Microenvironment mediated drug resistance in melanoma.

微环境介导黑色素瘤耐药性。

基本信息

批准号：
8666540
负责人：
Keiran Smalley
金额：
$ 33.61万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8666540
关键词：
Address Adhesions Adoption Apoptosis BRAF gene Belief Blood Vessels Bypass Cell Line Cells Clinic Clinical Clinical Trials Coculture Techniques Collagen Data Deposition Drug resistance Effectiveness Endothelial Cells Environment Extracellular Matrix Fibroblasts Fibronectins Future Genotype Goals Growth Growth Factor Heterogeneity Human Integrins Knowledge Laminin Lead Life Ligands MEKs Mediating Melanoma Cell Minor Modeling Mutate PTEN gene Patients Phase Phenotype Platelet-Derived Growth Factor Population Proliferating Proto-Oncogene Proteins c-akt Relapse Research Resistance Role Series Signal Transduction Specimen Testing Therapeutic Vascular Endothelial Growth Factors Work Xenograft Model angiogenesis autocrine cell motility improved in vivo inhibitor/antagonist melanoma neoplastic cell notch protein novel novel therapeutics prevent research study resistance mechanism response small molecule therapeutic development therapeutic target tumor tumor eradication tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): The long-term goals of this work are the development of therapeutic strategies to improve the survival of patients with disseminated melanoma. There is already good evidence that mutated BRAF is a bona fide therapeutic target in over 50% of melanomas, and that impressive but short-lived clinical responses can be achieved with small molecule BRAF inhibitors (such as PLX4032). Clinically, BRAF inhibitor resistance follows a course where tumor regression is followed by quiescence and eventual relapse. The overall hypothesis is that BRAF inhibition remodels both the melanoma and host microenvironments to provide a protective "sanctuary" for the minor populations of melanoma cells that escape therapy. Conceptually, it is believed that there are at least two forms of environment-mediated therapeutic escape; the first, defined as "tumor intrinsic", was observed in melanoma cell lines that lack PTEN function (PTEN-) and involved the establishment of autocrine integrin/extracellular matrix (ECM) signaling loops that bypass BRAF signaling and downregulate apoptosis. The second was host-mediated, where BRAF inhibition in primary human fibroblasts paradoxically activated AKT and MEK signaling leading to the expression of PDGF-D, VEGF and the Notch ligand Jagged as well as increasing the deposition of fibronectin, collagens and laminin. The first aim will investigate how BRAF inhibition leads to the acquisition of autocrine ECM-driven signaling loops and will determine how these altered adhesion signals "re-wire" the signaling of the escaping population and leads to the adoption of a phenotype that is slow-proliferating, apoptosis resistant and pro-invasive. We will then test whether therapeutic targeting of the melanoma cell/ECM interactions ameliorates intrinsic resistance by preventing the microenvironment- mediated reorganization of the melanoma signaling network. In aim 2, we will test the hypothesis that BRAF inhibition activates host fibroblasts leading to the creation of a "refuge" vascular microenvironment that allows PTEN+ melanoma cells to escape from therapy. We will address how BRAF inhibition in normal host fibroblasts leads to the establishment of autocrine growth factor signaling loops that drives their activation. We will then use novel 3D melanoma/fibroblast/endothelial cell co-culture and in vivo xenograft models to investigate the mechanisms by which inhibition of BRAF in fibroblasts drives the angiogenic response and will elucidate the role of the vascular niche as a protective "sanctuary" for the escaping melanoma cells. It is expected that knowledge gained from this work will provide novel therapeutic strategies for overcoming BRAF inhibitor resistance in the clinic. 1

描述（由申请人提供）：这项工作的长期目标是发展治疗策略，以改善散布黑色素瘤患者的生存。已经有充分的证据表明，在超过50％的黑色素瘤中，突变的BRAF是一个真正的治疗靶标，并且可以使用小分子BRAF抑制剂（例如PLX4032）实现令人印象深刻但短暂的临床反应。在临床上，BRAF抑制剂耐药性遵循一门肿瘤回归的过程，然后静止和最终复发。总体假设是，BRAF抑制作用重塑了黑色素瘤和宿主微环境，为逃脱治疗的黑色素瘤细胞的少数种群提供了保护性的“避难所”。从概念上讲，人们认为至少有两种形式的环境介导的治疗逃生。在缺乏PTEN功能（PTEN-）的黑色素瘤细胞系中观察到了第一个定义为“肿瘤固有的”，涉及绕过BRAF信号传导和下调凋亡的自分泌素整合素/细胞外基质（ECM）信号环的建立。第二个是宿主介导的，其中BRAF在原代人成纤维细胞中抑制了矛盾活化的Akt和MEK信号传导，导致PDGF-D，VEGF和Notch配体的表达以及凹陷的凹痕并增加了纤连蛋白，胶原蛋白，胶原蛋白和laminin的沉积。第一个目的将调查BRAF抑制如何导致Autocrine ECM驱动的信号循环的获取，并将确定这些改变的粘附信号如何“重新连接”逃避人群的信号传导，并导致采用缓慢增强，凋亡耐药性和侵入性的表型。然后，我们将测试黑色素瘤细胞/ECM相互作用的治疗靶向是否通过防止微环境介导的黑色素瘤信号网络的重组来缓解内在抗性。在AIM 2中，我们将检验以下假设：BRAF抑制激活宿主成纤维细胞，从而产生“避难”的血管微环境，从而使PTEN+黑色素瘤细胞从治疗中逃脱。我们将解决正常宿主成纤维细胞中的BRAF抑制如何导致建立驱动其激活的自分泌生长因子信号循环。然后，我们将使用新颖的3D黑色素瘤/成纤维细胞/内皮细胞共培养和体内异种移植模型来研究BRAF在成纤维细胞中抑制BRAF的机制，并将驱动血管生成反应，并阐明血管造成的作用，以使血管造成为保护性“ Sancture”的作用。预计从这项工作中获得的知识将为克服诊所中BRAF抑制剂的耐药性提供新的治疗策略。 1