Targeted Therapies in Melanoma

黑色素瘤的靶向治疗

基本信息

批准号：
8554403
负责人：
Meenhard F Herlyn
金额：
$ 256.73万
依托单位：
WISTAR INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-16 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8554403
关键词：
Accounting Active Sites Address Aging Apoptosis Area Autophagocytosis BRAF gene Biological Biology Cell Death Cells Chemistry Clinic Clinical Clinical Trials Collection Data Digestion Disease Distal Drug resistance FDA approved Fostering Funding Future Generations Genes Genetic Goals Growth Factor Heat shock proteins Heat-Shock Proteins 70 Intrinsic drive Knowledge Lead Learning Link MAP Kinase Gene Mediating Melanoma Cell Modeling Modification Mutation Necrosis Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Phosphotransferases Positioning Attribute Process Property Proteins Research Resistance STAT3 gene Series Signal Pathway Signal Transduction Specificity Stress Structural Biologist Technology Time Transactivation Translating advanced disease anticancer research base cancer cell cancer therapy chemotherapy design dimer experience high throughput screening improved inhibition of autophagy inhibitor/antagonist killings melanoma mutant neoplastic cell novel novel therapeutics prevent programs senescence tumor tumor microenvironment

项目摘要

The long-term goal of this P01 is to promote research to better understand the biology of melanomas and to translate this research to better therapies with the ultimate goal of achieving cures. Our overarching hypothesis is that intrinsic resistance to signaling inhibitors can be overcome if we take into account the genetic signatures of melanoma cells and the biological properties that are driven by intrinsic and extrinsic signals. For this competitive renewal, we will shift our focus away from the traditional targeting of kinase active sites that control canonical growth factor signaling. To achieve our goals we have developed three overarching aims, which require close coordination of projects and cores: In Aim 1 we will define cell fates for therapy of melanoma. While cell death due to apoptosis or necrosis is widely regarded to be the ultimate goal of any cancer therapy, in melanoma we now take into account two additional cell states that emerging data indicate are critical: autophagy (Projects 2 and 3) and senescence (Project 1). Our goal is to block cells from entering dormant survival states such as quiescence or pseudo-senescence and force them to die as a result of apoptosis or necrosis. In Aim 2, we will investigate the mechanism of action of signaling inhibitors. Project 4 will generate a series of novel targeted inhibitors to prevent dimer formatio of BRAF or CRAF and investigate a novel STAT3 inhibitor that resulted from recent screens. Under this aim we will combine the expertise of chemists, structural biologists and cell biologists to develop a new generation of compounds that promise a major impact on melanoma therapy in the future. In Aim 3, we will develop combination strategies for melanoma therapy. Since melanomas evolve through genetic alterations of multiple driver genes and are highly responsive to signals from the tumor microenvironment, the field has learned that single agents cannot cure by killing all malignant cells. In each project we will explore synergy among signaling inhibitor therapies using unique models for selection. The Cores for this P01 are essential for our progress in the coming funding cycle. To account for the increased needs for compound synthesis and modification, we have added a Medicinal Chemistry Core (D) in this renewal application.

该 P01 的长期目标是促进研究以更好地了解黑色素瘤的生物学，并将该研究转化为更好的疗法，最终目标是实现治愈。我们的总体假设是，如果我们考虑到黑色素瘤细胞的遗传特征以及由内在和外在信号驱动的生物特性，那么对信号抑制剂的内在抵抗就可以被克服。对于这种竞争性更新，我们将把重点从传统的激酶靶向转移控制典型生长因子信号传导的活性位点。为了实现我们的目标，我们制定了三个总体目标，这需要项目和核心的密切协调：在目标 1 中，我们将定义黑色素瘤治疗的细胞命运。虽然细胞凋亡或坏死导致的细胞死亡被广泛认为是任何癌症治疗的最终目标，但在黑色素瘤中，我们现在考虑新出现的数据表明至关重要的另外两种细胞状态：自噬（项目 2 和 3）和衰老（项目1).我们的目标是阻止细胞进入休眠或假衰老等休眠生存状态，并迫使它们因细胞凋亡或坏死而死亡。在目标 2 中，我们将研究信号抑制剂的作用机制。项目 4 将产生一系列新型靶向抑制剂，以防止 BRAF 或 CRAF 二聚体形成，并研究最近筛选的新型 STAT3 抑制剂。在此目标下，我们将结合化学家、结构生物学家和细胞生物学家的专业知识开发新一代化合物，有望对未来黑色素瘤治疗产生重大影响。在目标 3 中，我们将开发黑色素瘤治疗的组合策略。由于黑色素瘤是通过多个驱动基因的遗传改变而进化的，并且对来自肿瘤微环境的信号高度敏感，该领域已经认识到单一药物无法通过杀死所有恶性细胞来治愈。在每个项目中，我们将使用独特的模型进行选择，探索信号抑制剂疗法之间的协同作用。 P01 的核心对于我们在下一个融资周期中取得进展至关重要。为了满足化合物合成和修饰日益增长的需求，我们在此更新应用程序中添加了药物化学核心 (D)。