Synergistic Targeting of the MAP Kinase Pathway in Melanoma

黑色素瘤中 MAP 激酶通路的协同靶向

• 批准号: 8759675
• 负责人: Ronen Marmorstein
• 金额: $ 40.19万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-16 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8759675
• 关键词: Accounting; Autophagocytosis; BRAF gene; Binding; Biological; Biological Assay; Cancer Etiology; Cell Line; Cells; Clinic; Development; Dimerization; Drug resistance; Evaluation; Family; Feedback; Genotype; Goals; Heat-Shock Proteins 70; Human; In Vitro; Lead; Link; MAP Kinase Gene; MEK inhibition; Malignant Neoplasms; Melanoma Cell; Mitogen-Activated Protein Kinases; Modeling; Mutation; Naphthols; Normal tissue morphology; Pathway interactions; Patients; Pharmaceutical Chemistry; Phosphotransferases; Property; Proto-Oncogene Proteins B-raf; Resistance; Role; STAT3 gene; Signal Pathway; Signal Transduction; Stress Response Signaling; Structure; Testing; Therapeutic; base; biological adaptation to stress; chemotherapy; clinical efficacy; design; dimer; high throughput screening; in vitro Assay; in vitro activity; in vivo; inhibitor/antagonist; killings; melanoma; mimetics; mutant; neoplastic cell; novel; novel strategies; novel therapeutics; overexpression; pre-clinical; prevent; resistance mechanism; response; small molecule; src Homology Region 2 Domain; tool; tumor

The overall goal of project 4 is to develop novel approaches distinct from ATP mimetics to overcome resistance to BRAF inhibitors for treatment of melanoma. This project will focus on two mechanisms of resistance; BRAF dimerization leading to paradoxical MAPK activation and STATS activation which is downstream of a number of parallel signaling pathways that are activated in BRAF inhibitor resistant cells as well as in BRAF^'"^ cells. We will also determine if combination of BRAF inhibitors with the inhibition of broad cellular biological properties that sustain survival of resistant tumor cells, specifically the stress response or autophagy, can kill melanomas and prevent the emergence of drug resistance. Together, we hypothesize that targeting these pathways will overcome therapeutic resistance in a large subset of BRAF mutant melanomas, and possibly other melanoma genotypes. The Specific Aims of the proposal are to (1) Develop inhibitors that selectively target RAF dimers. Since BRAF inhibition can lead to paradoxical MAPK activation through RAF dimers in both normal tissues and in resistant melanoma tumors, we hypothesize that targeting RAF dimers will be more effective for melanoma therapy than targeting monomeric mutant BRAF. We will employ two complementary inhibitor design strategies to target RAF dimers and evaluate the biological activity of the resulting inhibitors. (2) Develop novel STAT3 inhibitors. STATS is activated in a high proportion of melanomas and is upregulated in response to BRAF and MEK inhibition. In preliminary studies, we have developed a family of quinolol/naphthol compounds that are low-micromolar inhibitors of STATS activation through the apparent binding to the SH2 phospho-binding domain of STATS. We will now use structure-based design and medicinal chemistry to prepare more potent and selective inhibitors and evaluate the biological activity of inhibitors alone and in combination with BRAF inhibitors. (3) Determine if combination of BRAF inhibitors with HSP70 or autophagy antagonists can kill melanomas and prevent the emergence of drug resistance. HSP70 is overexpressed in BRAF mutant melanoma and HSP70 inhibitors have shown promising pre-clinical efficacy in melanoma. High autophagy levels are also common in melanoma and correlate with poor response to chemotherapy and shortened overall survival; and BRAF inhibitors can induce autophagy as a survival mechanism. We hypothesize that dual inhibition of BRAF and HSP70 or autophagy will be an effective therapeutic strategy for melanoma. Together, we anticipate that these studies will provide novel and attractive avenues to overcome resistance to BRAF inhibition in melanoma in order to provide effective long-lasting therapies for melanoma patients.

项目4的总体目标是开发不同于ATP模拟物的新方法，以克服 用于治疗黑素瘤的BRAF抑制剂的抗性。该项目将侧重于两种机制， BRAF二聚化导致矛盾的MAPK激活和STATS激活， 在BRAF抑制剂抗性细胞中激活的许多平行信号传导途径的下游 以及BRAF细胞中。我们还将确定BRAF抑制剂与抑制 广泛的细胞生物学特性，维持耐药肿瘤细胞的存活，特别是应激 反应或自噬，可以杀死黑色素瘤，并防止耐药性的出现。一起我们 假设靶向这些通路将克服BRAF大亚群中的治疗抗性， 突变型黑色素瘤和可能的其他黑色素瘤基因型。该提案的具体目标是：（1） 开发选择性靶向RAF二聚体的抑制剂。由于BRAF抑制可以导致矛盾的MAPK 在正常组织和耐药黑色素瘤肿瘤中，我们假设 靶向RAF二聚体将比靶向单体突变体更有效地用于黑色素瘤治疗， BRAF。我们将采用两种互补的抑制剂设计策略来靶向RAF二聚体，并评估 所得抑制剂的生物活性。(2)开发新型STAT 3抑制剂。STATS在一个 高比例的黑色素瘤，并且响应于BRAF和MEK抑制而上调。初步 研究，我们已经开发了一个家庭的喹啉/萘酚化合物，是低微摩尔抑制剂， 通过与STATS的SH 2磷酸结合结构域的表观结合来激活STATS。我们现在将 使用基于结构的设计和药物化学来制备更有效和选择性的抑制剂， 评价单独的抑制剂和与BRAF抑制剂组合的抑制剂的生物活性。(3)确定是否 BRAF抑制剂与HSP 70或自噬拮抗剂的组合可以杀死黑色素瘤并防止黑色素瘤的发生。 耐药性的出现。HSP 70在BRAF突变型黑色素瘤中过表达和HSP 70抑制剂 在黑色素瘤中显示出有希望的临床前疗效。高自噬水平也很常见， 黑色素瘤，与化疗反应差和总生存期缩短相关; 抑制剂可以诱导作为存活机制的自噬。我们假设BRAF和 HSP 70或自噬将成为黑色素瘤的有效治疗策略。我们共同预计， 这些研究将提供新的和有吸引力的途径来克服对BRAF抑制的抗性， 黑色素瘤，以便为黑色素瘤患者提供有效的持久疗法。