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:
- 金额:$ 32.9万
- 依托单位:
- 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:
- 关键词:ApoptosisApoptoticAttentionAttenuatedAutomobile DrivingBindingBiological AssayBiological MarkersBiopsyBloodCancer CenterCancer cell lineCarboplatinCell DeathCell LineCell NucleusCellsCentrosomeChemicalsChromatinCisplatinCollaborationsDNA RepairDataDoctor of MedicineDoseDrug CombinationsDrug KineticsDrug resistanceEffectivenessEnzymesEpithelial ovarian cancerExhibitsGoalsGrowthHDAC5 geneInterphaseLeukocytesLiposomal DoxorubicinMalignant NeoplasmsMalignant neoplasm of ovaryMeasuresMediatingMitosisMolecular WeightOralPaclitaxelPatientsPeripheral Blood Mononuclear CellPharmaceutical PreparationsPharmacodynamicsPharmacologic SubstancePhosphorylationPhosphotransferasesPlatinumPolyploidyPrometaphaseProtein-Serine-Threonine KinasesProteinsProto-Oncogene Proteins c-aktResearch PersonnelResistanceSignal TransductionSignaling ProteinSmall Interfering RNASodium ChlorideSolventsStructural ProteinTestingTetraploidyToxic effectTumor DebulkingWomanXenograft ModelXenograft procedurebasecancer cellcancer therapychemotherapyimprovedinhibitor/antagonistknock-downneoplastic cellnoveloverexpressionpharmacodynamic biomarkerphase I trialpredicting responsepredictive markerresistance mechanismresponsestandard caresurvivinsynergismtaxanethree dimensional cell culturetumor
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概要/摘要
在过去的三十年里,上皮性卵巢癌患者的5年生存率有所提高,但长期以来,
长期生存率没有变化,总体保持在约30%。在手术细胞减少后,所有
新患者接受标准的主要化疗,包括卡铂和紫杉醇的组合。
单用铂类化合物的初级治疗在约70%的卵巢癌中产生消退。
而42%的人对紫杉醇单独治疗有反应,两种药物之间没有协同作用。我们长久以来-
长期翻译的目标是增加卵巢癌化疗的有效性。虽然许多
研究人员一直专注于克服对紫杉烷类的获得性耐药性,
在初次化疗期间给予紫杉醇以增强紫杉醇反应。使用功能性siRNA筛选
调节对紫杉醇敏感性的激酶,我们发现丝氨酸-苏氨酸激酶盐的敲低-
诱导激酶2(SIK2)诱导多倍体,抑制卵巢癌生长并增强紫杉醇敏感性
在细胞系和异种移植中。SIK2是正常中心体分裂所必需的,并且在34%的人中过表达。
所有组织类型的卵巢癌,与总生存率下降相关。在有丝分裂过程中,
自磷酸化和磷酸化C-Nap1,一种介导中心体分裂的结构蛋白。sik2
还磷酸化p85 α,驱动PI3K和HDAC 5的活化,修饰染色质和DNA修复。
我们与Arrien Pharmaceuticals建立了合作关系,开发口服小剂量
SIK 2分子量抑制剂:ARN-3236和ARN-3261,区别在于单一溶剂结合
替代。ARN-3236抑制10种卵巢癌细胞系的生长,IC50为0.8 - 2.6 μ M,其中
ARN-3236的IC50与内源性SIK2表达呈负相关(Pearson's r =-0.642,P =0.03)。
ARN-3236还在10个细胞系中的8个以及SKOv3ip中增强了对紫杉醇的敏感性(P = 0.028),
OVCAR8异种移植物。ARN-3236在间期使中心体与细胞核解偶联,
有丝分裂中的中心体分离,引起前中期停滞和诱导凋亡细胞死亡,以及
四倍性ARN-3236还抑制AKT磷酸化并减弱存活素表达。ARN-3261
在异种移植模型中增强了对紫杉醇和顺铂的敏感性,并表现出很小的毒性,以及
对PgP的抗性更强,效力是ARN-3236的13倍。我们将追求三个目标:1)执行
SIK2抑制剂ARN-3261单独使用(IA)和与每周紫杉醇联合使用(IB)的I期试验
测量ARN-3261和紫杉醇的药代动力学、预测(SIK2)和药效学(pSIK2和pSIK3)。
pHDAC 5)生物标志物,以及多倍性、pAKT、存活素和细胞凋亡的生物标志物的水平; 2)
确定SIK2抑制剂ARN-3261是否增强对卡铂/紫杉醇的反应,
卡铂/脂质体多柔比星在卵巢癌细胞系来源的和患者来源的异种移植物中的作用;和
鉴定在用SIK2抑制剂处理的卵巢癌细胞中产生合成致死性的靶点。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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ROBERT C BAST其他文献
ROBERT C BAST的其他文献
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{{ truncateString('ROBERT C BAST', 18)}}的其他基金
The SIK2 Inhibitor GRN-300 Enhances PARP Inhibitor Sensitivity and Cytotoxic T-Cell Function in Ovarian Cancer
SIK2 抑制剂 GRN-300 增强卵巢癌中 PARP 抑制剂的敏感性和细胞毒性 T 细胞功能
- 批准号:
10709229 - 财政年份:2023
- 资助金额:
$ 32.9万 - 项目类别:
The University of Texas MD Anderson Cancer Center SPORE in Ovarian Cancer
德克萨斯大学 MD 安德森癌症中心 SPORE 在卵巢癌中的应用
- 批准号:
10709227 - 财政年份:2023
- 资助金额:
$ 32.9万 - 项目类别:
DIRAS3 disrupts K-RAS clustering and signaling, enhancing autophagy and response to autophagy inhibition
DIRAS3 破坏 K-RAS 聚类和信号传导,增强自噬和对自噬抑制的反应
- 批准号:
10707965 - 财政年份:2022
- 资助金额:
$ 32.9万 - 项目类别:
Development of Novel Ovarian Cancer Biomarkers for Early Detection Algorithms
开发用于早期检测算法的新型卵巢癌生物标志物
- 批准号:
10410452 - 财政年份:2020
- 资助金额:
$ 32.9万 - 项目类别:
Development of Novel Ovarian Cancer Biomarkers for Early Detection Algorithms
开发用于早期检测算法的新型卵巢癌生物标志物
- 批准号:
10226017 - 财政年份:2020
- 资助金额:
$ 32.9万 - 项目类别:
Development of Novel Ovarian Cancer Biomarkers for Early Detection Algorithms
开发用于早期检测算法的新型卵巢癌生物标志物
- 批准号:
10670063 - 财政年份:2020
- 资助金额:
$ 32.9万 - 项目类别:
Development of Novel Ovarian Cancer Biomarkers for Early Detection Algorithms
开发用于早期检测算法的新型卵巢癌生物标志物
- 批准号:
9916297 - 财政年份:2020
- 资助金额:
$ 32.9万 - 项目类别:
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