进展的影响。在目标 1 中，我们建议系统地剖析 TERT 对黑色素瘤进展和生存的依赖和独立作用特别关注 NRAS 突变黑色素瘤，迄今为止尚无迫切需要新疗法的研究。系统地探索了黑色素瘤临床前和患者来源的异种移植模型中的 TERT 抑制，特别是与其他疗法相结合，我们将通过以下方式解决这一知识差距：评估基于 TERT 的新型方法与有前景的抗黑色素瘤疗法相结合的效率，包括线粒体代谢抑制剂和免疫疗法。我们预计所提议的工作。将使我们能够： i) 机械地确定端粒依赖和端粒-的贡献 TERT 在黑色素瘤中的独立功能；；ii) 针对 NRAS 突变体开发新的组合策略黑色素瘤和对治疗有抵抗力的黑色素瘤； iii) 提供可指导设计的可操作信息旨在预防和克服耐药性的新型基于 TERT 的联合疗法，以及此外，我们期望提高黑色素瘤患者的反应持久性和生存效益。我们的研究将为其他具有 TERT 和/或 RAS 突变的癌症的新疗法铺平道路，增强我们提案的潜在影响。