Project 4: SIK2 PROVIDES A NOVEL TARGET FOR OVARIAN CANCER THERAPY IN COMBINATION WITH PACLITAXEL AND INHIBITORS OF PARP

项目 4：SIK2 结合紫杉醇和 PARP 抑制剂为卵巢癌治疗提供新靶点

基本信息

批准号：
10005298
负责人：
ROBERT C BAST
金额：
$ 32.9万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-22 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10005298
关键词：
Apoptosis Apoptotic Attention Attenuated Automobile Driving Binding Biological Assay Biological Markers Biopsy Blood Cancer Center Cancer cell line Carboplatin Cell Death Cell Line Cell Nucleus Cells Centrosome Chemicals Chromatin Cisplatin Collaborations DNA Repair Data Doctor of Medicine Dose Drug Combinations Drug Kinetics Drug resistance Effectiveness Enzymes Epithelial ovarian cancer Exhibits Goals Growth HDAC5 gene Interphase Leukocytes Liposomal Doxorubicin Malignant Neoplasms Malignant neoplasm of ovary Measures Mediating Mitosis Molecular Weight Oral Paclitaxel Patients Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Phosphorylation Phosphotransferases Platinum Polyploidy Prometaphase Protein-Serine-Threonine Kinases Proteins Proto-Oncogene Proteins c-akt Research Personnel Resistance Signal Transduction Signaling Protein Small Interfering RNA Sodium Chloride Solvents Structural Protein Testing Tetraploidy Toxic effect Tumor Debulking Woman Xenograft Model Xenograft procedure base cancer cell cancer therapy chemotherapy improved inhibitor/antagonist knock-down neoplastic cell novel overexpression pharmacodynamic biomarker phase I trial predicting response predictive marker resistance mechanism response standard care survivin synergism taxane three dimensional cell culture tumor

项目摘要

Project 4 SUMMARY/ABSTRACT Over the last three decades, 5-year survival has improved for patients with epithelial ovarian cancer, but long- term survival has not changed and remains at approximately 30% overall. Following surgical cytoreduction, all new patients receive standard primary chemotherapy that includes a combination of carboplatin and paclitaxel. Primary therapy with platinum-based compounds alone produces regression in approximately 70% of ovarian cancers, whereas 42% respond to paclitaxel alone and there is no synergy between the two drugs. Our long- term translational goal is to increase the effectiveness of chemotherapy for ovarian cancer. While many investigators have focused on overcoming acquired resistance to taxanes, relatively little attention has been given to enhancing paclitaxel response during primary chemotherapy. Using a functional siRNA screen for kinases that regulate sensitivity to paclitaxel, we found that knockdown of the serine-threonine kinase salt- induced kinase 2 (SIK2) induces polyploidy, inhibits ovarian cancer growth and enhances paclitaxel sensitivity in cell lines and xenografts. SIK2 is required for normal centrosome splitting and is overexpressed in 34% of ovarian cancers of all histotypes, associated with decreased overall survival. During mitosis, SIK2 undergoes autophosphorylation and phosphorylates C-Nap1 a structural protein that mediates centrosome splitting. SIK2 also phosphorylates p85α, driving activation of PI3K, as well as HDAC5, modifying chromatin and DNA repair. We have established a collaboration with Arrien Pharmaceuticals to develop orally administered small molecular weight inhibitors of SIK2: ARN-3236 and ARN-3261 that differ by a single solvent binding substitution. ARN-3236 inhibited growth of 10 ovarian cancer cell lines at an IC50 of 0.8 to 2.6 μM, where the IC50 of ARN-3236 was inversely correlated with endogenous SIK2 expression (Pearson’s r = -0.642, P = 0.03). ARN-3236 also enhanced sensitivity to paclitaxel in 8 of 10 cell lines, as well as in SKOv3ip (P = 0.028) and OVCAR8 xenografts. ARN-3236 uncoupled the centrosome from the nucleus in interphase, blocked centrosome separation in mitosis, caused prometaphase arrest and induced apoptotic cell death as well as tetraploidy. ARN-3236 also inhibited AKT phosphorylation and attenuated survivin expression. ARN-3261 enhanced sensitivity to paclitaxel and cisplatin in xenograft models and exhibited little toxicity, as well as greater resistance to PgP and13-fold greater potency than ARN-3236. We will pursue three aims: 1) to perform a phase I trial of the SIK2 inhibitor ARN-3261 alone (IA) and in combination with weekly paclitaxel (IB) measuring pharmacokinetics of ARN-3261 and paclitaxel, predictive (SIK2) and pharmacodynamic (pSIK2 and pHDAC5) biomarkers, as well as levels of polyploidy, pAKT, survivin and biomarkers for apoptosis; 2) to determine whether the SIK2 inhibitor ARN-3261 enhances response to carboplatin/paclitaxel and carboplatin/liposomal doxorubicin in ovarian cancer cell line-derived and patient-derived xenografts; and 3) to identify targets that produce synthetic lethality in ovarian cancer cells treated with SIK2 inhibitors.

项目4摘要/摘要在过去的三十年中，上皮卵巢癌患者的5年生存率有所改善，但长期很长定期生存没有改变，总体上保持约30％。遵循手术的细胞训练，所有新患者接受标准的初级化疗，其中包括卡铂和紫杉醇的组合。单独使用铂基化合物的一级疗法可在大约70％的卵巢中产生回归癌症，而42％的人单独反应紫杉醇，两种药物之间没有协同作用。我们的长期术语翻译目标是提高化学疗法对卵巢癌的有效性。而很多调查人员的重点是克服对紫杉烷的抵抗，相对较少的关注在培训期间增强紫杉醇反应。使用功能性siRNA屏幕进行调节对紫杉醇敏感性的激酶，我们发现连续硫酸盐激酶盐的敲低诱导的激酶2（SIK2）诱导多倍体，抑制卵巢癌的生长并增强紫杉醇敏感性在细胞系和异种移植物中。 SIK2是正常的中心分裂所需的，并且在34％中过表达所有组织型的卵巢癌，与总体生存的改善有关。在有丝分裂期间，SIK2经历自磷酸化和磷酸化C-NAP1介导集中体分裂的结构蛋白。 sik2 还可以磷酸化p85α，驱动PI3K的激活以及HDAC5，从而改变染色质和DNA修复。我们已经与Arrien Pharmaceuticals建立了合作，以开发口服的小型 Sik2的分子量抑制剂：ARN-3236和ARN-3261，它们与单个溶剂结合不同替代。 ARN-3236在IC50的0.8至2.6μm处抑制10个卵巢癌细胞系的生长，其中 ARN -3236的IC50与内源性SIK2表达成反比（Pearson的R = -0.642，P = 0.03）。 ARN-3236还增强了对10个细胞系中8条以及SKOV3IP（p = 0.028）的紫杉醇的敏感性，并且 OVCAR8异种移植物。 ARN-3236将相互作用的核与核的中心体耦合，阻塞有丝分裂中的中心体分离，引起了前载酶停滞并诱发凋亡细胞死亡以及四倍体。 ARN-3236还抑制了Akt磷酸化并减弱了源性磷酸表达。 ARN-3261 对紫杉醇和顺铂模型中对紫杉醇和顺铂的敏感性增强，几乎没有毒性比ARN-3236，对PGP的阻力更大，效力更大。我们将追求三个目标：1） SIK2抑制剂ARN-3261（IA）的I期试验以及每周紫杉醇（IB）的结合测量ARN-3261和紫杉醇的药代动力学，预测性（SIK2）和药效学（PSIK2和 PHDAC5）生物标志物以及凋亡的多倍体，PAKT，Survivin和生物标志物的水平； 2）到确定SIK2抑制剂ARN-3261是否增强对卡铂/紫杉醇和紫杉醇的反应卵巢癌细胞系衍生和患者衍生的Xenographographics中的卡铂/脂质体阿霉素；和3）到确定在用SIK2抑制剂处理的卵巢癌细胞中产生合成致死性的靶标。