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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

基本信息

批准号：
10709229
负责人：
ROBERT C BAST
金额：
$ 30.66万
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：
2023
资助国家：
美国
起止时间：
2023-09-19 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10709229
关键词：
Affect BRCA mutations Binding Biopsy Blood CD8-Positive T-Lymphocytes Cancer Model Cancer cell line Carboplatin Cell physiology Cells Chromatin Clinical Cytotoxic T-Lymphocytes DNA DNA Damage DNA Double Strand Break DNA Repair DNA Repair Gene DNA Repair Inhibition DNA Repair Pathway DNA Sequence Alteration DNA replication fork Data Diagnosis Dose Double Strand Break Repair EXO1 gene Enhancers Excision Exhibits FANCD2 protein FOXP3 gene Frequencies Gene Expression Genetic Transcription Goals HDAC4 gene Human IL2RA gene IL6 gene IRF3 gene ITGAM gene Immunotherapy Impairment Infiltration Malignant Neoplasms Malignant neoplasm of ovary Marrow Maximum Tolerated Dose Mediating Messenger RNA Modeling Morbidity - disease rate Mus Muscle Cells Myeloid-derived suppressor cells Myelosuppression Names Nuclear Nucleic Acid Regulatory Sequences Organoids Outcome Ovarian Paclitaxel Pathway interactions Patients Peripheral Blood Mononuclear Cell Phase Phase I Clinical Trials Phase Ib Trial Phosphorylation Phosphotransferases Platinum Play Poly(ADP-ribose) Polymerase Inhibitor Polymerase Primary Neoplasm Progression-Free Survivals Regulatory T-Lymphocyte Relapse Repression Resistance Resistance development Sampling Second Look Surgery Site Sodium Chloride Stimulator of Interferon Genes T cell infiltration T-Lymphocyte TBK1 gene TGFB1 gene Testing Toxic effect University of Texas M D Anderson Cancer Center Woman Xenograft procedure brca gene cancer cell cancer immunotherapy cancer type checkpoint therapy conventional therapy cytotoxicity experience first-in-human homologous recombination immune checkpoint blockade inhibiting antibody inhibitor mRNA Expression mortality mouse model novel patient derived xenograft model phase I trial preclinical study prevent programmed cell death ligand 1 recombinational repair refractory cancer response restoration targeted agent transcriptome sequencing tumor

项目摘要

Ovarian cancer is a significant cause of morbidity and mortality that affects nearly 300,000 women worldwide each year. Its poor outcomes relate to delayed diagnosis and development of resistance to conventional therapy with carboplatin and paclitaxel. In the last SPORE cycle, we evaluated a novel inhibitor of salt-induced kinase 2 (SIK2) GRN-300 that enhances sensitivity to both carboplatin and paclitaxel. With the support of the SPORE, we carried out a first-in-human phase IA/B trial to define the maximum tolerated dose of GRN-300 alone and in combination with weekly paclitaxel. We also conducted preclinical studies to demonstrate that GRN-300 enhanced olaparib sensitivity in homologous recombination (HR)-proficient and deficient ovarian cancer cell lines and xenografts. We have demonstrated that GRN-300 enhances olaparib sensitivity by 1) abolishing the class IIa histone deacetylase 4/5/7-associated transcriptional activity of myocyte enhancer factor 2D (MEF2D), 2) decreasing MEF2D binding to regulatory regions with high chromatin accessibility in DNA repair genes, and 3) repressing critical gene expression in the DNA repair pathway. Whereas poly(ADP-ribose) polymerase inhibitors (PARPi) have played a large part in maintaining progression-free survival in patients with HR-deficient ovarian cancers, the majority of patients will have resistance to PARPi and experience relapse. Moreover, combining conventional or other targeted agents with PARPi has been limited by additive myelosuppression. To date, GRN- 300 has had no significant marrow toxicity in our phase I clinical trial. GRN-300 enhanced olaparib activity in both olaparib-sensitive and acquired olaparib-resistant ovarian cancer cells. Cancer immunotherapy, including immune checkpoint blockade (ICB), has shown great promise for cancers at multiple sites, but the frequency and duration of response of ovarian cancer has been limited. Recent studies suggest that a deficiency in DNA repair is associated with increased response of cancer cells to immunotherapy. We have found that GRN-300 increases phosphorylation of TBK1 and nuclear localization of IRF3 in murine ovarian cancer cells. Both TBK1 and IRF3 are downstream targets of the cGAS/STING pathway. GRN-300 or GRN-300 combined with olaparib increases the expression of programmed death-ligand 1 (PD-L1) in human and murine ovarian cancer cells. GRN-300 combined with anti-PD-L1 enhances CD8+ T-cell infiltration and antitumor activity in a syngeneic ovarian cancer model. The goal of our project is to determine whether GRN-300 overcomes resistance to PARPi and enhances PARPi sensitivity and whether GRN-300 promotes adaptive T-cell function and enhances immune checkpoint therapy. We will pursue three aims: 1) to perform a phase IB trial of GRN-300 in combination with a PARPi, 2) To determine the underlying mechanisms of olaparib resistance that can be overcome with the SIK2 inhibitor GRN-300 in combination with olaparib in ovarian cancer cell lines, xenografts and PDXs, and 3) To identify the mechanism(s) by which the SIK2 inhibitor GRN-300 sensitizes ovarian cancer cells to ICB and enhances T-cell cytotoxicity.

卵巢癌是影响全世界近30万妇女的发病率和死亡率的重要原因每年.其不良结局与延迟诊断和对常规治疗产生耐药性有关卡铂和紫杉醇在最后一个孢子周期，我们评估了一种新的盐诱导激酶2抑制剂（SIK 2）GRN-300，增强对卡铂和紫杉醇的敏感性。在孢子的支持下，我们进行了首次人体IA/B期试验，以确定GRN-300单独和联合给药的最大耐受剂量。联合每周一次的紫杉醇。我们还进行了临床前研究，以证明GRN-300 奥拉帕尼在同源重组（HR）熟练和缺陷卵巢癌细胞系中的敏感性增强和异种移植物。我们已经证明，GRN-300通过以下方式增强奥拉帕尼的敏感性：1）消除类 IIa组蛋白去乙酰化酶4/5/7相关的肌细胞增强因子2D（MEF 2D）转录活性，2）减少MEF 2D与DNA修复基因中具有高染色质可及性的调节区的结合，以及3）抑制DNA修复途径中的关键基因表达。而聚ADP-核糖聚合酶抑制剂（PARPi）在维持HR缺陷卵巢癌患者的无进展生存中发挥了重要作用。在癌症中，大多数患者将对PARPi具有抗性并经历复发。此外，结合传统的或其它靶向药物与PARPi的联合应用受到叠加性骨髓抑制的限制。到目前为止，GRN- 300在我们的I期临床试验中没有明显的骨髓毒性。GRN-300增强奥拉帕尼活性，奥拉帕尼敏感性和获得性奥拉帕尼抗性卵巢癌细胞。癌症免疫治疗，包括免疫检查点阻断（ICB）已显示出对多个部位癌症的巨大希望，但频率并且卵巢癌的反应持续时间有限。最近的研究表明，修复与癌细胞对免疫疗法的应答增加有关。我们发现GRN-300 增加小鼠卵巢癌细胞中TBK 1的磷酸化和IRF 3的核定位。两个TBK 1 和IRF 3是cGAS/STING途径的下游靶标。GRN-300或GRN-300联合奥拉帕尼增加人和鼠卵巢癌细胞中程序性死亡配体1（PD-L1）的表达。 GRN-300联合抗PD-L1增强同基因小鼠中CD 8 + T细胞浸润和抗肿瘤活性卵巢癌模型。我们项目的目标是确定GRN-300是否能克服对PARPi的抗性。以及GRN-300是否促进适应性T细胞功能和增强免疫功能检查点疗法我们将追求三个目标：1）进行GRN-300与一种抗肿瘤药物组合的IB期试验。 PARPi，2）确定可以用SIK 2克服的奥拉帕尼抗性的潜在机制抑制剂GRN-300与奥拉帕尼组合用于卵巢癌细胞系、异种移植物和PDX，以及3）鉴定SIK 2抑制剂GRN-300使卵巢癌细胞对ICB敏感的机制，增强T细胞的细胞毒性。