Elucidating the Mechanism of CDK4/6 Inhibitor-Mediated Radiosensitization of ER+ Breast Cancers

阐明 CDK4/6 抑制剂介导的 ER 乳腺癌放射增敏机制

基本信息

批准号：
10222542
负责人：
Andrea Michelle Pesch
金额：
$ 2.71万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10222542
关键词：
Affect Aftercare Agreement Aromatase Inhibitors Biological Assay Breast Breast Cancer Cell Breast Cancer cell line CDK4 gene CHEK1 gene Cell Cycle Cell Cycle Arrest Cell Cycle Progression Cell Cycle Regulation Cell Death Cell Line Cell Survival Cells Clinical Clinical Management Clinical Research Clinical Trials Critical Pathways Cyclin D1 Cyclins DNA Damage DNA Double Strand Break DNA Repair DNA Repair Gene DNA Repair Pathway Data Diagnosis Disease Double Strand Break Repair Drug resistance Estrogen Receptors Estrogen receptor positive G1/S Checkpoint Pathway Goals Head and neck structure Immunofluorescence Immunologic Immunohistochemistry Impairment In Vitro Ionizing radiation Lead Literature Malignant Neoplasms Mediating Michigan Modeling National Cancer Institute Nonhomologous DNA End Joining Nonmetastatic Pathway interactions Patient Care Patients Pharmacology Physiological Play Pre-Clinical Model Progression-Free Survivals Proteins Radiation Radiation therapy Radiosensitization Receptor Signaling Recurrence Regulation Reporter Resistance Role Selective Estrogen Receptor Modulators Survival Rate System Testing Therapeutic Universities Western Blotting Woman Work Xenograft Model Xenograft procedure base clinically relevant effective therapy efficacy evaluation fractionated radiation high risk homologous recombination improved in vivo in vivo Model inhibitor/antagonist malignant breast neoplasm patient population response standard of care therapeutically effective treatment strategy triple-negative invasive breast carcinoma tumor growth tumor xenograft

项目摘要

PROJECT SUMMARY/ABSTRACT Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are used as frontline therapy to treat women with metastatic estrogen receptor positive (ER+) breast cancers given their documented improvements in progression-free and overall survival in this patient population. Furthermore, clinical studies are currently defining their utility in the upfront, non-metastatic setting for women with high-risk ER+ breast cancers. Despite these promising studies, CDK4/6 inhibitors are not yet given in combination with the radiation therapy that patients receive as part of the standard of care. Preliminary data from our lab demonstrates that CDK4/6 inhibition leads to the radiosensitization of multiple ER+ breast cancer cell lines. This radiosensitization occurs to a similar degree with palbociclib, ribociclib, and abemaciclib, the three clinically approved CDK4/6 inhibitors. Although we have demonstrated that all three CDK4/6 inhibitors lead to the radiosensitization of ER+ breast cancer cells, the mechanism of this radiosensitization remains unclear. In this proposal, we aim to 1) determine the mechanism of CDK4/6 inhibitor-mediated radiosensitization of ER+ breast cancer cells and 2) determine the efficacy of CDK4/6 inhibitor-mediated radiosensitization in in vivo models of ER+ breast cancer. Radiosensitization typically occurs through changes in cell cycle distribution or decreases in the efficiency of DNA repair pathways like homologous recombination (HR) or non-homologous end joining (NHEJ). Our lab has preliminary data to suggest that short term CDK4/6 inhibition leads to a decrease in expression of DNA repair proteins like CHK1 and RAD51 that play a role in homologous recombination. CDK4/6 inhibitors halt progression through the G1/S cell cycle checkpoint, and we hypothesize that CDK4/6 inhibitor-mediated G1 cell cycle arrest may limit the ability of cells to undergo DNA double strand break repair through homologous recombination, leading to cell death both in vitro and in vivo. Thus, the overall hypothesis of this work is that pharmacologic CDK4/6 inhibition leads to inhibition of homologous recombination and leads to clinically relevant radiosensitization of ER+ breast cancers in vivo. In Aim 1, we will use reporter assays, immunofluorescence, western blots, qPCR, and cell cycle analysis to determine the effects of CDK4/6 inhibition and radiation on both cell cycle progression as well as HR and NHEJ efficiency in ER+ breast cancer cell lines. In Aim 2, we will use cell line and PDX xenograft models of ER+ breast cancer to assess the efficacy of CDK4/6 inhibitor-mediated radiosensitization in more physiologically relevant systems. The proposed studies will be conducted with guidance from Drs. Corey Speers, James Rae, Ted Lawrence, Lori Pierce, and Daniel Hayes, and will be performed at the University of Michigan. In addition to furthering our understanding of effective treatment strategies for ER+ breast cancer, this proposal advances the National Cancer Institute’s scientific priorities of ‘understanding mechanisms of cancer’ and ‘treating cancer’.

项目摘要/摘要依赖细胞周期蛋白的激酶4和6（CDK4/6）抑制剂用作前线治疗，以治疗女性鉴于其记录的改善该患者人群中的无进展和整体生存。此外，目前正在临床研究为高风险ER+乳腺癌女性的前期非转移环境定义效用。尽管这些有前途的研究，CDK4/6抑制剂尚未与放射疗法相结合。患者接受护理标准的一部分。我们实验室的初步数据表明CDK4/6 抑制作用导致多个ER+乳腺癌细胞系的放射敏化。这种放射敏化发生与Palbociclib，Ribociclib和Abemaciliclib（三种临床认可的CDK4/6抑制剂）的程度相似。尽管我们已经证明了所有三个CDK4/6抑制剂都会导致ER+乳房的放射敏化癌细胞，这种放射敏化的机制尚不清楚。在此提案中，我们的目标是1）确定 CDK4/6抑制剂介导的ER+乳腺癌细胞的放射敏的机理，2） ER+乳腺癌体内模型中CDK4/6抑制剂介导的放射敏化的效率。放射敏通常是通过细胞周期分布的变化或效率降低而发生的 DNA修复途径，例如同源重组（HR）或非理论末端连接（NHEJ）。我们的实验室具有初步数据，以表明短期CDK4/6抑制会导致DNA表达降低修复在同源重组中发挥作用的CHK1和RAD51等蛋白质。 CDK4/6抑制剂停止通过G1/S细胞周期检查点的进展，我们假设CDK4/6抑制剂介导的G1细胞周期停滞可能会限制细胞通过同源的DNA双链破裂修复的能力重组，导致体外和体内细胞死亡。那就是这项工作的总体假设是该药物CDK4/6抑制作用导致抑制同源重组，并导致 ER+乳腺癌在体内与临床相关的放射敏化。在AIM 1中，我们将使用记者测定法，免疫荧光，蛋白质印迹，QPCR和细胞周期分析，以确定CDK4/6的影响 ER+乳腺癌中的细胞周期进展以及HR和NHEJ效率的抑制和辐射细胞系。在AIM 2中，我们将使用ER+乳腺癌的细胞系和PDX异种移植模型来评估效率在更相关的系统中，CDK4/6抑制剂介导的放射性化。提议研究将在DRS的指导下进行。 Corey Speers，James Rae，Ted Lawrence，Lori Pierce和丹尼尔·海斯（Daniel Hayes），将在密歇根大学（University of Michigan）演出。除了增进我们的理解关于ER+乳腺癌的有效治疗策略，该提案推进了国家癌症研究所的 “理解癌症机制”和“治疗癌症”的科学优先事项。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Estrogen receptor inhibition mediates radiosensitization of ER-positive breast cancer models.

DOI：
10.1038/s41523-022-00397-y
发表时间：
2022-03-10
期刊：
NPJ breast cancer
影响因子：
5.9
作者：
Michmerhuizen AR;Lerner LM;Pesch AM;Ward C;Schwartz R;Wilder-Romans K;Liu M;Nino C;Jungles K;Azaria R;Jelley A;Zambrana Garcia N;Harold A;Zhang A;Wharram B;Hayes DF;Rae JM;Pierce LJ;Speers CW
通讯作者：
Speers CW

Androgen and oestrogen receptor co-expression determines the efficacy of hormone receptor-mediated radiosensitisation in breast cancer.

DOI：
10.1038/s41416-022-01849-9
发表时间：
2022-09
期刊：
BRITISH JOURNAL OF CANCER
影响因子：
8.8
作者：
Michmerhuizen, Anna R.;Lerner, Lynn M.;Ward, Connor;Pesch, Andrea M.;Zhang, Amanda;Schwartz, Rachel;Wilder-Romans, Kari;Eisner, Joel R.;Rae, James M.;Pierce, Lori J.;Speers, Corey W.
通讯作者：
Speers, Corey W.

RB expression confers sensitivity to CDK4/6 inhibitor-mediated radiosensitization across breast cancer subtypes.

DOI：
10.1172/jci.insight.154402
发表时间：
2022-02-08
期刊：
JCI insight
影响因子：
8
作者：
Pesch AM;Hirsh NH;Michmerhuizen AR;Jungles KM;Wilder-Romans K;Chandler BC;Liu M;Lerner LM;Nino CA;Ward C;Cobain EF;Lawrence TS;Pierce LJ;Rae JM;Speers CW
通讯作者：
Speers CW