Efficacy of combined inhibition of BRAF, MEK, and FAK in melanoma patient derived xenografts

BRAF、MEK 和 FAK 联合抑制对黑色素瘤患者来源的异种移植物的功效

• 批准号: 10326693
• 负责人: Sheri L Holmen
• 金额: $ 12.5万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-13 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10326693
• 关键词: AKT Signaling Pathway; AKT inhibition; AKT1 gene; Address; BRAF gene; Biological Models; Brain; CDKN2A gene; Cessation of life; Clinical Management; Clinical Trials; Collaborations; Collection; Data; Development; Diagnosis; Disease; Disease Resistance; Distant; Drug resistance; FDA approved; Fertilization; Focal Adhesion Kinase 1; Focal Adhesions; Funding; Gene Combinations; Gene Delivery; Genomics; Goals; Growth; Histologic; Human; Implant; Incidence; Knowledge; MEKs; Malignant Neoplasms; Mediator of activation protein; Melanoma Cell; Metastatic Melanoma; Metastatic Neoplasm to the Lung; Metastatic malignant neoplasm to brain; Modeling; Mus; Neoplasm Metastasis; Nonmetastatic; Organ; PTEN gene; PTK2 gene; Pathway interactions; Patient-Focused Outcomes; Patients; Penetrance; Pharmacology; Pre-Clinical Model; Principal Investigator; Process; Prognosis; Proteomics; Proto-Oncogene Proteins c-akt; Research; Research Personnel; Resistance; Risk; Sampling; Signal Transduction; Site; Skin Cancer; Testing; The Wistar Institute; Therapeutic; Time; Toxic effect; Translations; Treatment Failure; Universities; Utah; effective therapy; high risk; human data; human disease; improved; in vivo; inhibitor/antagonist; interest; melanocyte; melanoma; mouse model; mutant; next generation sequencing; novel; novel therapeutic intervention; novel therapeutics; patient derived xenograft model; postnatal; preclinical evaluation; prevent; programs; resistance mechanism; response; standard of care; subcutaneous; targeted treatment; therapeutic target; therapeutically effective; tumor

Summary “This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-21-009.” Significant advances in melanoma research have resulted in new therapies that have remarkably improved the management and overall survival of melanoma. However, many patients still succumb to the disease and more than half of all melanoma deaths are due to brain metastases. As a means to overcome this challenge, we developed a novel mouse model that allows postnatal delivery of genes of interest to melanocytes. Using genomic and proteomic data from human melanoma samples, we tested several gene combinations for their ability to induce metastatic melanoma in vivo. Hyperactivation of the PI3K/AKT pathway in the context of mutant BRAF and CDKN2A loss resulted in the development of spontaneous melanoma with full penetrance and a mean survival of only 6 weeks. The majority of these mice also developed multiple metastases to the lungs and brain. This model mimics the human disease genetically, histologically, and by sites of metastasis. Importantly, this model system provides a powerful platform to further study the mechanisms of melanoma metastasis. Elucidation of this network will allow the identification of key pathway nodes that represent potential therapeutic targets to disrupt this process. We used next generation sequencing and proteomics analysis of non-metastatic and metastatic tumor samples to identify downstream targets of AKT1 implicated in melanoma brain metastasis. Our data showed that tumors expressing activated AKT1 displayed elevated levels of focal adhesion (FA) factors and phosphorylated focal adhesion kinase (P-FAK). In addition, mutant AKT1 expression increased invasion and this was reduced by pharmacological inhibition of either AKT or FAK. Moreover, loss of PTEN, which also results in increased FAK activity, cooperated with activated AKT1 to further enhance brain metastasis in vivo. Despite these promising preliminary findings, a critical gap still remains in determining whether the AKT1-FAK-PTEN axis can be exploited as a therapeutic target in this disease. Our long-term goal is to use this knowledge to develop novel melanoma therapies and improve patient outcomes. Pursuant to this goal, we have formed a collaboration with Drs. Menhard Herlyn and Michael Davies, Principal Investigators of the U54-funded melanoma PDX program. This collaboration will bring together the melanoma PDX expertise of Drs. Herlyn and Davies with the AKT-FAK-PTEN signaling expertise of Dr. Holmen. Together, we will test the hypothesis that combined inhibition of BRAF, MEK, and FAK will inhibit the growth of primary melanoma as well as established brain metastases. Successful completion of the aims in this proposal will significantly impact the field by laying the groundwork for translation into clinical trials, leading to new and better treatments for patients with brain metastases and those who are at high risk of developing brain metastases.

概括 “本申请是为了响应特殊利益通知（NOSI）而提交的，该通知被确定为 NOT-CA-21-009。”黑色素瘤研究的重大进展带来了新的疗法 显着改善了黑色素瘤的治疗和总体生存率，但许多患者仍然死亡。 超过一半的黑色素瘤死亡是由于脑转移所致。 为了应对这一挑战，我们开发了一种新型小鼠模型，可以在出生后将感兴趣的基因传递给 使用人类黑色素瘤样本的基因组和蛋白质组数据，我们测试了几个基因。 其组合能够诱导体内 PI3K/AKT 通路过度激活。 突变型 BRAF 和 CDKN2A 缺失导致自发性黑色素瘤的发展 完全外显，平均存活期仅为 6 周。这些小鼠中的大多数还出现了多种症状。 该模型在遗传、组织学和部位上模拟了人类疾病。 重要的是，该模型系统为进一步研究转移机制提供了强大的平台。 阐明该网络将有助于识别关键通路节点。 我们使用了下一代测序 对非转移性和转移性肿瘤样本进行蛋白质组学分析，以确定 AKT1 的下游靶点 我们的数据显示，表达激活的 AKT1 的肿瘤与黑色素瘤脑转移有关。 此外，粘着斑 (FA) 因子和磷酸化粘着斑激酶 (P-FAK) 水平升高。 突变体 AKT1 表达增加侵袭，并且通过药理学抑制任一 AKT 来减少侵袭 此外，PTEN 的缺失也会导致 FAK 活性增加，并与激活的 AKT1 协同作用。 尽管有这些有希望的初步发现，但仍存在关键差距。 仍有待确定 AKT1-FAK-PTEN 轴是否可以用作该领域的治疗靶点 我们的长期目标是利用这些知识开发新的黑色素瘤疗法并改善患者的病情。 为了实现这一目标，我们与 Menhard Herlyn 和 Michael Davies 博士建立了合作关系。 U54 资助的黑色素瘤 PDX 项目的主要研究人员将聚集在一起。 Herlyn 和 Davies 博士的黑色素瘤 PDX 专业知识与 Holmen 博士的 AKT-FAK-PTEN 信号传导专业知识。 我们将一起检验以下假设：联合抑制 BRAF、MEK 和 FAK 将抑制 原发性黑色素瘤以及已确定的脑转移瘤成功完成本提案中的目标。 将通过为转化为临床试验奠定基础来影响该领域，从而产生新的和 为脑转移患者和脑发育高风险患者提供更好的治疗 转移。