A two-pronged “senolytic” approach to treatment of oral cavity cancer

口腔癌治疗的双管齐下的“senolytic”方法

基本信息

批准号：
10443829
负责人：
Thomas Julian Ow
金额：
$ 16.8万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-02 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10443829
关键词：
Aftercare Antineoplastic Agents Apoptosis Apoptotic Automobile Driving BCL1 Oncogene BCL2 gene BCL2L1 gene Biological Assay Biology Bromodeoxyuridine CDK4 gene CDKN2A gene Cell Cycle Cell Cycle Arrest Cell Cycle Progression Cell Cycle Regulation Cell Line Cell Proliferation Cell Survival Cells Cisplatin Defect Dependence Diagnosis Disease Dose Engraftment Exhibits Family Genomics HPV oropharyngeal cancer Heterogeneity Human Papillomavirus In Vitro Inflammatory Institution Laboratories Malignant Epithelial Cell Malignant Neoplasms Measures Metastatic breast cancer Methods Modeling Molecular Target Monitor Mus Mutation Nude Mice Operative Surgical Procedures Outcome Patients Peptides Persons Pharmaceutical Preparations Phosphotransferases Predisposition Prognosis Protein Family Proteins Radiation Recurrence Research Role Series Signal Transduction Signaling Molecule Stains TP53 gene Testing Therapeutic Tongue Toxic effect United States Work Xenograft Model base beta-Galactosidase cancer cell design efficacy testing experimental study high throughput screening in vivo inhibitor interest malignant mouth neoplasm molecular targeted therapies mouth squamous cell carcinoma neoplastic cell novel novel therapeutic intervention preservation rational design response senescence small molecule inhibitor standard care synergism targeted agent treatment strategy tumor tumor growth

项目摘要

ABSTRACT Standard therapies (surgery, radiation, and cisplatin) for oral cavity squamous cell carcinoma (OCSCC) have not changed for decades, and no molecularly targeted agents have an established role as first-line treatment. Unlike HPV-positive oropharynx cancer, which has an excellent prognosis, advanced OCSCC (which is predominantly HPV-negative) carries a high recurrence rate (~20-30%) and poor overall survival (~50% at 5 years). The biology of OCSCC is well described. Loss of p16INK4A (p16) function is the driving defect in cell cycle regulation. p16 inhibits cyclin-dependent kinases 4 and 6 (CDK4/6), which leads to cell cycle arrest in G1. The FDA-approved cancer therapeutic, palbociclib, is a small molecule inhibitor that targets CDK4/6. Our preliminary work shows that palbociclib consistently induces senescence in OCSCC cells. We have also shown that these cells consistently upregulate the pro-survival molecule, BCL-xL, in response to palbociclib. There has been growing interest in targeting senescent cells in cancer. Though senescent cells do not proliferate, they have been shown to produce inflammatory signals that promote and support neighboring cancer cells in the tumor micorenvironment. There has been growing interest in agents that specifically target senescent cells (‘senolytics’). Perhaps the most well- studied senolytic, ABT-263 (navitoclax), targets BCL2 family pro-survival anti-apoptotic signaling molecules, BCL2, BCL-xL, and BCL-w. Our preliminary work has shown that combining palbociclib (inducing senescence) with navitoclax (senolytic) results in profound apoptosis in OCSCC cells. In this proposal, we aim to study the palbociclib/navitoclax combination extensively in OCSCC. In Specific Aim #1, we will study the response to palbociclib in a panel of OCSCC cell lines, and concurrently in a ‘cell reprogramming’ model, which allows perpetual culture of primary OCSCC tumor cells derived from patients treated at our own institution. We will specifically measure the senescence response (Specific Aim#1a) and apoptosis signaling using a high throughput method called ‘BH3’ profiling (Specific Aim1b). In Specific Aim#2 we will measure synergy between palbociclib and ABT-263 (navitoclax) using cell viability assays, and evaluate in vivo efficacy using an orthotopic tongue xenograft model of OCSCC.

抽象的标准疗法（手术，辐射和顺铂）口腔鳞状细胞癌（OCSCC）几十年来一直没有改变，并且没有分子靶向剂具有确立了作为一线治疗的角色。与HPV阳性口咽癌不同，它具有出色的预后，高级OCSCC（主要是HPV阴性）具有很高的复发率（约20-30％）和总生存期差（5年时约50％）。 OCSCC的生物学得到很好的描述。 P16INK4A（p16）功能的损失是驾驶细胞周期调节缺陷。 P16抑制细胞周期蛋白依赖性激酶4和6（CDK4/6），这导致G1中的细胞周期停滞。 FDA批准的癌症疗法Palbociclib很小靶向CDK4/6的分子抑制剂。我们的初步工作表明，Palbociclib一贯诱导OCSCC细胞的感应。我们还表明这些细胞一致响应palbociclib，上调了促生存的分子Bcl-XL。对靶向癌症中的感觉细胞的兴趣越来越大。虽然有感觉细胞不会增殖，它们已被证明会产生促进的炎症信号并支持肿瘤微环境中相邻的癌细胞。已经成长对专门针对感官细胞的药物（“鼻溶剂”）的兴趣。也许是最美好的研究型塞溶性疫苗，ABT-263（NAVITOCLAX），针对BCL2家族亲苏属抗凋亡信号传导分子，BCL2，BCL-XL和BCL-W。我们的初步工作表明，结合带有Navitoclax（鼻溶剂）的palbociclib（诱导感应）导致深刻的凋亡 OCSCC细胞。在此提案中，我们旨在研究Palbociclib/Navitoclax的组合 OCSCC。在特定的目标＃1中，我们将研究OCSCC单元组中对Palbociclib的反应线条，并同时在“细胞重编程”模型中，该模型允许永久文化原发性OCSCC肿瘤细胞来自我们自己机构治疗的患者。我们将专门测量使用的感应响应（特定目标＃1A）和使用一种称为“ BH3”分析的高吞吐量方法（特定AIM1B）。在特定的目标＃2中，我们将使用细胞活力分析和使用OCSCC的原位舌异种移植模型评估体内效率。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

CDK4/6 Inhibition Induces Senescence and Enhances Radiation Response by Disabling DNA Damage Repair in Oral Cavity Squamous Cell Carcinoma.

DOI：
10.3390/cancers15072005
发表时间：
2023-03-28
期刊：
Cancers
影响因子：
5.2
作者：
通讯作者：

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Thomas Julian Ow其他文献

First-Line Surgery Is Associated with Longer Overall Survival in Locoregionally Advanced Hypopharyngeal Cancer in the National Cancer Database

DOI：
10.1016/j.jamcollsurg.2020.07.313
发表时间：
2020-10-01
期刊：
Conference abstract
影响因子：
作者：
Colleen Gabrielle Hochfelder;Aileen P. McGinn;Vikas Mehta;Enrico Castellucci;Rafi Kabarriti;Thomas Julian Ow
通讯作者：
Thomas Julian Ow