Developing therapeutic strategies for ERK-dependent tumors

开发 ERK 依赖性肿瘤的治疗策略

基本信息

批准号：
8741950
负责人：
NEAL ROSEN
金额：
$ 35.77万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
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：
2013-09-30 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8741950
关键词：
Address Aftercare Attenuated BRAF gene Biological Assay Cells Clinical Clinical Trials Clinical effectiveness Combined Modality Therapy Custom DNA Data Dependence Dimerization Disease Progression Dose Drug resistance Epigenetic Process Feedback Genes Genetic Genetically Engineered Mouse Goals Growth In Vitro KRAS2 gene Lesion MEKs Mediating Mediator of activation protein Methods Molecular Mutate Mutation Normal Cell Oncogenes Outcome Output Pathway interactions Patients Pharmaceutical Preparations Pre-Clinical Model RNA Sequences RNA Splicing Receptor Protein-Tyrosine Kinases Regimen Resistance Sampling Schedule Signal Pathway Signal Transduction Specimen Testing Therapeutic Therapeutic Index Time Tissues Toxic effect Treatment Protocols Work Xenograft Model base clinical effect clinical efficacy clinically relevant design dimer improved inhibitor/antagonist melanoma mouse model mutant neoplastic cell novel novel therapeutics prevent public health relevance receptor resistance mechanism response restoration therapy development tool transcriptome sequencing treatment strategy tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Tumors with mutant BRAF or mutant KRAS are dependent on ERK signaling and are sensitive to inhibitors of the pathway. Selective RAF, MEK and ERK inhibitor have now been developed as therapeutics for these tumors, however, their clinical efficacy is limited by toxicity, acquired resistance, and adaptive resistance due to relie of ERK-dependent feedback inhibition of mitogenic signaling. Our previous work shows that whereas MEK and ERK inhibitors suppress ERK signaling in all normal and tumor cells, RAF inhibitors only inhibit signaling in tumors with BRAF mutations and activate ERK signaling in other tissue. Thus, RAF inhibitors have a broader therapeutic index than MEK and ERK inhibitors, but only work in tumors with mutant BRAF. We have also shown that inhibition of ERK signaling by all of these inhibitors reactivates feedback inhibited signaling via RAF/ERK and non-RAF/ERK pathways and that this feedback activation limits the antitumor effects of RAF and MEK inhibitors. Our goals in this proposal are to develop therapies that maximally inhibit ERK output by combining RAF or MEK inhibitors with selective novel MEK and ERK inhibitors that suppress feedback reactivation of ERK signaling. Our data suggests that this is required for maximal antitumor activity, but that it will also relieve feedback inhibition of RTK activation resulting in potent activation of other signaling pathways that can attenuate efficacy. We plan to identify these reactivated pathways and then develop and test therapies that combine maximal ERK inhibition with inhibition of key reactivated pathways to prevent or limit adaptive resistance. Specific regimens will be designed for initial treatment of mutant BRAF tumors (which will employ RAF inhibitors) and for tumors with acquired resistance to RAF inhibitors or with RAS mutation (which will not). While preclinical models are powerful tools, ultimately mechanisms of resistance need to be identified and validated in clinical specimens from melanoma patients treated with these agents. We will thus use targeted DNA and RNA-sequencing methods to define the basis for RAF-inhibitor resistance using tumor samples collected pre-treatment and at the time of disease progression on RAF inhibitors. One goal of these latter studies will be to determine whether we can predict, prior to drug treatment, the mechanism of RAF-inhibitor resistance with the goal of using the data to develop individualized treatment strategies that delay or prevent the emergence of drug resistant clones.

描述（由申请人提供）：具有突变体BRAF或突变体KRA的肿瘤取决于ERK信号传导，并且对途径的抑制剂敏感。选择性RAF，MEK和ERK抑制剂现在已作为这些肿瘤的治疗剂开发，但是，由于毒性，获得的抗药性和适应性抗性，由于ERK依赖性反馈抑制有丝裂的信号，它们的临床功效受到限制。我们以前的工作表明，尽管MEK和ERK抑制剂抑制了所有正常和肿瘤细胞中的ERK信号传导，但RAF抑制剂仅抑制具有BRAF突变的肿瘤中的信号传导，并激活其他组织中的ERK信号传导。因此，RAF抑制剂比MEK和ERK抑制剂具有更广泛的治疗指数，但仅在具有突变BRAF的肿瘤中起作用。我们还表明，所有这些抑制剂对ERK信号的抑制作用会通过RAF/ERK和NON-RAF/ERK途径抑制反馈，并且这种反馈激活限制了RAF和MEK抑制剂的抗肿瘤作用。我们在该提案中的目标是开发疗法，通过将RAF或MEK抑制剂与选择性的小型MEK和ERK抑制剂相结合，从而最大程度地抑制ERK输出，从而抑制ERK信号的反馈重新激活。我们的数据表明，这是最大抗肿瘤活性所必需的，但它还将缓解RTK激活的反馈抑制，从而导致其他可以减弱功效的其他信号通路的有效激活。我们计划确定这些重新激活的途径，然后开发和测试疗法，将最大ERK抑制与抑制密钥重新激活途径相结合以预防或限制适应性抗性。特定方案将设计用于对突变体BRAF肿瘤（将采用RAF抑制剂）以及具有对RAF抑制剂或RAS突变具有耐药性的肿瘤的初始治疗（不会）。虽然临床前模型是强大的工具，但最终需要在用这些药物治疗的黑色素瘤患者的临床标本中鉴定和验证抗性机制。因此，我们将使用靶向的DNA和RNA序列方法来定义使用预处理前的肿瘤样品以及在RAF抑制剂上疾病进展时的RAF抑制剂耐药性的基础。这些后一项研究的目标是确定我们是否可以在药物治疗之前预测RAF抑制剂耐药性的机制，其目标是使用数据来制定延迟或防止抗药性克隆出现的个性化治疗策略。