Targeting Oncogenic BRAF And PI3'-Kinase Signaling For Melanoma Therapy

针对黑色素瘤治疗的致癌 BRAF 和 PI3-激酶信号传导

基本信息

批准号：
8636419
负责人：
MARTIN MCMAHON
金额：
$ 35.35万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8636419
关键词：
1-Phosphatidylinositol 3-Kinase Adverse effects Alleles Apoptosis BRAF gene Behavior Biochemistry Biology CDKN2A gene Cell Cycle Cell Line Cell Proliferation Cells Cessation of life Characteristics Clinic Clinical Collaborations Collection Combined Modality Therapy Complement Coupled Cytostatics Development Disease Disease Resistance Disease remission Drug resistance Epidemiology Extracellular Signal Regulated Kinases Foundations Genetic Genetically Engineered Mouse Goals HRAS gene Health Human Incidence Individual Knowledge Life MAP Kinase Signaling Pathways MEKs Maintenance Malignant Neoplasms Medicine Melanoma Cell Metastatic Melanoma Modification Molecular Mus Mutate Mutation Neoplasm Metastasis Neoplasms Oncogene Proteins Oncogenes Oncogenic PTEN gene Pathway interactions Patients Pharmaceutical Preparations Phase III Clinical Trials Physicians Point Mutation Protein Biosynthesis Protein Kinase Proto-Oncogene Proteins c-akt Proto-Oncogenes Quality of life Regimen Relapse Research Resources Role Scientist Signal Pathway Signal Transduction Skin Neoplasms Specimen System Testing Therapeutic Tissues Tumor Suppressor Proteins Ursidae Family Work base cancer diagnosis clinically relevant design genetic analysis genetic inhibitor human disease inhibitor/antagonist insight melanocyte melanoma mouse model pre-clinical protein expression public health relevance response sobriety success tool treatment strategy tumor tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Melanoma is noted for its alarming increase in incidence, especially amongst the young, aggressive clinical behavior and propensity for lethal metastasis, illustrating an urgent need for new treatment strategies for this disease. Despite the bleak clinical and epidemiological picture, genetic analysis has uncovered key driver oncogenes in melanoma such as mutationally activated BRAF. Indeed, when the BRAFV600E oncoprotein is pharmacologically inhibited with vemurafenib, BRAF mutated melanoma patients, even those with widely disseminated, metastatic disease, have enjoyed dramatic tumor regression coupled with significant health improvement. However, since not all BRAF mutated melanoma patients respond to vemurafenib and, those that do, generally relapse with lethal drug resistant disease, the paradigm of melanoma therapy is evolving towards rationally-targeted combinations of pathway-targeted inhibitors acting against BRAFV600E and cooperating signaling modules such as the PI3'-kinase->AKT pathway. Indeed, despite vemurafenib's clinical success and our growing scientific knowledge of the melanoma cell's inner workings, the challenge remains how best to employ BRAF inhibitors for melanoma therapy to: 1. Maximize therapeutic benefit; 2. Minimize emergence of lethal drug resistant disease; and; 3. Mitigate potentially harmful side effects. Consequently, the long-term, overarching goal of this research is to design BRAF inhibitor-based combination therapies that enhance the overall response rate and the depth of each patient's primary anti-tumor response and extend indefinitely the duration of remission of patients with BRAF mutated melanoma in collaboration with colleagues in the UCSF Melanoma Clinic. Towards these goals, the short-term aims of this proposal are to employ state-of-the-art genetically engineered mouse (GEM) models, bona fide human melanoma cells and a portfolio of clinically relevant pathway-targeted inhibitors to elucidate the molecular mechanism(s) of BRAFV600E/PI3'- kinase pathway cooperation in melanomagenesis and the consequences of combined pathway-targeted blockade in the pre-clinical setting. In Aim 1, GEM models will be used to probe the importance of PI3'- kinase->AKT signaling in cooperating with oncogenic BRAFV600E in converting normal melanocytes to metastatic melanoma cells. In Aim 2 the superiority of combined versus single agent inhibition of BRAFV600E or PI3'-kinase in promoting tumor regression will be evaluated using GEM models of BRAFV600E-initiated melanoma. To complement analysis of mouse melanoma specimens in Aim 2, a panel of bona fide human BRAFV600E expressing melanoma cell lines will be employed in Aim 3 to elucidate molecular mechanism(s) by which BRAFV600E cooperates with PI3'-kinase->AKT signaling in regulating the melanoma cell division cycle and/or apoptosis through effects on protein synthesis. When completed, these studies will provide the mechanistic foundation for the development of robust and rational, pathway-targeted combination therapeutic strategies to increase both the quantity and quality of life of patients with BRAF mutated melanoma.

描述（由申请人提供）：黑色素瘤因其令人震惊的发病率增加而闻名，尤其是在年轻的，激进的临床行为和致命转移的倾向中，这表明迫切需要对这种疾病的新治疗策略。尽管临床和流行病学表现黯淡，但遗传分析仍发现了黑色素瘤中的主要驱动因素，例如突变活化的BRAF。实际上，当BraFV600E癌蛋白被药理抑制与vemurafenib抑制时，BRAF突变的黑色素瘤患者，即使患有广泛传播的转移性疾病的患者也享有巨大的肿瘤回归，并具有显着的健康改善。但是，由于并非所有BRAF突变的黑色素瘤患者都对vemurafenib做出反应，并且那些通常会因耐致命的耐药性疾病复发的患者，所以黑色素瘤治疗的范式正在发展朝着靶向涉及途径靶向brafV600E和合作信号传播模态的途径抑制剂的途径抑制剂的靶向组合的范式发展。的确，尽管vemurafenib的临床成功以及我们对黑色素瘤细胞内部起作用的不断增长的科学知识，但挑战仍然是如何最好地利用BRAF抑制剂进行黑色素瘤疗法的挑战：1。最大化治疗益处； 2。最小化致命药物疾病的出现；和; 3。减轻潜在有害的副作用。因此，这项研究的长期总体目标是设计基于BRAF抑制剂的组合疗法，以提高每个患者的主要反应率和深度，并无限期地扩展BRAF突变性突变性黑色素瘤患者在与UCSF Melanoma临床中的同事中的缓解持续时间。朝向这些目标，该提案的短期目的是采用最先进的基因工程鼠标（GEM）模型，真正的人类黑色素瘤细胞和临床相关途径针对途径的抑制剂的组合来阐明BRAFV600E/PI3'-KINASE PATHWAINCON的分子机制（S）在临床前环境中。在AIM 1中，将使用GEM模型来探测PI3'-激酶 - > Akt信号传导与致癌性BRAFV600E合作的重要性，以将正常黑色素细胞转化为转移性黑色素瘤细胞。在AIM 2中，将使用BRAFV600E引发的黑色素瘤的GEM模型评估BRAFV600E或PI3'-激酶在促进肿瘤回归中的联合与单药抑制的优势。为了补充AIM 2中小鼠黑色素瘤样品的补体分析，将采用一组真正的人Brafv600E表达黑色素瘤细胞系的AIM 3，以阐明BRAFV600E与PI3'-Kinase-> Akt> AKT信号的brafV600E通过该机制进行调节，从而调节黑色素瘤细胞分裂和APOPTESISS的效果。完成后，这些研究将为稳健和理性，途径靶向的组合治疗策略的发展提供机械基础，以增加BRAF突变性黑色素瘤患者的生活数量和质量。