Integrative Consig: NLK as Attractive Drug Target for Intractable Breast Cancer

综合配置：NLK 作为难治性乳腺癌有吸引力的药物靶点

基本信息

批准号：
9114500
负责人：
Xiaosong Wang
金额：
$ 32.3万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9114500
关键词：
Adjuvant Adjuvant Therapy Aftercare Aromatase Inhibitors Bioinformatics Biological Assay Breast Cancer Cell Breast Cancer Patient Breast Cancer cell line Bypass Cancer Patient Caring Cell Death Cell Survival Cells Clinical Clinical Trials Complex Data Data Set Development Disease Drug Targeting Endocrine Estrogen Receptor Modulators Estrogen Receptors Estrogen receptor positive Estrogens Event Gene Expression Profile Genes Genetic Genetic Transcription Genomics Growth Growth Factor Hormones Immunohistochemistry Investigation Life Link MCF7 cell Malignant Neoplasms Mammary Neoplasms Mining Modeling Molecular Mus Neoadjuvant Therapy Oncogenes Ontology Outcome Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phenotype Population Protein Kinase Protein-Serine-Threonine Kinases Proteins Proto-Oncogene Proteins c-akt Receptor Signaling Recurrence Regimen Regulation Relapse Reporting Residual Tumors Resistance Role STAT3 gene Safety Sample Size Signal Transduction Stimulus T47D Tamoxifen Techniques Testing The Cancer Genome Atlas Therapeutic Tissue Microarray Toxic effect Transplantation Xenograft procedure breast cancer survival cancer cell cancer genome cell growth cellular engineering chemotherapy effective therapy genomic data hormone resistance hormone therapy in vivo inhibitor/antagonist innovation kinase inhibitor knock-down malignant breast neoplasm malignant endocrine gland neoplasm mouse model nemo-like kinase new therapeutic target non-genomic novel therapeutics overexpression precision medicine protein expression public health relevance response targeted treatment transcription factor tumor tumor molecular fingerprint tumor progression tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Despite many efforts, no effective therapy exists to overcome breast cancer endocrine resistance. The major drawback is that most of the known oncogenes cannot be matched with potent and safe drugs; for the few with inhibitors, clinical responses are limited and transient due to rapid development of escape pathways not yet understood. It is thus critical to uncover both the missing targets in the unknown survival pathways and the drugs that can tackle this disease. In this study, we apply a unique integrative analysis that identifies key drug targets from the complex cancer signaling network by combining genomic/pharmacological information with cancer-gene concept signature (ConSig). This analysis has revealed a new target, Nemo-like kinase (NLK), which is amplified and/or overexpressed in ~30% of breast cancers. We have shown that NLK drives more aggressive phenotypes, endows endocrine-resistant growth, and predicts worse outcome in tamoxifen- treated patients. Further investigation suggests that NLK modulates multiple key molecules in the estrogen receptor (ER) pathway or involved in endocrine resistance, such as STAT3, FOXOs, AKT, ERK, and p27. More important, a potent NLK inhibitor has been identified which effectively sensitizes breast cancer cells to tamoxifen. NLK can be activated by multiple growth factors distinct from the well-known breast cancer pathways. We thus hypothesize that this protein may be a hub molecule that drives previously uncharacterized survival signaling in a considerable subset of intractable breast tumors. As the safety of the NLK inhibitor has already been established in other clinical trials, it holds an immediate and high potential to transform th care of breast cancer patients. The following studies are proposed to test the hypothesis: Aim 1 will investigate how NLK crosstalks with the ER pathway to restore ER activity, and how NLK engages ER-independent signaling to provide alternative survival and invasive stimuli in the context of endocrine therapy. Aim 2 will establish NLK function in tumor formation and hormone resistance using transplanted NLK inducible genetic perturbation models. The therapeutic value of the NLK inhibitor in sensitizing endocrine therapy will be assessed on mice bearing NLK-high ER+ xenograft breast tumors. Aim 3 will investigate the correlation of NLK protein with the response or relapse of breast cancer patients treated with tamoxifen or aromatase inhibitors. This study will also establish an NLK immunohistochemistry (IHC) assay to select patients for NLK-targeted therapy. We expect that these studies will confirm the role of NLK in breast cancer endocrine resistance, elucidate the NLK-driven mechanisms to promote cancer cell survival, validate the NLK inhibitor as a sensitizing agent to endocrine therapy, and establish the NLK IHC as a predictive assay for precision medicine. This individualized targeted-therapy would benefit a considerable population of breast cancer patients that have developed or are likely to develop endocrine resistance.

描述（由申请人提供）：尽管做了许多努力，但仍未有有效的疗法来克服乳腺癌内分泌耐药性。主要的缺点是，大多数已知的肿瘤基因不能与有效和安全的药物相匹配。对于少数具有抑制剂的人，由于尚未理解的逃生途径的快速发展，临床反应是有限的和短暂的。因此，至关重要的是要揭示未知生存途径中缺失的靶标和可以解决该疾病的药物。在这项研究中，我们采用了独特的整合分析，该分析通过将基因组/药理学信息与癌症基因概念签名（CONG）相结合（CON）来确定复杂癌症信号网络中的关键药物靶标。该分析揭示了一种新的靶标，类似Nemo样激酶（NLK），该激酶（NLK）在〜30％的乳腺癌中被放大和/或过表达。我们已经表明，NLK驱动更具侵略性的表型，耐内分泌的生长，并预测在他莫昔芬治疗的患者中的结果较差。进一步的研究表明，NLK调节雌激素受体（ER）途径中的多个关键分子或参与内分泌耐药性，例如STAT3，FOXOS，AKT，ERK和P27。更重要的是，已经鉴定出有效的NLK抑制剂，该抑制剂有效地使乳腺癌细胞对他莫昔芬。 NLK可以通过与众所周知的乳腺癌途径不同的多种生长因子激活。因此，我们假设该蛋白可能是一个集线器分子，它可以在相当大的可怕乳腺肿瘤的大部分子集中驱动以前未表征的存活信号传导。由于在其他临床试验中已经建立了NLK抑制剂的安全性，因此它具有转化乳腺癌患者护理的直接和高潜力。提出了以下研究来检验假设：AIM 1将研究如何与ER途径恢复ER活性的NLK串扰，以及NLK如何在内分泌治疗的背景下与ER无关的信号传导以提供替代性生存和侵入性刺激。 AIM 2将使用移植的NLK诱导遗传扰动模型在肿瘤形成和激素耐药性中建立NLK功能。 NLK抑制剂在敏化内分泌疗法中的治疗值将在带有NLK-HIGH ER+异种移植乳腺肿瘤的小鼠上评估。 AIM 3将研究NLK蛋白与他莫昔芬或芳香酶抑制剂治疗的乳腺癌患者的反应或复发的相关性。这项研究还将建立NLK免疫组织化学（IHC）分析，以选择患者进行NLK靶向治疗。我们预计这些研究将证实NLK在乳腺癌内分泌耐药性中的作用，阐明NLK驱动的机制促进癌细胞的存活，验证NLK抑制剂作为内分泌治疗的敏化剂，并建立 NLK IHC作为精确医学的预测分析。这种个性化的靶向疗法将使已发展或可能发展内分泌耐药性的乳腺癌患者受益。